Can anyone make sense of this to explain to a layperson?

[[Su...]]

SufferingSixtie,

 

'So are you saying that some of us won't heal Liberty?' Some ? Some won't. Basically, I'm saying that the idea that everyone heals no matter what is nonsense.

 

' Any advice as to how to help those cholinergic systems?' That's complicated theory. I'd say avoid polydrugging when possible, and avoid unnecessary stress. Which does not mean 'do nothing at all'.

 

Ok Liberty,

pretty broad statements.... I'll keep plugging along the way i am and using the adjunct meds that are so helpful.

And yes we all need some stress to keep us in the loop of life! 

Wishing you well

SS

[[cs...]]

Thank you dm123!

In the end it doesn't matter does it?  we heal as we heal as we heal and it takes as long a it takes.. BUT it is good to know some of the science behind these things.  Somehow it eases the ruminative thinking that is so easy to get into at this juncture....

I remember my Mom giving me a Valium when my grandmother died when I was age 6  She didn't know any better, who knows what that set up in a young system.. Or perhaps that  started my system readying itself for this journey..

Again many thanks for the time and effort that you put into this thread....

:smitten:

SS

 

Hi SS,

 

I do believe we all heal eventually, but in my research physiological and psycho-social stress keeps popping up as a perpetuating factor in slow healers.  It also comes up in neural circuit studies as well.  When neural circuits in various individuals are exposed to the same stressors, the circuits disrupt and ultimately crash each in a unique fashion.  I don't know if we can extrapolate this to the differential recovery rates that we see in real life benzodiazaphine recovery, but it's an interesting thought.

 

Stress affects GABAergic and glutamatergic systems as well as neuroplasticity as well.  As liberty posted above, it's interesting that the brain area studied was the hippocampus as well, a highly plastic region of the brain.    Liberty had sent that study to me a while back, but I don't have access to the full article.  I wish I did....

 

It's all terribly complicated.  For example, in that cholinergic study, I don't know much about how  NGF affects real life biological specimens.  I also don't know if different types of kindling (for example, induced repeated seizure methodologies vs. benzodiazaphine kindling). would express these growth factors differentially.  If it does, it might play a larger factor in one type of kindling, vs another.

 

Abberant Tonic inhibition seems to play a big part in slow recovery from kindling.

 

Another good example of confounding factors are the classic kindling studies involving live rats that are kindled by repeated seizures.  The seizures would no doubt involve the stress system as well(these are really stressful tests . ) .  Also, if the mice become aware of the environmental conditions preceding each inducement of the seizure, this in and of itself could cause environmental LTP changes in the brain, which of course can involve sensitization of the glutamatergic system

[[cs...]]

SufferingSixtie,

 

'  we heal as we heal as we heal and it takes as long a it takes..' I wouldn't go as far as 'everyone heals, no matter what ...'

 

dm123, good post although obviously complicated.

 

I have a special place in my heart for those cholinergic neurons (animal studies, muscarinic receptors return to their previous state after abstinence convulsions, physical dependence being mediated via cholinergic neurons ...) http://onlinelibrary.wiley.com/doi/10.1002/syn.10064/abstract

'These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. ' I know it's a lot of work ...

 

Yes liberty, I remember when you first sent me that interesting study. Thanks for reposting...  It's all very complicated, especially in areas of kindling , where the studies themselves need to be propely controlled.  This can be challenging, especially when live specimens are used.  See my post above.

 

Tonic inhibitory signaling is also playing a big part. Some types of kindling heavily affect these particular receptors. These extra synaptic GABAa receptors seem to heal very very slowly.

[[cs...]]

SufferingSixtie,

 

'So are you saying that some of us won't heal Liberty?' Some ? Some won't. Basically, I'm saying that the idea that everyone heals no matter what is nonsense.

 

' Any advice as to how to help those cholinergic systems?' That's complicated theory. I'd say avoid polydrugging when possible, and avoid unnecessary stress. Which does not mean 'do nothing at all'.

 

Good stressors are the environmental stressors in an earlier post.  Definitely keep moving (both your body and your brain)

 

Bad stress in every study indicates stressors that are unpredictable, constant, unremitting, and the stressors that we cannot control.  Basically real life 

[[Be...]]

I've sure got alot of that bad stress in my life.  Things for which I have no control over.  Life keeps throwing stuff at me that is very hard for me to handle.  No wonder I'm still so sick.

[[Su...]]

Thank you dm123!

In the end it doesn't matter does it?  we heal as we heal as we heal and it takes as long a it takes.. BUT it is good to know some of the science behind these things.  Somehow it eases the ruminative thinking that is so easy to get into at this juncture....

I remember my Mom giving me a Valium when my grandmother died when I was age 6  She didn't know any better, who knows what that set up in a young system.. Or perhaps that  started my system readying itself for this journey..

Again many thanks for the time and effort that you put into this thread....

:smitten:

SS

 

 

Hi SS,

 

I do believe we all heal eventually, but in my research physiological and psycho-social stress keeps popping up as a perpetuating factor in slow healers.  It also comes up in neural circuit studies as well.  When neural circuits in various individuals are exposed to the same stressors, the circuits disrupt and ultimately crash each in a unique fashion.  I don't know if we can extrapolate this to the differential recovery rates that we see in real life benzodiazaphine recovery, but it's an interesting thought.

 

Stress affects GABAergic and glutamatergic systems as well as neuroplasticity as well.  As liberty posted above, it's interesting that the brain area studied was the hippocampus as well, a highly plastic region of the brain.    Liberty had sent that study to me a while back, but I don't have access to the full article.  I wish I did....

 

It's all terribly complicated.  For example, in that cholinergic study, I don't know much about how  NGF affects real life biological specimens.  I also don't know if different types of kindling (for example, induced repeated seizure methodologies vs. benzodiazaphine kindling). would express these growth factors differentially.  If it does, it might play a larger factor in one type of kindling, vs another.

 

Abberant Tonic inhibition seems to play a big part in slow recovery from kindling.

 

Another good example of confounding factors are the classic kindling studies involving live rats that are kindled by repeated seizures.  The seizures would no doubt involve the stress system as well(these are really stressful tests . ) .  Also, if the mice become aware of the environmental conditions preceding each inducement of the seizure, this in and of itself could cause environmental LTP changes in the brain, which of course can involve sensitization of the glutamatergic system

 

Hi all,

It's pretty clear that I don't have the science background to be commenting on things much in this section.  The systems in the body are so very complex and I'm not going to get that biology degree at this time    I went a different direction. 

So I'll continue to read this all and who knows, maybe with this and some supplemental reading I'll get a bigger picture.  What it really boils down to what can help us?  And what can harm us who are w/d from benzos.

Stress is a huge culprit and it is a personal thing as to who much stress each organism can tolerate or needs.

And for what it's worth I do believe in magic at times.  Why Not?!? Not being flakey here but honest.  I'll keep some making decisions and hope for a bit of magic to help the process......

Thanks for the time you've spent explain things dm123!

:smitten:

SS

 

 

[[cs...]]

I've sure got alot of that bad stress in my life.  Things for which I have no control over.  Life keeps throwing stuff at me that is very hard for me to handle.  No wonder I'm still so sick.

 

I hear you on that.  It's the single most important negative factor for me as well.

[[cs...]]

Thank you dm123!

In the end it doesn't matter does it?  we heal as we heal as we heal and it takes as long a it takes.. BUT it is good to know some of the science behind these things.  Somehow it eases the ruminative thinking that is so easy to get into at this juncture....

I remember my Mom giving me a Valium when my grandmother died when I was age 6  She didn't know any better, who knows what that set up in a young system.. Or perhaps that  started my system readying itself for this journey..

Again many thanks for the time and effort that you put into this thread....

:smitten:

SS

 

 

Hi SS,

 

I do believe we all heal eventually, but in my research physiological and psycho-social stress keeps popping up as a perpetuating factor in slow healers.  It also comes up in neural circuit studies as well.  When neural circuits in various individuals are exposed to the same stressors, the circuits disrupt and ultimately crash each in a unique fashion.  I don't know if we can extrapolate this to the differential recovery rates that we see in real life benzodiazaphine recovery, but it's an interesting thought.

 

Stress affects GABAergic and glutamatergic systems as well as neuroplasticity as well.  As liberty posted above, it's interesting that the brain area studied was the hippocampus as well, a highly plastic region of the brain.    Liberty had sent that study to me a while back, but I don't have access to the full article.  I wish I did....

 

It's all terribly complicated.  For example, in that cholinergic study, I don't know much about how  NGF affects real life biological specimens.  I also don't know if different types of kindling (for example, induced repeated seizure methodologies vs. benzodiazaphine kindling). would express these growth factors differentially.  If it does, it might play a larger factor in one type of kindling, vs another.

 

Abberant Tonic inhibition seems to play a big part in slow recovery from kindling.

 

Another good example of confounding factors are the classic kindling studies involving live rats that are kindled by repeated seizures.  The seizures would no doubt involve the stress system as well(these are really stressful tests . ) .  Also, if the mice become aware of the environmental conditions preceding each inducement of the seizure, this in and of itself could cause environmental LTP changes in the brain, which of course can involve sensitization of the glutamatergic system

 

Hi all,

It's pretty clear that I don't have the science background to be commenting on things much in this section.  The systems in the body are so very complex and I'm not going to get that biology degree at this time    I went a different direction. 

So I'll continue to read this all and who knows, maybe with this and some supplemental reading I'll get a bigger picture.  What it really boils down to what can help us?  And what can harm us who are w/d from benzos.

Stress is a huge culprit and it is a personal thing as to who much stress each organism can tolerate or needs.

And for what it's worth I do believe in magic at times.  Why Not?!? Not being flakey here but honest.  I'll keep some making decisions and hope for a bit of magic to help the process......

Thanks for the time you've spent explain things dm123!

:smitten:

SS

 

Hi SS, we are all just glad you are here participating on this thread.  If readers just get 10% of the material in this thread, it's worth it, and I'm ok with that.

 

Someone might stumble upon this old thread years from now, and it might help them understand what's going on inside of their body.  It might help them get through their taper.  Just "understanding" is sometimes enough to get us over the hump.....and help us rationalize our way out of this mess.

 

I haven't forgotten about the immune system either.  As you know, it's affected (suppressed) by stress.  The other thread mentioned how our gut is tied to the immune system.  The gut is also affected by stress (and a lot of other things!). 

[[cs...]]

Hi all, i hope everyone is doing well.  I'm posting a paper I wrote from a while back.  I've stripped out a lot of references so that it's more accessible and readable.  I'm glad that there are several recent posts on the hippocampus.  It plays a large role in the be benzodiazaphine model.  I hope the paper below ties up some loose ends.  I pulled some material from a recent post about depression that aligned well with the paper.  I also pulled a quote from the Briggin neurotoxin post, and integrated it into the paper,

 

 

Adult Neurogenesis,  stress, exercise, and the benzodiazaphine model (PART I)

 

 

 

~”Through one very vulnerable receptor type, benzodiazaphines insidiously and mercilessly tear down the very  ‘Pillars’ upon which our fragile nervous system is built.” -dm123

 

 

 

Introduction

 

 

 

 

Why research neurogenesis?  As we will see, neurogenesis plays a large role in the benzodiazaphine withdrawal model.  There are a lot of neurotransmitters and growth factors that affect adult neurogenesis, including some like dopamine and serotonin that are not included in the model.This is to keep an already complex evolving model understandable.  These other neurotransmitters and growth factors are implicitly part of the model, if they are affected by chronic benzodiazaphine use and withdrawal.  Some of these neurotransmitters and neurotrophic factors are not affected, and thus should be implicitly left out of the model.   

 

I’ve also stripped out a lot of the direct research quotes to simplify the discussion, and simply summarize the findings and correlations to the model.

 

The critical neurotransmitters and systems that are part of the benzodiazaphine neurogenesis model are referred to as “pillars” because they are profoundly affected by chronic benzodiazaphine use, and because they have a very large impact on neurogenesis in the hippocampus.  These same systems along with “other systems”(acetylcholine, dopamine, serotonin, neurotrophic and growth factors, Neurosteroids, etc.) also affect the individual neuronal action potential dynamics.  Thus there are two overlays on the model, that of the individual neuron action potential dynamics, and that of brain specific regional neurogenesis.  There’s a third overlay on the model, and that is of neural circuits and what is called homeostatic plasticity.  Neuroplasticity, and more specifically homeostatic plasticity, is a necessary part of the model dynamics, because neurons in real life biological systems don’t live in an isolated environment by themselves.They exist in neural circuits.  I will briefly touch upon this area in this post, but the main thrust of that research is in the Neural Circuits presentation, which is ongoing in the thread.

 

I hope everyone gets as much out of this research post as I have.  I’ve summarized several application takeaways from the post at the end.

 

 

 

 

 

 

 

1.Adult neurogenesis basics

 

In order to understand adult neurogenesis, one first has to look at a small region in the brain called the SGZ.  The focus on the hippocampus will become clear as the model is explained. However, newer research is revealing that even striatal areas (and other regions) of the brain undergo neurogenesis, hence the magnitude of the effects of neurogenesis on the model should not be underestimated.  Our knowledge of neurogenesis in these other regions of the brain are just beginning to be understood, and this has profound ramifications on the impact of neurogenesis in the benzodiazaphine withdrawal model.  Neurogenesis plays a very large part in benzodiazaphine withdrawal and recovery.

The SGZ is a zone in the hippocampal dentate gyrus(DG). 

 

https://en.m.wikipedia.org/wiki/Subgranular_zone

 

Quote

The subgranular zone is a narrow layer of cells located between the granule cell layer and hilus of the dentate gyrus. This layer is characterized by several types of cells, the most prominent type being neural stem cells (NSCs) in various stages of development. However, in addition to NSCs, there are also astrocytes, endothelial cells, blood vessels, and other components, which form a microenvironment that supports the NSCs and regulates their proliferation, migration, and differentiation. The discovery of this complex microenvironment and its crucial role in NSC development has led some to label it as a neurogenic “niche”.[1][2][3] It is also frequently referred to as a vascular, or angiogenic, niche due to the importance and pervasiveness of the blood vessels in the SGZ.[4]

 

…….

 

The main function of the SGZ is to carry out hippocampal neurogenesis, the process by which new neurons are bred and functionally integrated into the granular cell layer of the dentate gyrus(DG). Contrary to long-standing beliefs, neurogenesis in the SGZ occurs not only during prenatal development but throughout adult life in most mammals, including humans.

 

End quote

 

 

 

Differentiation is a term used to describe how “specialized” the cell is.  At some point during the cell’s development process, the cell becomes a neuroblast, which means that it is destined to become a neuron, and not any other neural cell type.  The quote below describes this process in more detail.

 

https://en.m.wikipedia.org/wiki/Neuroblast

 

Quote

Adult neurogenesis is characterized by neural stem cell differentiation and integration in the mature adult mammalian brain. This process occurs in the dentate gyrus of the hippocampus and in the subventricular zones of the adult mammalian brain. Neuroblasts are formed when a neural stem cell, which can differentiate into any type of mature neural cell (i.e. neurons, oligodendrocytes, astrocytes, etc.), divides and becomes a transit amplifying cell. Transit amplifying cells are slightly more differentiated than neural stem cells and can divide asymmetrically to produce postmitotic neuroblasts or glioblasts, as well as other transit amplifying cells. A neuroblast, a daughter cell of a transit amplifying cell, is initially a neural stem cell that has reached the "point of no return." A neuroblast has differentiated such that it will mature into a neuron and not any other neural cell type.[4]

End quote

 

 

 

 

Regulatory mechanisms of adult neurogenesis in the hippocampus (DG) and a word about stress/stress hormones

There are many influences on adult neurogenesis in the hippocampus.  For the purposes of this module we will be focusing on primarily the GABAergic mechanisms affecting DG neurogenesis, in addition to  the glutamatergic and stress system mechanisms as well.

The quote below indicates how many other regulators of DG neurogenesis are in place for this complex process. Note serotonin is also included, which may be why antidepressants positively affect neurogenesis in the DG. We will discuss this further in context of the stress system in a section below.  Chronic benzodiazaphine use affects all the neurotransmitter levels below as well, and since these neurotransmitters are the substrate for neurogenesis, chronic benzodiazaphine use, in and of itself directly affects neurogenesis .  Note also that glucocorticoids, in general,  have a negative effect on neurogenesis inhibiting proliferation, differentiation, and ultimately survival, if levels are chronically elevated.  The stress system has a huge impact on neurogenesis, and it is the most crucial player in the benzodiazaphine withdrawal model.

The most potent environmental inhibitor of neurogenesis in the SGZ is (negative) stress like sleep deprivation, psychosocial stress, and psychological stress. (See quote below). This part of the text below is very important.  Negative stressors, in general,  are inhibitory to neurogenesis, but positive stressors like learning new things, spatial exercise,  and physical exercise(which is the focus of this module) clearly have a positive effect on SGZ induced neurogenesis.  Positive and negative stressors have been presented in earlier posts, and this time we will look at exactly why exercise and “enriched environments” contribute positively to adult neurogenesis.  Exercise might appear to be counterproductive because it does raise cortisol levels, but the key, as will be pointed out, is the temporal aspect of the cortisol levels.  Transient rises in serum cortisol are physiologically normal and build resiliency , whereas chronic elevations in cortisol are the type that cause a deterioration in healthy rates of neurogenesis, particularly in the hippocampus.

Regarding the many many neurogenesis regulators in the brain:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541438/

 

 

Quote

The self-renewal, fate-choice, proliferation, migration, and differentiation of neural stem cells in the SGZ are regulated by many signaling molecules in the SGZ, including several neurotransmitters. For example, Notch is a signaling protein that regulates fate-choice, generally maintaining stem cells in a state of self-renewal. Neurotrophins such as brain derived neurotrophic factor (BDNF) and nerve growth factor(NGF) are also present in the SGZ and are presumed to affect neurogenesis, though the exact mechanisms are unclear. Wnt and bone morphogenic protein (BMP) signaling also are neurogenesis regulators, as well as classical neurotransmitters such as glutamate, GABA, dopamine, and serotonin.[10] Neurogenesis in the SGZ is also affected by various environmental factors such as age and stress. Age-related decreases in the rate of neurogenesis are consistently observed in both the laboratory and the clinic, but the most potent environmental inhibitor of neurogenesis in the SGZ is stress. Stressors such as sleep deprivation and psychosocial stress induce the release of glucocorticoids from the adrenal cortex into circulation, which inhibits neural cell proliferation, survival, and differentiation. There is experimental evidence that stress-induced reductions in neurogenesis can be countered with antidepressants. Other environmental factors such as physical exercise and continual learning can also have a positive effect on neurogenesis, stimulating cell proliferation despite increased levels of glucocorticoids in circulation.

 

Note that in this discussion “adult “ neurogenesis is the topic.  Prenatal neurogenesis is a completely different type of neurogenesis physiologically.

 

End quote

 

https://en.m.wikipedia.org/wiki/Neurogenesis

 

 

Quote

After embryonic brain development, neural stem cells reside primarily in the subventricular zone and in another area called the subgranular zone (SGZ) of the dentate gyrus of the hippocampus, and will continue to do so during adulthood

 

Postnatally, neurogenesis occurs in response to signals coming from either inside or outside of the body (dm123:i.e., environmental, hormonal, neuromodulatory, or neurotransmitter influences) instead of occurring automatically as it does in prenatal development[10]

 

Many environmental factors, such as exercise, stress, and antidepressants, have been shown to change the rate of neurogenesis within the hippocampus.[8][9]

End quote

 

 

Ref 8 Hanson, Nicola D.; Owens, Michael J.; Nemeroff, Charles B. (2011-12-01). "Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal". Neuropsychopharmacology. 36 (13): 2589–2602. doi:10.1038/npp.2011.220. ISSN 0893-133X. PMC 3230505  . PMID 21937982.

 

Ref 9 Santarelli, Luca; Saxe, Michael; Gross, Cornelius; Surget, Alexandre; Battaglia, Fortunato; Dulawa, Stephanie; Weisstaub, Noelia; Lee, James; Duman, Ronald (2003-08-08). "Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants". Science. 301 (5634): 805–809. doi:10.1126/science.1083328. ISSN 0036-8075. PMID 12907793.

 

 

Quote

Significant neurogenesis also occurs after birth in the hippocampus. The hippocampus plays a crucial role in the formation of new declarative memories, and it has been theorized that the reason infants cannot form declarative memories because they are still undergoing extensive neurogenesis in the hippocampus.[11] Previous cognitive research suggested that infants could not form declarative memories because of their lack of language skills, but the fact that analogs to this “infantile amnesia” can be observed in non-human mammals indicates that a lack of language does not account for the entire phenomenon. Significant neurogenesis also occurs in the hippocampus just after birth, and much of adult neurogenesis occurs in the dentate gyrus of the hippocampus as well.

End quote

 

 

http://www.human-memory.net/types_declarative.html

 

https://en.m.wikipedia.org/wiki/Explicit_memory

 

As a side note: The SVG is also another part of the adult brain that is highly plastic and amenable to neurogenesis.

 

https://en.m.wikipedia.org/wiki/Subventricular_zone

 

https://en.m.wikipedia.org/wiki/Ventricular_system

 

 

 

 

 

More on adult neurogenesis….

 

https://en.m.wikipedia.org/wiki/Adult_neurogenesis

 

Quote

Much more attention has been paid to neurogenesis in the dentate gyrus than in the other areas. Many of the newborn dentate gyrus neurons die shortly after they are born,[4] but a number of them become functionally integrated into the surrounding brain tissue.[8][9][10] In adult humans about 700 new neurons are added in the hippocampus every day.[11]However, the functional significance of nascent neurons remains controversial.

 

Adult neurogenesis poses many implications in terms of its functioning in learning and memory, emotion, stress, depression, and other conditions.[12] Extensive research has been implemented in several classical animal models to further the understanding of neurogenesis, particularly in response to damage.

 

Many studies have observed how inhibiting adult neurogenesis in other mammals, such as rats and mice, affect their behavior.[12] Inhibition of adult neurogenesis in the hippocampus has been shown to have various affects on learning and memory, conditioning, and investigative behaviors.

 

Impaired fear conditioning has been seen in studies involving rats with a lack of adult neurogenesis in the hippocampus.[34] Inhibition of adult neurogenesis in the hippocampus has also been linked to changes in behavior in tasks involving investigation.[35] Rats also show decreased contextualized freezing behaviors in response to contextualized fear and impairment in learning spatial locations when lacking adult neurogenesis.[36][37]

End quote

 

 

https://en.m.wikipedia.org/wiki/Fear_conditioning

 

Ref 34  Shors, Tracey J.; Miesegaes, George; Beylin, Anna; Zhao, Mingrui; Rydel, Tracy; Gould, Elizabeth. "Neurogenesis in the adult is involved in the formation of trace memories". Nature. 410(6826): 372–376. doi:10.1038/35066584.

 

 

Quote

Studies show that rats with inhibited adult neurogenesis demonstrate difficulty in differentiating and learning contextualized fear conditioning.[12] [Rats with blocked adult neurogenesis also show impaired differential freezing when they are required to differentiate between similar contexts.[40] This also affects their spatial recognition in radial arm maze tests when the arms are closer together rather than when they are further apart.[41] A meta-analysis of behavioral studies evaluating the effect of neurogenesis in different pattern separation tests has shown a consistent effect of neurogenesis ablation on performance, although there are exceptions in the literature. "[42]

 

Behavioral inhibition is important in rats and other animals in halting whatever they are currently doing in order to reassess a situation in response to a threat or anything else that may require their attention.[12]

 

Rats with lesioned hippocampi show less behavioral inhibition when exposed to threats, such as cat odor.[43] The disruption of normal cell proliferation and development of the dentate gyrus in developing rats also impairs their freezing response, which is an example of behavior inhibition, when exposed to an unfamiliar adult male rat.[44]

 

This impairment in behavioral inhibition also ties into the process of learning and memory, as repressing wrong answers or behaviors requires the ability to inhibit that response.[12]

End quote

 

 

 

 

 

 

 

 

 

2.More on Stress and adult neurogenesis

 

Temporal aspects of cortisol

 

Cortisol is necessary to sustain life, and has a very precise phasic effect on synaptic currents.  This phasic effect is what helps us consolidate event memories and emotionally process them through an LTP and then an LTD of post synaptic excitatory and inhibitory currents.  An earlier post detailed how the cellular neurophysiology is designed to support this through surface (membrane) and intranuclear glucocorticoid and mineralocorticoid receptors, that have varying affinities for their respective steroid hormones (note: glucocorticoid receptors can be ligand bound only by glucocorticoids, whereas mineralocorticoid receptors can be ligand bound by either mineralocorticoids (like aldosterone), or glucocorticoids (like cortisol)

 

 

Quote

Aldosterone and cortisol (a glucosteroid) have similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids.

End quote

 

 

  Intranuclear receptor types act via slower genomic mechanisms, whereas membrane surface receptor types act via faster non-genomic mechanisms.  This and the different receptor types, and variable affinities for cortisol , give rise to a cortisol phasic effect (it’s actually triphasic) on membrane potentials (via VGCCs, metabotropic glutamate receptors and NMDARs).  It should also be noted that intranuclear mineralocorticoid receptors have a very high affinity for cortisol and are tonically (persistently)active. Membrane mineralocorticoid receptors and intranuclear glucocorticoid receptors are next in line for cortisol affinity, and membrane glucocorticoid receptors are only ligand bound by cortisol at high peaking levels of cortisol……

The various types of steroid receptors above are distributed differentially relative to brain region.  Thus the effect of cortisol  on the post synaptic currents of neurons in different brain regions varies. 

 

The DG/Hippocampal areas have been researched quite well.  As expected, given receptor distribution heterogeneity, the  ventral (VH) and dorsal (DH) aspects of the hippocampus are differentially affected as a stressor is encountered and cortisol levels rise.  As cortisol levels rise, there is a primarily excitatory LTP phase that processes the event emotionally(VH).  The VH has twice as many mineralocorticoid receptors as glucocorticoid receptors, and the membrane mineralocorticoid receptors in the VH are very quick to respond to the rapidly rising cortisol levels, due to their relatively high affinity for cortisol.

 

As cortisol levels continue to rise to peak, weak membrane glucocorticoid receptors are activated at ~1 hour post the stress event, LTP drops and LTD rises as inhibitory post synaptic current amplitudes rise,  and the DH is able to consolidate the event in memory, as the cortisol levels peak and begin to decline….

 

 

 

Stress, stress regulation, depression, and adult neurogenesis

 

https://en.m.wikipedia.org/wiki/Adult_neurogenesis

 

 

Quote

 

Adult Neurogenesis and Major Depressive Disorder

 

Research indicates that adult hippocampal neurogenesis is inversely related to Major Depressive Disorder (MDD).[63] Neurogenesis is decreased in the hippocampus of animal models of major depressive disorder, and many treatments for the disorder, including antidepressant medication and electroconvulsive therapy, increase hippocampal neurogenesis. It has been theorized that decreased hippocampal neurogenesis in individuals with major depressive disorder may be related to the high levels of stress hormones called glucocorticoids, which are also associated with the disorder. The hippocampus instructs the hypothalamic-pituitary-adrenal axis to produce less glucocorticoids when glucocorticoid levels are high. A malfunctioning hippocampus, therefore, might explain the chronically high glucocorticoid levels in individuals with major depressive disorder. However, some studies have indicated that hippocampal neurogenesis is not lower in individuals with major depressive disorder and that blood glucocorticoid levels do not change when hippocampal neurogenesis changes, so the associations are still uncertain.

End quote

 

This quote below elucidates on the misconceptions about the mechanism of action behind antidepressants .  I quote it here only because of the excellent references on the relationships between stress, the HPA axis, stress resiliency, and (hippocampal) neurogenesis. 

 

 

Please note: I do not condemn or endorse the use of antidepressants.  The mechanisms below, however, could explain why antidepressants offer some individuals significant relief during benzodiazaphine withdrawal.

 

This antidepressant effect would be through a route of increased serotonin as a growth factor for increased neurogenesis, as opposed to increased serotonin as a mood altering neurotransmitter . 

 

Serotonin is a known regulator of neurogenesis (see part 1 above).  It’s thought that it does this primarily by lowering CRH and lowering  tonically elevated cortisol levels. (See quote below). 

Aberrant neurogenesis is an integral part of the benzodiazaphine withdrawal model. Reducing  aberrant neurogenesis would break a physiological feedback cycle that perpetuates adverse withdrawal symptoms.  However, antidepressants are not the only way to reduce aberrant Neurogenesis.  More on this later…

 

 

 

Quote

 

Stress and depression

 

Many now believe stress to be the most significant factor for the onset of depression, aside from genetics. As discussed above, hippocampal cells are sensitive to stress which can lead to decreased neurogenesis. This area is being considered more frequently when examining the causes and treatments of depression. Studies have shown that removing the adrenal gland in rats caused increased neurogenesis in the dentate gyrus.[64] The adrenal gland is responsible for producing cortisol in response to a stressor, a substance that when produced in chronic amounts causes the down regulation of serotonin receptors and suppresses the birth of neurons.[65]

 

It was shown in the same study that administration of corticosterone to normal animals suppressed neurogenesis, the opposite effect.[64]

 

The most typical class of antidepressants administered for this disease are selective serotonin reuptake inhibitors (SSRIs)[66] and their efficacy may be explained by neurogenesis. In a normal brain, an increase in serotonin causes suppression of the corticotropin-releasing hormone(CRH) through connection to the hippocampus. It directly acts on the paraventricular nucleus to decrease CRH release and down regulate norepinephrine functioning in the locus coeruleus.[64] Because CRH is being repressed, the decrease in neurogenesis that is associated with elevated levels of it is also being reversed. This allows for the production of more brain cells, in particular at the 5-HT1a receptor in the dentate gyrus of the hippocampus which has been shown to improve symptoms of depression.

 

It normally takes neurons approximately three to six weeks to mature,[67] which is approximately the same amount of time it takes for SSRIs to take effect.

 

This correlation strengthens the hypothesis that SSRIs act through neurogenesis to decrease the symptoms of depression. Some neuroscientists have expressed skepticism that neurogenesis is functionally significant, given that a tiny number of nascent neurons are actually integrated into existing neural circuitry. However, a recent study used the irradiation of nascent hippocampal neurons in rodents to demonstrate that neurogenesis is required for antidepressant efficacy.[68]

 

Adult-born neurons appear to have a role in the regulation of stress.[69][70] Studies have linked neurogenesis to the beneficial actions of specific antidepressants, suggesting a connection between decreased hippocampal neurogenesis and depression.[71][72]

 

In a pioneer study, scientists demonstrated that the behavioral benefits of antidepressant administration in mice is reversed when neurogenesis is prevented with x-irradiation techniques.[73] In fact, newborn neurons are more excitable than older neurons due to a differential expression of GABA receptors.[74] (Dm123: we will learn a lot more about this in a later post)

 

A plausible model, therefore, is that these neurons augment the role of the hippocampus in the negative feedback mechanism of the HPA-axis (physiological stress) and perhaps in inhibiting the amygdala (the region of brain responsible for fearful responses to stimuli).[vague] (dm123: Note the footnote on this is “vague”.  If true, impaired  hippocampal neurogenesis could thus provoke anxiety, and an unrealistic anxiety response to mild stressors.  I haven’t had a chance to research this link to the amygdala yet, and it would be nice to see this referenced.  I’ve researched hippocampus brain anatomy as it correlates to psychological and physiological function and the stress response, and it is very plausible.  More on this amplified stress response to mild stressors below, reference 69 cited below……)

 

Indeed, suppression of adult neurogenesis can lead to an increased HPA-axis stress response in mildly stressful situations.[69]

 

This is consistent with numerous findings linking stress-relieving activities (learning, exposure to a new yet benign environment, and exercise) to increased levels of neurogenesis, as well as the observation that animals exposed to physiological stress (cortisol) or psychological stress (e.g. isolation) show markedly decreased levels of newborn neurons.

 

Interestingly, under chronic stress conditions, the elevation of newborn neurons by antidepressants improves the hippocampal-dependent control on the stress response; without newborn neurons, antidepressants are unable to restore the regulation of the stress response and recovery becomes impossible.[70]

 

 

End quote

 

 

Ref 64 Jacobs, B. L.; H. van Praag; F. H. Gage (2000). "Depression and the Birth and Death of Brain Cells". American Scientist. 88.

 

Ref 65 Kandel, E. R.; J. H. Schwartz & T. M. Jessell (2012-10-26). Principles of Neural Science (fifth ed.). ISBN 0071390111.

 

 

Ref 69  Schloesser RJ, Manji HK, Martinowich K (April 2009). "Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response". NeuroReport. 20(6): 553–7. doi:10.1097/WNR.0b013e3283293e59. PMC 2693911  . PMID 19322118

 

 

Ref 70  Surget A, Tanti A, Leonardo ED, et al. (December 2011). "Antidepressants recruit new neurons to improve stress response regulation". Molecular Psychiatry. 16 (12): 1177-88. doi:10.1038/mp.2011.48. PMC 3223314  . PMID 21537331.

 

 

Ref 74 Bradley, Joseph (2015). Addiction: From Suffering to Solution. Las Vegas, NV: Breaux Press International. p. 173. ISBN 978-0-9854418-0-7.

 

 

 

 

A functional esoteric perspective on this…..

 

 

To further elaborate on the points made above, a fellow BB recently posted this excellent article on misconceptions about the causes of depression and anxiety. 

 

https://www.theguardian.com/society/2018/jan/07/is-everything-you-think-you-know-about-depression-wrong-johann-hari-lost-connections?CMP=share_btn_fb

 

There’s a few points that I want to make on this article that support and reinforce the material above from a functional and physiological perspective:

 

a.The author points to empirical population studies revealing that those who work in job environments and positions where things are uncontrollable, unpredictable, continuously routine, and non-stimulating, suffer depression and anxiety.  The boss at the top who has control and is doing what he wants is the least likely to suffer depression.  Depression rates increase as one moves down the ladder.  The premise in the article states that this negative type of stress is to blame.  The article goes on to state:

 

“It turns out if you have no control over your work, you are far more likely to become stressed – and, crucially, depressed. Humans have an innate need to feel that what we are doing, day-to-day, is meaningful. When you are controlled, you can’t create meaning out of your work.”

 

 

b.The adjectives above describe what is clinically known as negative stress.  The environment is not an “enriched environment”, but quite the opposite.  From the perspective of the material above, this means the rate of normal neurogenesis will decline.

 

 

c.” It turns out that between 65 and 80% of people on antidepressants are depressed again within a year. “ 

 

As with all pharmaceuticals, there is a natural inclination for the neural system to restore homeostasis.  Serotonin levels are boosted, the rate of Neurogenesis increases (via reduced cortisol levels), the body recognizes serotonin levels are elevated, the body homeostatically adjusts systems to normalize artificially elevated serotonin levels, the rate of neurogenesis returns back to baseline, and depression returns.

 

  I would add that the depression is far more likely to return if the person is in the same environment, and is experiencing the same negative stressors from day to day. Recovery is far more likely if the environment is supportive, negative stress is reduced,  and positive stress is introduced (exercise, for example).

 

 

d.The article correctly points out that there has never been any clinical proof that depression is caused by low serotonin.  In light of the material in the section above , one of many causes of depression is excessive negative stress and a subsequent low rate of neurogenesis.

 

  Neurogenesis is regulated by many different neurotransmitters and growth factors.  Focusing solely on serotonin, a neurotransmitter that happens to foster healthy rates of neurogenesis, is an overly simplistic band-aid approach.  All band-aids fail at one point or another as the body invariably homeostatically re-adjusts…..There was nothing originally wrong with the depressed person’s serotonin levels; there was a pattern of dysfunctional neurogenesis due to negative stressors and possibly any of the other factors that affect neurogenesis, benzodiazaphines included.

 

“Josh had seen for himself that depressions are very often, as he put it, ‘rational reactions to the situation, not some kind of biological break’. “

 

Physiologically, the brain becomes less efficient in dealing with negative stress (lowered stress resiliency), and the cycle feeds on itself.

 

 

e.” Professor John Cacioppo of Chicago University taught me that being acutely lonely is as stressful as being punched in the face by a stranger – and massively increases your risk of depression.”    Recall: An “enriched environment” is one of stimulating learning, social interaction, and freedom to move around. Enriched environments stimulate neurogenesis.  There’s a lot of research in this area.

 

 

f.Having control: “We need to move from focusing on ‘chemical imbalances’,  they said, to focusing more on ‘power imbalances’. “.  Lack of control over our stressors is a very negative stressor.

 

 

 

 

On the flip side, another BB recently posted this articulate article on antidepressants as neurotoxins:

 

https://www.madinamerica.com/2018/01/what-really-call-psychiatric-drugs/

 

“Neurogenesis (the growth of new neurons) does occur, but it is not an indicator that the psychiatric neurotoxin is improving brain function. To the contrary, neurogenesis is usually a response to and a marker for injury, such as stroke, traumatic brain injury, ECT, or toxic assault. In addition, dying neurons are easily confused in their appearance with newly generated neurons."

 

 

While I do agree with Dr Breggins views on neuropsychiatric drugs, there are morphological differences between aberrant neurogenesis and the healthy and natural regenerative neurogenesis that our brains undergo every day. Neurogenesis occurs as a part of normal brain physiology in normal adults. 

 

New neurons with altered dendritic lengths and spine densities can be differentiated from normal healthy newborn neurons.  Alcohol, for example,  is a neurotoxin that restricts neurogenesis via altered GABAergic signaling (see the alcohol study below). 

 

As I noted above, even if antidepressants do foster healthy neurogenesis (I do believe they do), this is short lived, because homeostatic processes re-establish the neurotransmitter levels (that fostered this growth) back to baseline.  There are other ways to achieve a more permanent long lasting healthy rate of neurogenesis.

 

 

 

 

 

 

 

3.Stress, adult neurogenesis, and the Benzodiazaphine withdrawal model

 

 

Given the information presented above, if there is lack of sufficient neurogenesis in the hippocampus (ie, a decreased rate of neurogenesis as occurs with negative stress), this will directly adversely affect stress resiliency and the regulation of stress responses (a hypersensitive HPA axis response to even mild stress, i.e. A Reduced threshold for stress).  A vicious cycle ensues whereupon dysfunctional stress feeds into aberrant neurogenesis, which further deteriorates the regulation of the stress response.

 

  As we will see, the GABAergic and glutamatergic systems are both affected by the stress system (the GABAergic system actually has a bidirectional reciprocal relationship with the stress system). Furthermore , the stress, GABAergic and glutamatergic systems directly influence  hippocampal neurogenesis.  Destabilizing any or all of these 3 pillars (stress, GABAergic, glutamatergic) has the potential to instigate the feedback loop.  It’s quite easy to recognize that given this model, it can be a self perpetuating feedback loop leading to protracted illness. 

 

  If benzodiazaphine induced dysfunction in the GABAergic system does occur (via withdrawal, tolerance, or simply physiological instability in neuronal action potential dynamics), effectively knocking out one of the pillars, this can affect the natural process of normal healthy ongoing  neurogenesis in the hippocampus, and start the feedback loop. 

 

We don’t really know what effects the benzodiazaphine has on the natural process of ongoing neurogenesis, but in an alcohol study that will be presented below,  it is proposed that dysfunction in the GABAergic system could lead to aberrant neurogenesis in plastic regions of the brain, like the hippocampus, and this could account for protracted, slow-to-reverse neurological changes.  In this particular paper, it is proposed that this might explain why some types of cognitive recovery (dependent on the hippocampus) lag recovery relative to other brain-region specific areas,  during alcohol withdrawal and abstinence from alcohol. The authors cite alcohol’s direct  negative effects on the GABAergic system as the cornerstone of the differential recovery times in various regions of the brain.  We know for certain that ongoing neurogenesis is heavily dependent on a healthy GABAergic system.  This area of cellular neurophysiology has been studied very well.  In developing neurons, GABA receptors  and GABA are actually excitatory and  they are involved in almost every stage of neurogenesis.  They  even play a crucial role in “unsilencing”’  , which drives the insertion of AMPARs into the developing neuron’s membrane.

 

Extrapolating the alcohol study to benzodiazaphines is possible if the differential recovery rates in brain regions in that paper are primarily due to alcohol-induced  GABAergic system dysfunction (as it proposes).  Given the critical role that stress has in the feedback loop, as an ongoing instigator, it’s  obvious that stress plays at least a partial  role in perpetuating the symptoms of benzodiazaphine withdrawal after the drug intake has been ceased.  In addition to stress’ role in perpetuating the loop through its direct effects on neurogenesis, as mentioned earlier, it also directly affects the GABAergic system and to a greater extent, the inhibitory system via corticosteroid, mineralocorticold, and Neurosteroid actions on steroid and GABAa receptors. This proposed 3 pillar neurogenesis model does not exclude “other systems” (such as acetylcholine, dopamine and serotonin disturbances, and neurotrophic factors, etc…), that have a profound effect on the action potential dynamics of the neuron.  Aberrant action potential dynamics plays a crucial role in the benzodiazaphine withdrawal scenario, but it does not and cannot fully explain protracted withdrawal.  The neurogenesis-stress feedback loop aspect of the model gives us insight into how and why withdrawal can be protracted.

 

It’s also important to note that the feedback loop itself can slow the healing of the receptors themselves, given the direct effects of the stress system on the GABAergic system.  Thus, action potential dynamics would also be dysfunctional during protracted withdrawal.

 

Issues like sleep deprivation have a clear link to the stress processes described above, and this is especially relevant given that  insomnia is a common condition during benzodiazaphine withdrawal.  Thus, it’s important to recognize that, in general, the withdrawal symptoms themselves serve as perpetuating factors via increased levels of glucocorticoid levels in the blood.  Nerva pain, and many other benzodiazaphine withdrawal symptoms fall into this bucket.

 

 

 

Hence, two aspects of stress feed back into this model, and it’s important to make the distinction between the two:

 

a. lower stress threshold (overactive HPA axis) directly attributable to adverse neurogenesis hippocampal effects (see discussion above), and

b. collateral external and internal negative stressors both from the withdrawal itself, and everyday negative stress.

 

 

Quote

 

One study has linked lack of sleep to a reduction in rodent hippocampal neurogenesis. The proposed mechanism for the observed decrease was [ ]increased levels of glucocorticoids. [/b]It was shown that two weeks of sleep deprivation acted as a neurogenesis-inhibitor, which was reversed after return of normal sleep and even shifted to a temporary increase in normal cell proliferation.[77] More precisely, when levels of corticosterone are elevated, sleep deprivation inhibits this process. Nonetheless, normal levels of neurogenesis after chronic sleep deprivation return after 2 weeks, with a temporary increase of neurogenesis.[78]

 

End quote

 

 

 

 

Note that neurogenesis has recently been found to occur in the striatum.(and other higher cortical areas of the brain, although the later is still under investigation ).  This has profound implications given all of the physiological functions that depend on the striatal brain region.  If there is substantial neurogenesis in other regions of the brain, this would explain why benzodiazaphines have such a broad detrimental physiological profile, and why protracted withdrawal can be far reaching and severe. Striatal circuits will be differentially analyzed in the Neural Circuits presentation, and in that material we will see exactly what these circuits are responsible for.

 

 

Quote

Newer research has shown that there in fact is neurogenesis in the striatum.[84]

End quote

 

Full source:

 

http://www.cell.com/cell/fulltext/S0092-8674(14)00137-8

 

This is one of many such papers.

 

 

 

 

 

 

 

 

 

 

 

4.The alcohol study on hippocampal neurogenesis and protracted cognitive dysfunction

 

 

I’ve extracted out the relevant quotes and inserted some comments.  The quotes are very revealing and self explanatory, supporting the general model above.  This is a wonderful paper and I encourage a full reading. 

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043052/

 

 

Thinking after Drinking: Impaired Hippocampal-Dependent Cognition in Human Alcoholics and Animal Models of Alcohol Dependence

Miranda C. Staples and Chitra D. Mandyam

Front Psychiatry. 2016; 7: 162.

Published online 2016 Sep 30. doi:  10.3389/fpsyt.2016.00162

 

 

Hippocampus-dependent cognitive dysfunction seems to be protracted after cessation of alcohol and abstinence.  Temporally, hippocampal cognitive recovery is much longer than prefrontal cortex cognitive recovery.

 

 

 

Quotes

 

This is most widely apparent as frontal cortex-dependent cognitive dysfunction, where executive function and decision-making are severely compromised, as well as hippocampus-dependent cognitive dysfunction, where contextual and temporal reasoning are negatively impacted. This review discusses the relevant clinical literature to support the theory that cognitive recovery in tasks dependent on the prefrontal cortex and hippocampus is temporally different across extended periods of abstinence from alcohol. Additional studies from preclinical models are discussed to support clinical findings. Finally, the unique cellular composition of the hippocampus and cognitive impairment dependent on the hippocampus is highlighted in the context of alcohol dependence.

…..

 

It is possible that this disparity [between hippocampal and PFC recovery rates] is due to, at least in part, the ongoing adult neurogenesis in the hippocampus which occurs at a much lesser rate in the PFC of mammals  [when compared to the hippocampus](146); neurons which would be generated during critical periods of withdrawal would be developing into mature neurons during a time of negative affect (147, 148), potentially resulting in a pathologic phenotype and dysfunctional characteristics (149). This problematic phenomenon would be far more impactful in a region with high neurogenesis (such as the hippocampus) as compared with a region of low or absent neurogenesis, where the typical functioning of the existing circuitry may return upon complete washout of the drug.

 

End quote

 

 

And this, for more detail on the proposed mechanisms of action, involved in the aberrant morphology.  Note the role of alcohol’s effect on GABAergic transmission, one of the 3 “pillars” in the benzodiazaphine model.  The role of GABAergic signaling in neurogenesis is very well established in the clinical literature.

 

 

 

Quote

The granule cells of the hippocampus are maintained in a quiescent [quiet or inacitve] state by the mossy fibers of the hilus viaGABA-ergic regulation [reviewed in Ref. (161)]. Evidence has demonstrated that these cells do express GABAaRs (162), as do the surrounding cells of the DG( 163, 164); therefore, not only are the granule cells sensitive to enhanced GABA-ergic transmission during exposure to chronic alcohol but are also subject to secondary regulation due to the modulation of activity of surrounding cells by alcohol’s actions on the GABAaR.

 

As specific subunit compositions of the GABAaR can modulate important stages of neurogenesis (particularly the maintenance of quiescent cells and proliferation), this could provide a potential mechanism by which alcohol could be modulating neurogenesis in dependent individuals.

 

During periods of alcohol intake, GABAaR function would be supported and facilitated such that quiescent cells would be maintained (165, 166) as such and proliferation would be reduced (167–169).

 

In the acute absence of alcohol, the facilitation of GABAaR activity would be lost (dm123: due to downregulation or desensitization of the receptor; the same would occur with abrupt cessation of benzodiazaphines) and quiescent cells would be allowed to proliferate, and these effects could result in increase or decrease in cell survival in the days following withdrawal (169–171).

 

However, impaired GABA-ergic receptor function has been shown to restrict morphology[the form] of newly born cells (172), which could reduce the number of synaptic connections and network integration required for survival and function of the granule cells and, therefore, result in net reduction of the number of surviving cells during protracted abstinence (171). This finding serves as a potential argument for the reduced survival subsequent to the increased proliferation following withdrawal in dependent animals (171).

 

End quote

 

 

 

The implications of the above are clear.  A restriction in morphology in new born cells would reduce dendritic length and spine density, ultimately reducing the number of synaptic connections , and the integration of the new neuron into the neural circuit fabric.

 

Finally, this last part emphasizes that although it’s clear that hippocampal neurogenesis results in aberrant morphology post withdrawal, this cannot be definitively linked to the protracted cognitive dysfunction, without further studies directly linking the morphology with physiological deficits in cognition. Thus, further research is required……

 

 

Quote

Unfortunately, there is no conclusive evidence linking aberrant neurogenesis subsequent to alcohol dependence and impaired hippocampal cognitive function. Future studies will be required to demonstrate the plausibility of this mechanism as an underlying explanation for the deleterious effect of alcohol dependence on hippocampal function.

 

Preclinical findings in animal models of alcohol exposure support the clinical observation; mechanistic studies support that this temporally differential rescue (dm123: i.e., recovery) of PFC-dependent tasks is potentially due to the neurogenic deficits in the hippocampus during abstinence, such that the birth of new neurons during periods of negative affect result in the persistence of the hippocampal-specific cognitive disparities.(dm123: a post withdrawal syndrome)

 

Many questions remain unanswered with regard to human hippocampal function during periods of alcohol abstinence. For example, it is clear that employing cognitive therapy can support individuals in successful attempts at abstinence

 

End quote

 

 

 

The key takeaway is that dysfunctional GABAergic signaling (from chronic use, withdrawal, tolerance, or complete cold turkey) has the potential to start the downward spiral into what we understand as long drawn out recovery.  Regions of the brain that are highly plastic, according to this theory, would be affected most severely.

 

 

 

 

 

 

 

 

 

 

5.Neural circuits and neuroplasticity

 

 

Another addition to the model is required as well.  Neurons do not act in isolation, thus neural circuit dynamics must be overlayed on the neurogenesis and action potential dynamics aspects of the model.  Neural circuit dynamics explain why and how compensatory homeostatic plasticity occurs in response to perturbations to our many different neural circuits.  This homeostatic plasticity is a sub-type of the umbrella term neuroplasticity. 

 

Synaptic scaling is one of the mechanisms behind homeostatic plasticity. Homeostatic plasticity  involves both synaptic plasticity and non-synaptic plasticity.  Hebbian plasticity, which is the potentiation that builds up between neuronal synapses as they fire together (for example LTP) is balanced out by this homeostatic plasticity.  Homeostatic plasticity does this via modification of synaptic strengths and by changing the properties of the ion channels (conductance densities).  This discussion will be continued at length in the Neural Circuits presentation. 

 

This overlay  integrates the dynamic aspects of neuroplasticity into the the model,  helping one to understand homeostatically why and how the neurons behave as a collective whole in a circuit, and why each of us has unique responses to the perturbations and stressors to our neural circuits (perturbations like inhibitory disruptors i.e.  benzodiazaphines).  Both neurogenesis and circuit level homeostatic plasticity help explain why each of our recoveries are so very unique.

 

Homeostatic plasticity sort of puts the brakes on classical hebbian plasticity. When homeostatic plasticity breaks down due to extreme stress on the circuit, the circuit crashes, and this manifests itself as physiological and/or psychological dysfunction. Hyperexcitability is the expected result.

 

 

 

 

Quote

Persisting correlated neural activity—without a homeostatic feedback loop—causes LTP mechanisms to continually up regulate synaptic connection strengths. Unspecified strengthening of synaptic weights causes neural activity to become unstable to the point that insignificant stimulatory perturbations can trigger chaotic, synchronous network-wide firing known as bursts. This renders the neural network incapable of computing.[10] Since homeostatic plasticity normalizes the synaptic strengths of all neurons in a network, the overall neural network activity stabilizes.

End quote

 

 

 

 

 

 

 

 

 

 

 

6.Neurogenesis therapeutic benefits of exercise in the adult (how exercise beneficially affects adult neurogenesis)

 

Note in the quote below, that the exercise is voluntary.  The context of the stressor as well as how we perceive the stressor are crucial in determining how the body physiologically responds to the stress.  Involuntary, forced, unpredictable, uncontrollable, constant, and relentless stressors are physiologically the worst kinds of stressors.  One reason for this is because of how the brain naturally perceives such stressors.  Psychosocial stressors are often physiologically detrimental because they cannot be controlled and are completely unpredictable.

 

 

Quote

Scientists have shown that physical activity in the form of voluntary exercise results in an increase in the number of newborn neurons in the hippocampus of mice and rats.[93][94] These and other studies have shown that learning in both species can be enhanced by physical exercise.[95] Recent research has shown that brain-derived neurotrophic factor and insulin-like growth factor 1 are key mediators of exercise-induced neurogenesis.[94][96]

 

Exercise increases the production of BDNF, as well as the NR2B subunit of the NMDA receptor.[94]Exercise increases the uptake of IGF-1 from the bloodstream into various brain regions, including the hippocampus. In addition, IGF-1 alters c-fos expression in the hippocampus. When IGF-1 is blocked, exercise no longer induces neurogenesis.[96] Other research demonstrated that exercising mice that did not produce beta-endorphin, a mood-elevating hormone, had no change in neurogenesis. Yet, mice that did produce this hormone, along with exercise, exhibited an increase in newborn cells and their rate of survival.[97] While the association between exercise-mediated neurogenesis and enhancement of learning remains unclear, this study could have strong implications in the fields of aging and/or Alzheimer's disease.

End quote

 

 

https://en.m.wikipedia.org/wiki/Neurobiological_effects_of_physical_exercise#Neuroplasticity

 

 

In this quote below, the positive aspects of exercise in terms of neuroplasticity and neurogenesis are lumped together.  Some references loosely use both terms interchangeably.  We will explore the different types of neuroplasticity in the Neural Circuits presentation…..

 

Quote

Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli.[38] Aerobic exercise increases the production of neurotrophic factors[note 1] (e.g., BDNF, IGF-1, VEGF) which mediate improvements in cognitive functions and various forms of memory by promoting blood vessel formation in the brain, adult neurogenesis,[note 2] and other forms of neuroplasticity.[2][5][18][40][41]

 

Consistent aerobic exercise over a period of several months induces clinically significant improvements in executive functions and increased gray matter volume in nearly all regions of the brain,[42] with the most marked increases occurring in brain regions that give rise to executive functions.[1][5][6][7][9] The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex, caudate nucleus, and hippocampus;[1][5][6][8]less significant increases in gray matter volume occur in the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens.[5][6][8] The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the dopamine and norepinephrine systems that give rise to cognitive control.[6][43]

 

Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory.[6][8][19][44] Higher physical fitnessscores, as measured by VO2 max, are associated with better executive function, faster information processing speed, and greater gray matter volume of the hippocampus, caudate nucleus, and nucleus accumbens.[1][6] Long-term aerobic exercise is also associated with persistent beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and increased neuronal activity (c-Fos and BDNF signaling).[4][45]

End quote

 

 

 

 

Quote

The various functions of the brain structures that show exercise-induced increases in gray matter volume include:

 

 Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior, particularly: working memory, attentional control, decision-making, cognitive flexibility, social cognition, and inhibitory control of behavior;[56][57] implicated in attention deficit hyperactivity disorder (ADHD) and addiction[56]

 

 Nucleus accumbens – responsible for incentive salience ("wanting" or desire, the form of motivation associated with reward) and positive reinforcement; implicated in addiction[58]

 

 Hippocampus – responsible for storage and consolidation of declarative memory and spatial memory;[6][59] implicated in depression[8]

 

 Cerebellum – responsible for motor coordination and motor learning[60]

 

 Caudate nucleus – responsible for stimulus-response learning and inhibitory control; implicated in Parkinson's disease, Huntington's disease and ADHD[56][59]

 

 Parietal cortex – responsible for sensory perception, working memory, and attention[56][61]

End quote

 

 

Quote

Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched environment have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus.[105][106][107][108] Another factor is central nervous system injury since neurogenesis occurs after cerebral ischemia,[109]epileptic seizures,[110] and bacterial meningitis.[111]

 

Epigenetic regulation also plays a large role in neurogenesis. DNA methylation is critical in the fate-determination of adult neural stem cells in the subventricular zone for post-natal neurogenesis through the regulation of neuronic genes such as Dlx2, Neurog2, and Sp8. Many microRNAs such as miR-124 and miR-9 have been shown to influence cortical size and layering during development.[115]

 

End quote

 

 

 

 

 

 

 

 

 

 

7.Controlled Physical stress (exercise) vs psychological stress: short vs long term alterations in cortisol are the differentiating factor

 

 

If stress hormones do indeed cause lower rates of neurogenesis via altered elevated glucocorticoid levels, why does exercise actually increase neurogenesis?

 

The answer lies in both the type of perceived stress and how long the stressor lasts.  Exercise, in fact, lowers long term cortisol levels as it desensitizes the HPA axis.  A sensitized HPA axis is a main contributor to the feedback loop described earlier.  I’ve found this to be true as long as the exercise is moderate and consistent from day to day.  Stress resiliency toward psychological stress does slowly improve over time.  This added stress resiliency is absolutely necessary to insure a good post benzodiazaphine withdrawal recovery.  Without it, one is more  susceptible to physiological neural circuit crashes when faced with extreme negative stress.(This  has no bearing on one’s proclivity to relapse back on to the drug)

 

 

Quote

 

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors.[69][70][71] Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis).[69][70][71] Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;[41][70][71] however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has neurotoxic effects in the human brain.[41][62][71] For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.[41][69]

 

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;[70] however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative energy balance.[note 7][70]

 

Individuals who have recently exercised exhibit improvements in stress coping behaviors.[4][41][45] Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response).[13][41][72] Exercise also reverses stress-induced decreases in BDNF expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.[41][69][72]

End quote

 

 

 

 

 

 

 

 

 

 

 

8.Environmental enrichment and neurogenesis and neuroplastic benefits

 

 

There’s a few earlier posts on this topic, along with what activities constitute and enriched environment. I do recommend reading those earlier posts….. The link below has further information on this interesting topic.

 

https://en.m.wikipedia.org/wiki/Environmental_enrichment

 

Quote

Environmental enrichment is the stimulation of the brain by its physical and social surroundings. Brains in richer, more stimulating environments have higher rates of synaptogenesis and more complex dendrite arbors, leading to increased brain activity. This effect takes place primarily during neurodevelopment, but also during adulthood to a lesser degree. With extra synapses there is also increased synapse activity, leading to an increased size and number of glial energy-support cells. Environmental enrichment also enhances capillary vasculation, providing the neurons and glial cells with extra energy. The neuropil (neurons, glial cells, capillaries, combined together) expands, thickening the cortex. Research on rodent brains suggests that environmental enrichment may also lead to an increased rate of neurogenesis.

End quote

 

 

 

 

 

 

 

 

 

 

 

9.GABAergic system and adult neurogenesis

 

 

As mentioned earlier, there is a lot of recent research on how the GABAergic system affects neurogenesis.  Benzodiazaphines tend to have a negative effect on neurogenesis because they are disruptors of healthy inhibitory signaling.  However, there are many studies in this area and not all of them are consistent, but if GABAergic dysfunction is induced by benzodiazaphines it will indeed lead to aberrant neurogenesis.  This area of cellular neuroscience will be explored in a separate post. 

 

 

Quote

Recent research has elucidated the regulatory effect of GABA on neural stem cells. GABA's well-known inhibitory effects across the brain also affect the local circuitry that triggers a stem cell to become dormant. They found that diazepam (Valium) has a similar effect.[131]

End quote

 

 

The hippocampus is one of the most densely populated GABAaR regions of the brain, and the most plastic region of the brain. As mentioned earlier, it is tightly coupled to stress regulation, i.e. Resiliency against stress.

 

 

A great research paper on GABAergic regulation of adult neurogenesis can be found below. I’ve read it through several times and highly recommend it:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064292/

 

 

Regulation of adult neurogenesis by GABAergic transmission: signaling beyond GABAA-receptors

Marta Pallotto and Francine Deprez

Front Cell Neurosci. 2014; 8: 166.

Published online 2014 Jun 20. doi:  10.3389/fncel.2014.00166

 

 

 

 

 

 

 

 

 

 

 

 

10.Key application takeaways

 

CONTINUED IN PART II......

 

[[cs...]]

PART I above

 

 

Benzodiazaphines create that initial crack in the wall to our normally resilient physiology....

 

 

~”Through one very vulnerable receptor type, benzodiazaphines insidiously and mercilessly tear down the very  ‘Pillars’ upon which our fragile nervous system is built.” -dm123

 

 

 

Adult Neurogenesis,  stress, exercise, and the benzodiazaphine model (PART II)

 

 

 

 

 

10.Key application takeaways

 

a.If you do not have severe hypothalamic pituitary dysfunction, that’s presenting as extremely low morning cortisol, do not take hydrocortisone or fludrocortisone.  Hydrocortisone has a relatively short half life, and elevates serum cortisol to very high level peaks that are not physiologically normal relative to the circadian rhythm.  It’s the sustained high serum level of cortisol that has the negative effects on neurogenesis. Glucocorticoids and mineralocorticoids also have an effect on both the  amplitude and frequency of post synaptic inhibitory currents in a phasic fashion.  Unless you have Addison’s or severe hypothalamic dysfunction due to extreme chronic stress, it’s best not to take these medications.  If you are on them, talk to your doctor about tapering off of them slowly.  I personally had to get off of them. The negative neurogenesis effects are completely reversible.  It is very important that one does the taper under a doctor’s supervision. The  hypothalamic-pituitary axis may be transiently suppressed, and ACTH output may initially be slow to recover.

 

 

 

b.The brain is highly adaptable (neuroplastic) and has an enormous ability to regenerate (neurogenesis).  This makes benzodiazaphine recovery not only possible, but probable.  Neuroplastic and neurogenesis changes are not one way streets to damage.. Quite the opposite.  The brain can adapt in both directions: good to bad, and bad to good.  We don’t physiologically return to 100% of what we were prior to encountering benzodiazaphines.  However, not being exactly the same does not mean we are “worse” off.  We are just different, and will have to watch and monitor the negative stressors in our life, once the benzodiazaphine is flushed out of our bodies.

 

 

 

c.Keep moving your body and your mind. There’s no magic pill that can take the place of learning and exercising.  It has to be consistent day to day.  It’s hard, but nothing worth anything is ever easy.  If you can’t move and are not paralyzed you need to talk to your doctor about finding a physical therapist who can start mobilizing your body.

 

 

 

d. Minimize the negative stressors in your life.  It’s almost impossible in today’s society, and that’s why a lot of people have trouble during benzodiazaphine withdrawal and recovery, and it’s a major cause of crashing and PWS.  Stress is the single most important thing that we can control, that has the potential to adversely affect withdrawal and recovery.  It is the most powerful influence on adult neurogenesis.  I hope the information above makes this statement plausible from a clinical and scientific view. 

 

I’m having a very hard time controlling this one.  It’s very difficult,  because as indicated in the material above, stress itself causes changes in hippocampal neurogenesis that causes us to be less resilient to stress. In addition, the anxiety from benzodiazaphine withdrawal itself has similar effects on our resiliency against stress.  A double edged sword indeed…..

 

 

 

e.Taper slowly and do a symptom based taper simply to mitigate the withdrawals symptoms. Withdrawal symptoms in and of themselves act as potent stressors, and perpetuate the feedback loop in the model.  Changes in the brain due to aberrant neurogenesis need time to heal and revert.  See the alcohol study cited above.  If you need adjunctive medications to help in mitigating withdrawal symptoms, relieving physical pain, and/or  relieving psychological stress, talk to your doctor about it. 

 

 

 

f.Get morning sunlight.  Upon waking, stand in front of a sun facing window first thing in the morning.  It’s a natural way to stimulate cortisol production that’s aligned to the circadian rhythm.  Let the sun light hit your face.  Don’t look directly into the sun, but make sure your eyes are taking in the full brightness of the rays.  The hypothalamus will take care of the rest of the job.  Chronic benzodiazaphine use (pre withdrawal and pre tolerance) blunts cortisol response.  If you’ve crossed over to a very long half life benzodiazaphine, this will help get the morning cortisol back up.

 

[[Su...]]

This paper, with all the paper's that it cites is amazingly easy for a lay person such as me to understand.  Thank you dm123

And that the benefits of exercise -- consistent daily --  is essential to recovery.  That can be included easily into my life, and for many others as well I think.  Each person can see what level of exercise is  right for their body.

And that learning helps with neurogenesis is an intuitive and interesting idea. Again daily and consistent.  (Time to learn another language? or a musical instrument? )

And staying away from stress, which again is a real reason to do a symptom based taper -- along with all the multiple other reasons that you have outlined previously. 

 

Rather than speeding up the taper, one could add more exercise and see how the body and systems respond, or that's what I intend to do.

 

And as I have asked in the past about kindling I guess it is simply more or more dramatic changes to  the brain structures that have changed detrimentally, which simply means it will take more time for them to recover or to change.  One of this "what it is -- is"  things...

 

I find this thread so helpful to take the questions out of the tapering process and to put them into plausible reasons for all of us having a different time with it all. 

 

As an aside, the description of how AD's change the brain is fascinating as it has long been said in my field (psychology) that the "too little serotonin in the brain " theory is one that was made up to placate patients.... and docs.  Again thanks for these informative pieces!

SS

[[Re...]]

PART I above

 

 

Benzodiazaphines create that initial crack in the wall to our normally resilient physiology....

 

 

~”Through one very vulnerable receptor type, benzodiazaphines insidiously and mercilessly tear down the very  ‘Pillars’ upon which our fragile nervous system is built.” -dm123

 

 

 

Adult Neurogenesis,  stress, exercise, and the benzodiazaphine model (PART II)

 

 

 

 

 

10.Key application takeaways

 

a.If you do not have severe hypothalamic pituitary dysfunction, that’s presenting as extremely low morning cortisol, do not take hydrocortisone or fludrocortisone.  Hydrocortisone has a relatively short half life, and elevates serum cortisol to very high level peaks that are not physiologically normal relative to the circadian rhythm.  It’s the sustained high serum level of cortisol that has the negative effects on neurogenesis. Glucocorticoids and mineralocorticoids also have an effect on both the  amplitude and frequency of post synaptic inhibitory currents in a phasic fashion.  Unless you have Addison’s or severe hypothalamic dysfunction due to extreme chronic stress, it’s best not to take these medications.  If you are on them, talk to your doctor about tapering off of them slowly.  I personally had to get off of them. The negative neurogenesis effects are completely reversible.  It is very important that one does the taper under a doctor’s supervision. The  hypothalamic-pituitary axis may be transiently suppressed, and ACTH output may initially be slow to recover.

 

 

 

b.The brain is highly adaptable (neuroplastic) and has an enormous ability to regenerate (neurogenesis).  This makes benzodiazaphine recovery not only possible, but probable.  Neuroplastic and neurogenesis changes are not one way streets to damage.. Quite the opposite.  The brain can adapt in both directions: good to bad, and bad to good.  We don’t physiologically return to 100% of what we were prior to encountering benzodiazaphines.  However, not being exactly the same does not mean we are “worse” off.  We are just different, and will have to watch and monitor the negative stressors in our life, once the benzodiazaphine is flushed out of our bodies.

 

 

 

c.Keep moving your body and your mind. There’s no magic pill that can take the place of learning and exercising.  It has to be consistent day to day.  It’s hard, but nothing worth anything is ever easy.  If you can’t move and are not paralyzed you need to talk to your doctor about finding a physical therapist who can start mobilizing your body.

 

 

 

d. Minimize the negative stressors in your life.  It’s almost impossible in today’s society, and that’s why a lot of people have trouble during benzodiazaphine withdrawal and recovery, and it’s a major cause of crashing and PWS.  Stress is the single most important thing that we can control, that has the potential to adversely affect withdrawal and recovery.  It is the most powerful influence on adult neurogenesis.  I hope the information above makes this statement plausible from a clinical and scientific view. 

 

I’m having a very hard time controlling this one.  It’s very difficult,  because as indicated in the material above, stress itself causes changes in hippocampal neurogenesis that causes us to be less resilient to stress. In addition, the anxiety from benzodiazaphine withdrawal itself has similar effects on our resiliency against stress.  A double edged sword indeed…..

 

 

 

e.Taper slowly and do a symptom based taper simply to mitigate the withdrawals symptoms. Withdrawal symptoms in and of themselves act as potent stressors, and perpetuate the feedback loop in the model.  Changes in the brain due to aberrant neurogenesis need time to heal and revert.  See the alcohol study cited above.  If you need adjunctive medications to help in mitigating withdrawal symptoms, relieving physical pain, and/or  relieving psychological stress, talk to your doctor about it. 

 

 

 

f.Get morning sunlight.  Upon waking, stand in front of a sun facing window first thing in the morning.  It’s a natural way to stimulate cortisol production that’s aligned to the circadian rhythm.  Let the sun light hit your face.  Don’t look directly into the sun, but make sure your eyes are taking in the full brightness of the rays.  The hypothalamus will take care of the rest of the job.  Chronic benzodiazaphine use (pre withdrawal and pre tolerance) blunts cortisol response.  If you’ve crossed over to a very long half life benzodiazaphine, this will help get the morning cortisol back up.

 

Great work, dm123

 

I have been doing so much research that I have reached saturation.  I know I am perhaps somewhat of an anomaly compared to some given that I am trying to taper gabapentin.  I'm also on 75mg of Effexor that I was put on at the same time I was given Ativan for sleep.  Now, I understand that there are many complicated interactions which an SSRI may be influencing as well.  I never paid much attention to the SSRI and thought it was kind of independent of this process but now I see that is possibly very wrong.  So much lacking in information by our doctors can cause horrendous problems. 

 

For the last while I was looking at LTP and LDP processes and that in healthy individuals, transcranial Direct Curent Stimulation (tDCS) could have some effect with inducing LTP or LDP.  There are many variables to consider but, without getting into it, the basic observation is that anodal tDCS can cause LTP whereas cathodal tDCS can cause LTD.  The question is, what are we after?  It would seem LTD is what we'd like to observe unless I'm wrong.  However, the people who benefit from tDCS treatment for depression seem to respond to anodal tDCS.  Interestingly, an observation from the studies I've read indicates that Ca+ ions are important in neural plasticity and must be present in the neuron to some degree for neuroplasticity to occur  (LTP or LTD).  Also, the introduction of seratonin via an SSRI seems to reverse the effect of cathodal tDCS (LTD) and furthermore, enhance the LTP effect of anodal tDCS. 

 

For someone like me, who is taking gabapentin and the SNRI effexor (75mg), this poses interesting and somewhat frightening possibilities.  If gabapentin blocks the VGCC such that Ca+ ions aren't available in sufficient quantities to facilitate neuroplasticity or neuronal recovery then that is quite concerning.  It seems that there are some of us who do fine on gabapentin or have some problems and a small few of us who have horrific problems with it.  There are only a few on this board that have spoken about the same experiences I am having with it.  I'm down to 150mg dosing 50mg TID and it is hard going.  I also wonder if counter-intuitively, the effexor is making extracellular seratonin available to the degree that it amplified LTP while I originally took Ativan, which may explain why I was into interdose withdrawal after only 8 or 9 days of 1mg per day?

 

I don't know because I don't quite understand all the biology on this.  I'll attached a link to an interesting article on tDCS from which I've gained some of this information.  Again, I don't know if I understand LTP and LTD correctly in respect of what we are experiencing because the main references for LTP and LTD are in respect to memory formation.  I.E.  LTP is good for memory formation in the neuron whereas LTD does not permit formation of long term memory.  I don't know....maybe I read it wrong and now I just don't remember.  HAHAHAHAH.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127836/

 

-RST

[[cs...]]

This paper, with all the paper's that it cites is amazingly easy for a lay person such as me to understand.  Thank you dm123

And that the benefits of exercise -- consistent daily --  is essential to recovery.  That can be included easily into my life, and for many others as well I think.  Each person can see what level of exercise is  right for their body.

And that learning helps with neurogenesis is an intuitive and interesting idea. Again daily and consistent.  (Time to learn another language? or a musical instrument? )

And staying away from stress, which again is a real reason to do a symptom based taper -- along with all the multiple other reasons that you have outlined previously. 

 

Rather than speeding up the taper, one could add more exercise and see how the body and systems respond, or that's what I intend to do.

 

And as I have asked in the past about kindling I guess it is simply more or more dramatic changes to  the brain structures that have changed detrimentally, which simply means it will take more time for them to recover or to change.  One of this "what it is -- is"  things...

 

I find this thread so helpful to take the questions out of the tapering process and to put them into plausible reasons for all of us having a different time with it all. 

 

As an aside, the description of how AD's change the brain is fascinating as it has long been said in my field (psychology) that the "too little serotonin in the brain " theory is one that was made up to placate patients.... and docs.  Again thanks for these informative pieces!

SS

 

Hi SS,

 

I'm glad it was understandable.  I agree with you about mental and physical exercise.  It's a tool that we can use to modulate the withdrawal process.  There's no pill that can replace or substitute what these things can do for us.  The hardest one is removing negative stressors from one's life.  Life relentlessly moves forward whether we are in benzodiazaphine wd or not.....

The neural circuits stuff will overlay neuroplasticity into the model.

 

 

[[cs...]]

PART I above

 

 

Benzodiazaphines create that initial crack in the wall to our normally resilient physiology....

 

 

~”Through one very vulnerable receptor type, benzodiazaphines insidiously and mercilessly tear down the very  ‘Pillars’ upon which our fragile nervous system is built.” -dm123

 

 

 

Adult Neurogenesis,  stress, exercise, and the benzodiazaphine model (PART II)

 

 

 

 

 

10.Key application takeaways

 

a.If you do not have severe hypothalamic pituitary dysfunction, that’s presenting as extremely low morning cortisol, do not take hydrocortisone or fludrocortisone.  Hydrocortisone has a relatively short half life, and elevates serum cortisol to very high level peaks that are not physiologically normal relative to the circadian rhythm.  It’s the sustained high serum level of cortisol that has the negative effects on neurogenesis. Glucocorticoids and mineralocorticoids also have an effect on both the  amplitude and frequency of post synaptic inhibitory currents in a phasic fashion.  Unless you have Addison’s or severe hypothalamic dysfunction due to extreme chronic stress, it’s best not to take these medications.  If you are on them, talk to your doctor about tapering off of them slowly.  I personally had to get off of them. The negative neurogenesis effects are completely reversible.  It is very important that one does the taper under a doctor’s supervision. The  hypothalamic-pituitary axis may be transiently suppressed, and ACTH output may initially be slow to recover.

 

 

 

b.The brain is highly adaptable (neuroplastic) and has an enormous ability to regenerate (neurogenesis).  This makes benzodiazaphine recovery not only possible, but probable.  Neuroplastic and neurogenesis changes are not one way streets to damage.. Quite the opposite.  The brain can adapt in both directions: good to bad, and bad to good.  We don’t physiologically return to 100% of what we were prior to encountering benzodiazaphines.  However, not being exactly the same does not mean we are “worse” off.  We are just different, and will have to watch and monitor the negative stressors in our life, once the benzodiazaphine is flushed out of our bodies.

 

 

 

c.Keep moving your body and your mind. There’s no magic pill that can take the place of learning and exercising.  It has to be consistent day to day.  It’s hard, but nothing worth anything is ever easy.  If you can’t move and are not paralyzed you need to talk to your doctor about finding a physical therapist who can start mobilizing your body.

 

 

 

d. Minimize the negative stressors in your life.  It’s almost impossible in today’s society, and that’s why a lot of people have trouble during benzodiazaphine withdrawal and recovery, and it’s a major cause of crashing and PWS.  Stress is the single most important thing that we can control, that has the potential to adversely affect withdrawal and recovery.  It is the most powerful influence on adult neurogenesis.  I hope the information above makes this statement plausible from a clinical and scientific view. 

 

I’m having a very hard time controlling this one.  It’s very difficult,  because as indicated in the material above, stress itself causes changes in hippocampal neurogenesis that causes us to be less resilient to stress. In addition, the anxiety from benzodiazaphine withdrawal itself has similar effects on our resiliency against stress.  A double edged sword indeed…..

 

 

 

e.Taper slowly and do a symptom based taper simply to mitigate the withdrawals symptoms. Withdrawal symptoms in and of themselves act as potent stressors, and perpetuate the feedback loop in the model.  Changes in the brain due to aberrant neurogenesis need time to heal and revert.  See the alcohol study cited above.  If you need adjunctive medications to help in mitigating withdrawal symptoms, relieving physical pain, and/or  relieving psychological stress, talk to your doctor about it. 

 

 

 

f.Get morning sunlight.  Upon waking, stand in front of a sun facing window first thing in the morning.  It’s a natural way to stimulate cortisol production that’s aligned to the circadian rhythm.  Let the sun light hit your face.  Don’t look directly into the sun, but make sure your eyes are taking in the full brightness of the rays.  The hypothalamus will take care of the rest of the job.  Chronic benzodiazaphine use (pre withdrawal and pre tolerance) blunts cortisol response.  If you’ve crossed over to a very long half life benzodiazaphine, this will help get the morning cortisol back up.

 

Great work, dm123

 

I have been doing so much research that I have reached saturation.  I know I am perhaps somewhat of an anomaly compared to some given that I am trying to taper gabapentin.  I'm also on 75mg of Effexor that I was put on at the same time I was given Ativan for sleep.  Now, I understand that there are many complicated interactions which an SSRI may be influencing as well.  I never paid much attention to the SSRI and thought it was kind of independent of this process but now I see that is possibly very wrong.  So much lacking in information by our doctors can cause horrendous problems. 

 

For the last while I was looking at LTP and LDP processes and that in healthy individuals, transcranial Direct Curent Stimulation (tDCS) could have some effect with inducing LTP or LDP.  There are many variables to consider but, without getting into it, the basic observation is that anodal tDCS can cause LTP whereas cathodal tDCS can cause LTD.  The question is, what are we after?  It would seem LTD is what we'd like to observe unless I'm wrong.  However, the people who benefit from tDCS treatment for depression seem to respond to anodal tDCS.  Interestingly, an observation from the studies I've read indicates that Ca+ ions are important in neural plasticity and must be present in the neuron to some degree for neuroplasticity to occur  (LTP or LTD).  Also, the introduction of seratonin via an SSRI seems to reverse the effect of cathodal tDCS (LTD) and furthermore, enhance the LTP effect of anodal tDCS. 

 

For someone like me, who is taking gabapentin and the SNRI effexor (75mg), this poses interesting and somewhat frightening possibilities.  If gabapentin blocks the VGCC such that Ca+ ions aren't available in sufficient quantities to facilitate neuroplasticity or neuronal recovery then that is quite concerning.  It seems that there are some of us who do fine on gabapentin or have some problems and a small few of us who have horrific problems with it.  There are only a few on this board that have spoken about the same experiences I am having with it.  I'm down to 150mg dosing 50mg TID and it is hard going.  I also wonder if counter-intuitively, the effexor is making extracellular seratonin available to the degree that it amplified LTP while I originally took Ativan, which may explain why I was into interdose withdrawal after only 8 or 9 days of 1mg per day?

 

I don't know because I don't quite understand all the biology on this.  I'll attached a link to an interesting article on tDCS from which I've gained some of this information.  Again, I don't know if I understand LTP and LTD correctly in respect of what we are experiencing because the main references for LTP and LTD are in respect to memory formation.  I.E.  LTP is good for memory formation in the neuron whereas LTD does not permit formation of long term memory.  I don't know....maybe I read it wrong and now I just don't remember.  HAHAHAHAH.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127836/

 

-RST

 

Hi RST,

 

Hi RST, I hope the information below helps.  I know you’ve gone through a lot.

 

Just wanted to be clear that the paper above is referring to neurogenesis as a perpetuating factor in PWS.  Neuroplasticity will be dealt with in the neural circuits thread.  LTP and LTD fall more in line with neuroplasticity.  A lot of people use these terms , neurogenesis and neuroplasticity, interchangeably. I’ve even used “neuroplastic” to refer to neurogenesis .    Although neurogenesis is plasticity of the brain, I’m going to separate them out clearly from this point forward.  Neurogenesis is the birth of new neurons.  Aberrant neurogenesis would result in neurons that structurally look different from normal neurons.  Neuroplasticity can induce morphological structural changes as well, for example,  in the dendritic spine structure (see below, synaptic plasticity ) .  Neuroplastic changes in the brain can refer to both types.

 

 

I will post 2 parts, RST1 and RST2

RST1 is probably information you already know .

RST1 and RST2 are very technical and can be skipped by most viewers.....

 

 

 

 

-In RST2, I will explain LTP and LTD in the context of the stress response.    It will help you understand them better, understand why balance is the key and understand why brain region is critical.  Indiscriminately suppressing or enhancing them by pharmaceuticals or other therapeutics is risky because these instruments are blunt and not targeted to specific brain regions.  To answer your question , we don’t want one over the other, and determining which one is imbalanced in your nervous system is clinically difficult.  Also, even if we determine that LTD, for example, needs a “boost”, how do we determine and target the “deficient” brain region appropriately and effectively?  I do agree that your research is on the right path.  It’s like what we discussed a few weeks ago.  We know what’s going on, but it doesn’t give us a clear therapeutic protocol.

 

 

-I will have to read up in tDNS first, and get back to you on that therapy.  I don’t know anything about it (yet), but I’m glad you are looking at therapies to help us out.

 

-I know next to nothing about antidepressants.  There are people on BB much more knowledgeable than I, in this area.    The only thing that I’m sure about in this area, is that very few people have genetically insufficient serotonin, or defective serotonin receptor sensitivity, as the pharmaceutical industry would like us to believe.  This is like telling someone they need benzodiazaphines because they have genetically defective GABAaRs and dysfunctional GABA turnover. There are real life genetic diseases that do have these issues, but they are extremely rare and completely debilitating. We (BBs) certainly don’t have these neurological diseases .    Antidepressants definitely work by increasing a growth factor that influences the rate of neurogenesis.  That growth factor happens to be serotonin.  But there are many such growth factors.  I believe the pharmaceutical companies picked the one that could be easily modulated, and one that would have a very slick marketing message: enter serotonin, the feel good hormone.

 

 

-Given the above, it’s not surprising that antidepressants affect the tDCS as you noted above. It’s confirming that the neurogenesis that’s occurring from the antidepressant is fostering healthy new neurons that are able to make strong synaptic connections with their neighboring neurons .  Aberrant neurogenesis results in morphologically stunted neurons with disfigured dendrites and abnormal spine densities and development,  that prevent them from assimilating into the brain’s neural circuitry.  These new neurons don’t survive without the potentiation to other neurons.

 

 

 

 

 

RST1:VGCCs and neuroplasticity and neurogenesis

 

 

 

 

1.Neuroplasticity and calcium

 

 

We will get into neuroplasticity in depth in the neural circuits paper.  For now:

 

 

I referred to homeostatic plasticity briefly in the paper posted above.  We will see a lot more if this in the neural circuits paper.  VGCCs do affect homeostasic plasticity.  Homeostatic plasticity puts the “brakes” on Hebbian plasticity.  Without it neurons would “over-potentiate” with one another and hyperexcitability would result.  This might be what’s going on with your case.  VGCCs play a big role in modulating the homeostatic plasticity response.

 

 

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924756/pdf/fncel-08-00040.pdf

 

Quote

Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage- gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2- type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response— homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies—such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.

End quote

 

 

 

 

If you are experiencing rebound VGCC activity that would explain the pain

https://www.sciencedirect.com/topics/neuroscience/voltage-dependent-calcium-channel

 

Quote

In response to changes in membrane potential, voltage-gated calcium channels mediate the influx of calcium ions into many types of excitable and nonexcitable cells. Calcium flux subsequently regulates crucial physiological functions, including neurotransmitter release, muscle contraction, calcium-dependent enzyme and protein modulation, cell growth and differentiation, neuronal excitability, and calcium-dependent gene transcription. The aberrant elevation of intracellular calcium levels through altered calcium channel function is related to a variety of serious human pathophysiological conditions, including cardiovascular disease, muscle disorders, acute and chronic pain, epilepsy, cerebellar ataxia, migraine, mood disorders, and certain types of cancer. To date, clinical agents blocking specific calcium channel subtypes have proven highly beneficial for the treatment of certain cardiovascular and neurological conditions.

End quote

 

 

 

 

 

http://www.jneurosci.org/content/jneuro/37/5/1240.full.pdf

 

Quote

Long-term potentiation (LTP) is widely perceived as a memory substrate and in the hippocampal CA3-CA1 pathway, distinct forms of LTP depend on NMDA receptors (nmdaLTP) or L-type voltage-gated calcium channels (vdccLTP). LTP is also known to be effectively regulated by extracellular proteolysis that is mediated by various enzymes. Herein, we investigated whether in mice hippocampal slices these distinct forms of LTP are specifically regulated by different metalloproteinases (MMPs). We found that MMP-3 inhibition or knock-out impaired late-phase LTP in the CA3-CA1 pathway. Interestingly, late-phase LTP was also decreased by MMP-9 blockade. When both MMP-3 and MMP-9 were inhibited, both early- and late-phase LTP was impaired. Using immunoblotting, in situ zymography, and immunofluorescence, we found that LTP induction was associated with an increase in MMP-3 expression and activity in CA1 stratum radiatum. MMP-3 inhibition and knock-out prevented the induction of vdccLTP, with no effect on nmdaLTP.

 

L-type channel-dependent LTP is known to be impaired by hyaluronic acid digestion. We found that slice treatment with hyaluronidase occluded the effect of MMP-3 blockade on LTP, further confirming a critical role for MMP-3 in this form of LTP. In contrast to the CA3-CA1 pathway, LTP in the mossy fiber-CA3 projection did not depend on MMP-3, indicating the pathway specificity of the actions of MMPs. Overall, our study indicates that the activation of perisynaptic MMP-3 supports L-type channel- dependent LTP in the CA1 region, whereas nmdaLTP depends solely on MMP-9.

End quote

 

 

 

 

 

The glutamatergic system plays a large role here.  Excitatory potentiation is required to sustain spines.  See below.  VGCCs play a big role in calcium transients which play a role in synaptic plasticity. VGCCs have been found in neuron spine heads…. .

 

https://en.m.wikipedia.org/wiki/Long-term_potentiation

https://en.m.wikipedia.org/wiki/Dendritic_spine#Modeling

https://en.m.wikipedia.org/wiki/Neuroplasticity

 

Quotes

Signalling from GluRs is mediated by the presence of an abundance of proteins, especially kinases, that are localized to the postsynaptic density. These include calcium-dependent calmodulin, CaMKII (calmodulin-dependent protein kinase II), PKC (Protein Kinase C), PKA(Protein Kinase A), Protein Phosphatase-1 (PP-1), and Fyn tyrosine kinase. Certain signallers, such as CaMKII, are upregulated in response to activity.

 

Spines are particularly advantageous to neurons by compartmentalizing biochemical signals. This can help to encode changes in the state of an individual synapse without necessarily affecting the state of other synapses of the same neuron. The length and width of the spine neck has a large effect on the degree of compartmentalization, with thin spines being the most biochemically isolated spines.

 

…..

 

The cytoskeleton of dendritic spines is particularly important in their synaptic plasticity; without a dynamic cytoskeleton, spines would be unable to rapidly change their volumes or shapes in responses to stimuli. These changes in shape might affect the electrical properties of the spine. The cytoskeleton of dendritic spines is primarily made of filamentous actin (F-actin). tubulin Monomers and microtubule-associated proteins (MAPs) are present, and organized microtubules are present.[6] Because spines have a cytoskeleton of primarily actin, this allows them to be highly dynamic in shape and size. The actin cytoskeleton directly determines the morphology of the spine, and actin regulators, small GTPases such as Rac, RhoA, and CDC42, rapidly modify this cytoskeleton. Overactive Rac1 results in consistently smaller dendritic spines.

 

Dendritic spines are very "plastic", that is, spines change significantly in shape, volume, and number in small time courses. Because spines have a primarily actin cytoskeleton, they are dynamic, and the majority of spines change their shape within seconds to minutes because of the dynamicity of actin remodeling. Furthermore, spine number is very variable and spines come and go; in a matter of hours, 10-20% of spines can spontaneously appear or disappear on the pyramidal cells of the cerebral cortex, although the larger "mushroom"-shaped spines are the most stable.

 

Spine maintenance and plasticity is activity-dependent[7] and activity-independent. BDNF partially determines spine levels,[8] and low levels of AMPA receptor activity is necessary to maintain spine survival, and synaptic activity involving NMDA receptors encourages spine growth. Furthermore, two-photon laser scanning microscopy and confocal microscopy have shown that spine volume changes depending on the types of stimuli that are presented to a synapse.

 

 

Spine plasticity is implicated in motivation, learning, and memory.[9][10][11] In particular, long-term memory is mediated in part by the growth of new dendritic spines (or the enlargement of pre-existing spines) to reinforce a particular neural pathway. Because dendritic spines are plastic structures whose lifespan is influenced by input activity,[12]spine dynamics may play an important role in the maintenance of memory over a lifetime.

 

 

Age-dependent changes in the rate of spine turnover suggest that spine stability impacts developmental learning. In youth, dendritic spine turnover is relatively high and produces a net loss of spines.[13][14][15] This high rate of spine turnover may characterize critical periods of development and reflect learning capacity in adolescence—different cortical areas exhibit differing levels of synaptic turnover during development, possibly reflecting varying critical periods for specific brain regions.[10][14] In adulthood, however, most spines remain persistent, and the half-life of spines increases.[13] This stabilization occurs due to a developmentally regulated slow-down of spine elimination, a process which may underlie the stabilization of memories in maturity.[13][14]

 

Experience-induced changes in dendritic spine stability also point to spine turnover as a mechanism involved in the maintenance of long-term memories, though it is unclear how sensory experience affects neural circuitry. Two general models might describe the impact of experience on structural plasticity. On the one hand, experience and activity may drive the discrete formation of relevant synaptic connections that store meaningful information in order to allow for learning. On the other hand, synaptic connections may be formed in excess, and experience and activity may lead to the pruning of extraneous synaptic connections.[13]

 

In lab animals of all ages, environmental enrichment has been related to dendritic branching, spine density, and overall number of synapses.[13] In addition, skill training has been shown to lead to the formation and stabilization of new spines while destabilizing old spines,[9][16] suggesting that the learning of a new skill involves a rewiring process of neural circuits. Since the extent of spine remodeling correlates with success of learning, this suggests a crucial role of synaptic structural plasticity in memory formation.[16] In addition, changes in spine stability and strengthening occur rapidly and have been observed within hours after training.[9][10]

 

Conversely, while enrichment and training are related to increases in spine formation and stability, long-term sensory deprivation leads to an increase in the rate of spine elimination[13][14] and therefore impacts long-term neural circuitry. Upon restoring sensory experience after deprivation in adolescence, spine elimination is accelerated, suggesting that experience plays an important role in the net loss of spines during development.[14] In addition, other sensory deprivation paradigms—such as whisker trimming—have been shown to increase the stability of new spines.[17]

 

Research in neurological diseases and injuries shed further light on the nature and importance of spine turnover. After stroke, a marked increase in structural plasticity occurs near the trauma site, and a five- to eightfold increase from control rates in spine turnover has been observed.[18] Dendrites disintegrate and reassemble rapidly during ischemia—as with stroke, survivors showed an increase in dendritic spine turnover.[19] While a net loss of spines is observed in Alzheimer's disease and cases of intellectual disability, cocaine and amphetamine use have been linked to increases in dendritic branching and spine density in the prefrontal cortex and the nucleus accumbens.[20] Because significant changes in spine density occur in various brain diseases, this suggests a balanced state of spine dynamics in normal circumstances, which may be susceptible to disequilibrium under varying pathological conditions.[20]

 

There is also some evidence for loss of dendritic spines as a consequence of aging. One study using mice has noted a correlation between age-related reductions in spine densities in the hippocampus that and age-dependent declines in hippocampal learning and memory.[21]

 

 

 

Importance contested

Despite experimental findings that suggest a role for dendritic spine dynamics in mediating learning and memory, the degree of structural plasticity’s importance remains debatable. For instance, studies estimate that only a small portion of spines formed during training actually contribute to lifelong learning.[16]

 

 

In addition, the formation of new spines may not significantly contribute to the connectivity of the brain, and spine formation may not bear as much of an influence on memory retention as other properties of structural plasticity, such as the increase in size of spine heads.[22]

 

 

Theoreticians have for decades hypothesized about the potential electrical function of spines, yet our inability to examine their electrical properties has until recently stopped theoretical work from progressing too far. Recent advances in imaging techniques along with increased use of two-photon glutamate uncaging have led to a wealth of new discoveries; we now suspect that there are voltage-dependent sodium,[23] potassium,[24] and calcium[25] channels in the spine heads.[26]

Cable theory provides the theoretical framework behind the most "simple" method for modelling the flow of electrical currents along passive neural fibres. Each spine can be treated as two compartments, one representing the neck, the other representing the spine head. The compartment representing the spine head alone should carry the active properties.

 

End quotes

 

 

 

 

Calcium transients in neuromuscular contraction.  (They are also present in potentiation for memory,learning, etc)

 

Calcium ions mediate and modulate extracellular signals on intracellular processes.

https://answers.yahoo.com/question/index?qid=20110601001942AAyPgQN

 

Quote

The calcium transient is fancy way of saying that the amount of calcium in your sarcoplasm has increased for a short period of time. You're right when you say that an action potential causes the DHPR receptor to open up so that calcium flows into the cell causing a calcium induced calcium released process to happen. Which is when the calcium that has flowed in, causes the calcium channels in the sarcoplasmic reticulum to open up and even more calcium to flow into the sarcplasm. Hence the bindning of calcium to the troponin, which communicates with the tropomyosin to under go a conformational/rotation so that the myosin heads can bind. 

But remember, then the calcium is quickly pumped back into the sarcoplasmic reticulum and extruded out of the cell by the Ca/Na exchanger so that another action potential can occur as the cell is repolarised back to its steady state. So the change in calcium in the sarcoplasm (increase and decrease) occurs for a short period of time AKA transient.

End quote

 

 

Quote

Modeling spine calcium transients

 

Calcium transients in spines are a key trigger for synaptic plasticity.[29] NMDA receptors, which have a high permeability for calcium, only conduct ions if the membrane potential is suffiently depolarized. The amount of calcium entering a spine during synaptic activity therefore depends on the depolarization of the spine head. Evidence from calcium imaging experiments (two-photon microscopy) and from compartmental modelling indicates that spines with high resistance necks experience larger calcium transients during synaptic activity.[26][30]

 

Cognitive disorders such as ADHD, autism, intellectual disability, and fragile X syndrome, may be resultant from abnormalities in dendritic spines, especially the number of spines and their maturity.[32] The ratio of matured to immature spines is important in their signaling, as immature spines have impaired synaptic signaling. Fragile X syndrome is characterized by an overabundance of immature spines that have multiple filopodia in cortical dendrites.

End quote

 

 

 

 

 

 

 

2.Neurogenesis and calcium

 

 

 

Adult neurogenesis, on the other hand is the birth of new neurons.  Different from neuroplasticity from a technical standpoint, but from a brain perspective, it is plasticity.

The glutamatergic system plays a big role here as well.  VGCCs play a role here.  See below.  At your low dose, the VGCCs are most likely not horribly impaired. It’s hard to say if you have dysfunctional neurogenesis due to what’s going on with the VGCCs.  If it is, it could account for protracted withdrawal symptoms.

 

 

 

https://www.ncbi.nlm.nih.gov/pubmed/27020657

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228525/

 

Quote

Calcium (Ca(2+)) signaling has essential roles in the development of the nervous system from neural induction to the proliferation, migration, and differentiation of neural cells. Ca(2+) signaling pathways are shaped by interactions among metabotropic signaling cascades, intracellular Ca(2+) stores, ion channels, and a multitude of downstream effector proteins that activate specific genetic programs. The temporal and spatial dynamics of Ca(2+) signals are widely presumed to control the highly diverse yet specific genetic programs that establish the complex structures of the adult nervous system. Progress in the last two decades has led to significant advances in our understanding of the functional architecture of Ca(2+) signaling networks involved in neurogenesis. In this review, we assess the literature on the molecular and functional organization of Ca(2+) signaling networks in the developing nervous system and its impact on neural induction, gene expression, proliferation, migration, and differentiation. Particular emphasis is placed on the growing evidence for the involvement of store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels in these processes.

End quote

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999846/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349005/

https://www.sciencedirect.com/science/article/pii/S0092867408001347

https://www.nature.com/articles/nrn1446

https://www.scholars.northwestern.edu/en/publications/regulation-of-neurogenesis-by-calcium-signaling

https://www.ncbi.nlm.nih.gov/pubmed/16000159

 

 

 

Quote

Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. The signals that regulate neurogenesis in the dentate gyrus following ischemic stroke insult are not well known. We have previously reported that inducible nitric oxide synthase (iNOS) expression is necessary for ischemia-stimulated neurogenesis in the adult dentate gyrus. Here, we show that mice subjected to 90 min of middle cerebral artery occlusion (MCAO) significantly increased the number of new neurons and up-regulated iNOS expression in the dentate gyrus. Blockade of the L-type voltage-gated Ca(2+) channel (L-VGCC) prevented neurogenesis in the dentate gyrus and subventricular zone (SVZ), and down-regulated iNOS expression in the dentate gyrus after cerebral ischemia. This study suggests that Ca(2+) influx through L-VGCC is involved in ischemia-induced neurogenesis by up-regulating iNOS expression.

End quote

 

 

 

https://www.ncbi.nlm.nih.gov/pubmed/26459417

 

Quote

L-type voltage gated Ca(2+) channels (LTCCs) are widely expressed within different brain regions including the hippocampus. The isoforms Cav1.2 and Cav1.3 have been shown to be involved in hippocampus-dependent learning and memory, cognitive functions that require proper hippocampal neurogenesis. In vitro, functional LTCCs are expressed on neuronal progenitor cells, where they promote neuronal differentiation. Expression of LTCCs on neural stem and progenitor cells within the neurogenic regions in the adult brain in vivo has not been examined so far, and a contribution of the individual isoforms Cav1.2 and Cav1.3 to adult neurogenesis remained to be clarified. To reveal the role of these channels we first evaluated the expression patterns of Cav1.2 and Cav1.3 in the hippocampal dentate gyrus and the subventricular zone (SVZ) in adult (2- and 3-month old) and middle-aged (15-month old) mice on mRNA and protein levels. We performed immunohistological analysis of hippocampal neurogenesis in adult and middle-aged Cav1.3(-/-) mice and finally addressed the importance of Cav1.3 for hippocampal function by evaluating spatial memory and depression-like behavior in adult Cav1.3(-/-) mice. Our results showed Cav1.2 and Cav1.3 expression at different stages of neuronal differentiation. While Cav1.2 was primarily restricted to mature NeuN(+) granular neurons, Cav1.3 was expressed in Nestin(+) neural stem cells and in mature NeuN(+) granular neurons. Adult and middle-aged Cav1.3(-/-) mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. Further, Cav1.3(-/-) mice showed impairment in the hippocampus dependent object location memory test, implicating Cav1.3 as an essential element for hippocampus-associated cognitive functions. Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.

End quote

 

 

 

 

https://www.frontiersin.org/articles/10.3389/fncel.2010.00008/full

 

Quote

In the adult neurogenic subventricular zone (SVZ), the behavior of astrocyte-like cells and some of their functions depend on changes in intracellular Ca2+ levels and tonic GABAA receptor activation. However, it is unknown whether, and if so how, GABAA receptor activity regulates intracellular Ca2+ dynamics in SVZ astrocytes. To monitor Ca2+ activity selectively in astrocyte- like cells, we used two lines of transgenic mice expressing either GFP fused to a Gq-coupled receptor or DsRed under the human glial fibrillary acidic protein (hGFAP) promoter. GABAA receptor activation induced Ca2+ increases in 40–50% of SVZ astrocytes. GABAA-induced Ca2+ increases were prevented with nifedipine and mibefradil, blockers of L- and T-type voltage- gated calcium channels (VGCC). The L-type Ca2+ channel activator BayK 8644 increased the percentage of GABAA-responding astrocyte-like cells to 75%, suggesting that the majority of SVZ astrocytes express functional VGCCs. SVZ astrocytes also displayed spontaneous Ca2+ activity, the frequency of which was regulated by tonic GABAA receptor activation. These data support a role for ambient GABA in tonically regulating intracellular Ca2+ dynamics through GABAA receptors and VGCC in a subpopulation of astrocyte-like cells in the postnatal SVZ.

End quote

 

 

 

http://www.sciencedirect.com/science/article/pii/S0143416015001517

 

Quote

L-type voltage gated Ca2+ channels (LTCCs) are widely expressed within different brain regions including the hippocampus. The isoforms Cav1.2 and Cav1.3 have been shown to be involved in hippocampus-dependent learning and memory, cognitive functions that require proper hippocampal neurogenesis. In vitro, functional LTCCs are expressed on neuronal progenitor cells, where they promote neuronal differentiation. Expression of LTCCs on neural stem and progenitor cells within the neurogenic regions in the adult brain in vivo has not been examined so far, and a contribution of the individual isoforms Cav1.2 and Cav1.3 to adult neurogenesis remained to be clarified. To reveal the role of these channels we first evaluated the expression patterns of Cav1.2 and Cav1.3 in the hippocampal dentate gyrus and the subventricular zone (SVZ) in adult (2- and 3-month old) and middle-aged (15-month old) mice on mRNA and protein levels. We performed immunohistological analysis of hippocampal neurogenesis in adult and middle-aged Cav1.3−/− mice and finally addressed the importance of Cav1.3 for hippocampal function by evaluating spatial memory and depression-like behavior in adult Cav1.3−/− mice. Our results showed Cav1.2 and Cav1.3 expression at different stages of neuronal differentiation. While Cav1.2 was primarily restricted to mature NeuN+ granular neurons, Cav1.3 was expressed in Nestin+neural stem cells and in mature NeuN+ granular neurons. Adult and middle-aged Cav1.3−/− mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. Further, Cav1.3−/−mice showed impairment in the hippocampus dependent object location memory test, implicating Cav1.3 as an essential element for hippocampus-associated cognitive functions. Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.

End quote

 

 

 

http://www.eneuro.org/content/3/6/ENEURO.0118-16.2016

 

 

 

[[Re...]]

WOW!!!  DM123 IS A ROCKSTAR!!!

 

Thank you so much for the considerate and informative response.  I have much to consider.  I think you made a point that struck home powerfully with respect to aberrant neurogenesis.  Twice in my past I've experienced months long periods of intense stress.  In each of those situations, I eventually experienced phenomenon that mirrored benzo withdrawal, albeit less intensely.  Over time, the phenomenon slowly resolved.  In the first instance during my late 20s, it resolved after 2 weeks of bed rest.  Some years later, in my mid 30s, the stress period was longer but the subsequent recovery was about 5 months (although I wasn't bedridden).  Now, as I approach my 49th birthday I reflect on that history and although it is purely subjective, I am almost positive I have preexisting neurogenesis problems.  As a side note, when I was a child I was exposed to a high concentration of gasoline and other petrochemicals due to my father's business.  I often wonder about the potential impact of that exposure on a child's developing brain.

 

Anyway.  It's incredible to see the work you put into this trying to help us all make sense of our suffering.  I am humbly in your debt and so very appreciative.

 

-RST

[[Su...]]

WOW!!!  DM123 IS A ROCKSTAR!!!

 

Thank you so much for the considerate and informative response.  I have much to consider.  I think you made a point that struck home powerfully with respect to aberrant neurogenesis.  Twice in my past I've experienced months long periods of intense stress.  In each of those situations, I eventually experienced phenomenon that mirrored benzo withdrawal, albeit less intensely.  Over time, the phenomenon slowly resolved.  In the first instance during my late 20s, it resolved after 2 weeks of bed rest.  Some years later, in my mid 30s, the stress period was longer but the subsequent recovery was about 5 months (although I wasn't bedridden).  Now, as I approach my 49th birthday I reflect on that history and although it is purely subjective, I am almost positive I have preexisting neurogenesis problems.  As a side note, when I was a child I was exposed to a high concentration of gasoline and other petrochemicals due to my father's business.  I often wonder about the potential impact of that exposure on a child's developing brain.

 

Anyway.  It's incredible to see the work you put into this trying to help us all make sense of our suffering.  I am humbly in your debt and so very appreciative.

 

-RST

 

Isn't that the truth and so well said RST!  :thumbsup:

:smitten:

SS

[[cs...]]

WOW!!!  DM123 IS A ROCKSTAR!!!

 

Thank you so much for the considerate and informative response.  I have much to consider.  I think you made a point that struck home powerfully with respect to aberrant neurogenesis.  Twice in my past I've experienced months long periods of intense stress.  In each of those situations, I eventually experienced phenomenon that mirrored benzo withdrawal, albeit less intensely.  Over time, the phenomenon slowly resolved.  In the first instance during my late 20s, it resolved after 2 weeks of bed rest.  Some years later, in my mid 30s, the stress period was longer but the subsequent recovery was about 5 months (although I wasn't bedridden).  Now, as I approach my 49th birthday I reflect on that history and although it is purely subjective, I am almost positive I have preexisting neurogenesis problems.  As a side note, when I was a child I was exposed to a high concentration of gasoline and other petrochemicals due to my father's business.  I often wonder about the potential impact of that exposure on a child's developing brain.

 

Anyway.  It's incredible to see the work you put into this trying to help us all make sense of our suffering.  I am humbly in your debt and so very appreciative.

 

-RST

 

Hi RST

 

I wiill post RST2 as well.  You will have to read i through several times, but once you understand it, you will have insight into  the dynamic interplay between LTP and LTD.  I'll look at the tDCS next week.  Thanks for looking for alternative therapies, based on what we've learned.  It helping to make this thread more applicable.

 

Pre benzodiazaphine, I had one instance of a stress related ailment, similar to those you mentioned above.....negative stress is one of the big players.

[[cs...]]

Hi RST, here it is (drum roll.......)

 

I hope this makes sense.   

 

 

 

RST2:Example of LTP and LTD interplay in the stress response (Neuroplasticity)

 

 

 

-I think many of us have a biased view of LTP, because in excess it is correlated with the glutamate hypothesis for benzodiazaphine PWS.  Calcium plays a huge role in LTP (see RST1) , because an abrupt cold turkey cessation of benzodiazaphines can cause a massive depolarization of neurons, activating CCs, and resulting in very long term changes between excitatory synapses.  This is unabated potentiation that leads to hyperexcitability.

 

 

 

-The below is an excerpt from a paper that I wrote a while back for an LTP vs LTD example.

  It’s very technical, and I’m posting it just so that you can understand the complex interplay between LTP and LTD.  I hadn’t planned to post it, but I think it will help you understand these two topics and the dynamic interplay between the two,

 

  I personally don’t think that the low gabapentin dose that you are on is blocking out LTP and neurogenesis, but it might have disrupted the normal healthy balance of LTP and LTD in certain regions of your brain, so that physiological function is not optimal.  In your case it’s  your sensory nervous system function, and a rebound of too much LTP between certain synapses in the sensory area of your brain, that’s not being counterbalanced by LTD in other regions of the brain.(?).  In the neural circuits paper we will see when homeostatic plasticity is overwhelmed by a perturbation (or stressor, and this can be induced pharmacologically) the circuit can become hyperexcitable.  For the sensory nervous system this translates to neuropathic pain.

 

 

-Regarding the material below:

You will probably have to read it through a few times, but once you get it you will understand that neither LTP or LTD are “bad” in and if themselves.  It’s only when they get out of balance, that one or the other becomes a nuisance to normal physiological function. 

 

The example below illustrates the complex interplay between cortisol and the various types of cortisol receptors that I alluded to in the neurogenesis paper , section 2, and how they facilitate a stress response that can be emotionally processed and consolidated to memory.  This is necessary for  a resilient response to stress.  When maladaptive changes occur in response to negative stress, as we will see below, LTP gets out of control, and does not allow a particular portion of the hippocampus (ventral, or VH) to process the stressor (this is done via  LTD of the dorsal hippocampus, DH).  The DH needs to be quieted down so that the VH can  pass event information to the amygdala for emotional processing.  Without this emotional processing of the event  we simply cannot handle stress.  Thus LTP and LTD are required at different points in time, in different regions of the brain, for normal physiological function.

 

- LTP and LTD occur differentially with respect to time and with respect to the region of the brain.  When its working well, it is an awe inspiring orchestrated masterpiece.

 

  Certain steroid receptor types (membrane vs intranuclear , and GRs vs MRS)are differentially distributed in various regions of the brain(for example, the DH and VH), and this helps to facilitate the processing of a stressor.  The temporal aspects of the stress response are also facilitated by the variable affinities for cortisol between the different receptor types.

 

-We are dealing with neuroplasticity in this second post, not neurogenesis.

 

-You are right in focusing on the VGCCs.  We really don’t know how big of a wrench would be thrown into the interplay below, if VGCCs were blunted by chronic gabapentin use,  and then the blunting was tapered.  You might be experiencing a rebound imbalance of LTP over LTD, now that you are off most of the gabapentin .    I’m glad you are keeping the serum levels steady.

 

-Are you able to psychologically handle stress?  You mentioned a strenuous bike ride causing relapse in the neuropathic pain.  Was your ability to handle negative stress or was your perception of everyday stressors detrimentally affected during this time shortly after the strenuous bike ride?

 

 

 

 

 

The hippocampus VH: stress and emotional memory regulation via LTP and LTD  neuroplastic changes in a complex triphasic response to stress hormones

 

https://www.frontiersin.org/articles/10.3389/fncel.2012.00012/full

 

Front. Cell. Neurosci., 20 March 2012 | https://doi.org/10.3389/fncel.2012.00012

Steroid modulation of hippocampal plasticity: switching between cognitive and emotional memories

Nicola Maggio and Menahem Segal

 

 

Quote

 

Several new observations have shifted the view of the hippocampus from a structure in charge of cognitive processes to a brain area that participates in the formation of emotional memories, in addition to its role in cognition. Specifically, while the dorsal hippocampus is involved in the processing of cognitive memories; the ventral sector is mainly associated with the control of behavioral inhibition, stress, and emotional memory.

 

Stress is likely to cause this switch in control of hippocampal functions by modulating synaptic plasticity in the dorsal and ventral sectors of the hippocampus through the differential activation of mineralocorticosteroid or glucocorticosteroid receptors. Herein, we will review the effects of stress hormones on synaptic plasticity in the hippocampus and outline the outcomes on stress-related global functions of this structure. We propose that steroid hormones act as molecular switches: by changing the strength of synaptic connectivity in the hippocampus following stress, they regulate the routes by which the hippocampus is functionally linked to the rest of the brain.

 

End quote

 

 

 

 

From an earlier section we know that the hippocampal CA1 and DG, and central amygdala are highly neuroplastic in their response to steroid hormones, in a complex biphasic fashion.  First fast non-genomic effects kick in (mainly membrane receptor types) and then slow genomic effects kick in (mainly intranuclear).  The response is actually triphasic if you refer to the figure below.

 

  (iMRs at steady tonic state -- mMRs and iGRs activated -- mGRs now also  activated at peak -- back down to mMR and iGR activation which then fades back to tonic iMR only)

 

 

https://www.frontiersin.org/files/Articles/21559/fncel-06-00012-HTML/image_m/fncel-06-00012-g001.jpg

 

 

 

 

I suggest everyone print the diagram above out, because the following discussion will be impossible to follow without referring to the diagram

 

Quote

 

FIGURE 1. (A) Time course of MR and GR activation following stressful stimuli. At a resting level, iMR are already saturated by the baseline levels of corticosterone. Rising concentration of corticosterone activates both mMR and iGR, whereas an additional increase in corticosterone levels also activates mGR.

 

mMR- and mGR-mediated effects appear in a faster time course than those mediated by the intracellular receptors. Modified from Maggio and Segal (2010).

 

(B) Proposed mechanism by which corticosteroid receptors differently regulate LTP and LTD in the hippocampus.

 

iMR are believed to be fully occupied at baseline level of corticosterone, therefore they might play a marginal role in synaptic plasticity.

mMR might play a fundamental role in synaptic plasticity especially in VH: mMR activation reduces IPSC frequency. This determines an increase in the excitability of the pyramidal cells and raises the possibility of VGCC activation, thus enhancing LTP.

In addition, a decrease in GABAergic inhibition can impair LTD through a group I mGluR-mediated mechanism.

 

 

iGR are thought to both decrease NMDA-mediated LTP and increase VGCCs mediated LTP both in the hippocampus and amygdale. Their effects may occur at longer time scale due to their lower affinity to corticosterone.

 

mGR might be involved in the regulation of synaptic plasticity mainly in DH: mGR activation increases IPSC amplitude and following hyperpolarization of the pyramidal cell membrane and inactivation of NMDA receptors, might impair LTP and enhance LTD. Modified from Maggio and Segal (2010).

VH = ventral hippocampus

DH = dorsal hippocampus

 

 

End quote

 

 

 

The figure above represents normal receptor activation during a normal stress response. The LTP experienced in the VH due to mMRs (via VGCCs) strengthens synaptic connections and permits emotional processing of the stressor.  In the VH, the genomic iGR response kicks in (also to further increase VH LTP) to continue emotional  processing of the stressor.

 

    Meanwhile, LTP is attenuated in the DH rather quickly (less than 1 hour post stress event) via mGRs , as serum cortisol levels peak, via inactivation of NMDARs, so that the memory of the stressor can be consolidated  and to allow the VH to continue routing the emotional content of the stressor to the amygdaloid .   

 

 

If chronic stress occurs (very high continued cortisol levels),  the DH LTP no longer becomes constructive, as it continues unabated,  and this results in deleterious neuroplastic changes. See Joels 2008 below.  It seems that the VH must in some way be  involved as well,  because stress resiliency and tolerance to stress from an emotional perspective likewise deteriorates.(see references below)

 

 

This could explain why the chronically stress induced  neuroplastic changes in the hippocampus can be accompanied by reduced ability to cope under stress, emotional liability, and psychological issues. As explained in the previous section, the hippocampal VH is responsible for regulation of stress, and emotional affect,  amongst other functions, and the mechanism by which corticosteroids facilitate this, in a time dependent manner relative to VH neuroplastic changes, is explained by the above.  Voltage gated Calcium channels (VGCCs) seem to play a large role in the VH neuroplasticity response to stress.

 

When stress becomes chronic, as with benzodiazaphine tolerance or withdrawal, this  maladaptive response to chronic stress develops.(see Joels 2008 below).  This falls in line with the quote below implicating VH neuroplasticity in the organization and regulation of the stress response.  When these changes become maladaptive, stress resiliency deteriorates, because LTP in the DH continues unabated, and there’s no opportunity for the VH to route the information through to the amygdala for emotional processing of the stressor.(which would normally occur during LTD of the DH.  But in a maladaptive state, LTD in the DH is insufficient or absent. See below)

 

 

 

 

 

 

 

A.The VH:

 

Quote

 

Specifically, MR has an earlier effect than GR and it could be that in the VH stress mediates a fast enhancement of LTP by MR followed by a second, slow increase in LTP due to GR activation. This proposal is compatible with the proposed role of the VH as a key player in the pathway that conveys stressful information to the hypothalamus and the amygdale so as to organize the stress response (Moser and Moser, 1998; Maggio and Segal, 2010; Segal et al., 2010).

 

 

Following stress, the quick MR-mediated increase in LTP facilitates the flow of the information related to stress from the VH to the ventral hypothalamus and other lower brain centers, so that the autonomic response to stress can be organized. Later on, the MR-mediated response fades away and the effect of GR dominates. As previously mentioned, GR enhancement of VGCC LTP has been shown to have a role in the formation of fear memories in the amygdale (Blair et al., 2001; Bauer et al., 2002).

 

In this respect, GR could play the same function in the VH: the formation of the memory for the stressful event at the VH–amygdala pathway. Indeed, the evidence that MR and GR act on the same mechanism can have different purposes due to the time window of the respective outcomes that take place. Considering this, it could be interesting to study the relationship between the MR and GR responses in the VH.

 

 

End quote

 

 

 

 

 

 

B.The DH:

The last part of this quote is key.

 

Quote

 

In the DH, the reduction of LTP is mediated by GR (Maggio and Segal, 2007b). This effect seems to occur in less than 1 h, a relatively quick response that is unlikely to be mediated by a genomic mechanism. GR could reduce NMDA-mediated LTP either by a direct or an indirect mechanism. As far as it concerns the indirect mechanism hypothesis, we have demonstrated that a GR agonist, dexamethasone, increases IPSCs and mIPSCs amplitude in the DH within 10 min (Maggio and Segal, 2009a, 2012), consistent with the possible activation of mGR. Therefore, the increase in GABAA conductance could hyperpolarize the membrane, thus preventing the cell from reaching the threshold of depolarization that unlocks NMDA receptors from the Mg2+ block (Figure 1B).

 

All in all, our experiments indicate that GR affect LTP through a fast, probably non-genomic mechanism. Even though this hypothesis needs to be explored further, the fast suppression of LTP in the DH can underlie the switch in the weight between the DH and VH; by reducing DH LTP and simultaneously enhancing LTP in the VH, the stressful stimuli could temporarily suppress the cognitive route of the hippocampus to cortical structures and enable the transmission of the emotional information through the VH to the amygdala.

 

End quote

 

 

 

 

 

C.LTD in VH:

 

Regarding plastic LTD changes in the VH, the mMRs appear to facilitate a quick acting suppression of LTD about 1 hour after the onset of stress, similar to the changes in LTP described above.  This suppression of LTD appears to serve as a transition period between LTD decreasing and LTP increasing around the first hour of stress.  This is facilitated by Metabotropic glutamate receptor group 1s, which help facilitate the plastic changes from LTD decrease to LTP increasing in the VH. 

 

The LTP appears to increase when the VGCCs are activated. This facilitates the routing to the amygdale for emotional stress processing.  See figure above.

 

 

Quote

 

Specifically in the latter case, LTD is transformed into a slow-onset LTP following the exposure to stressful stimulation (Maggio and Segal, 2009b).

 

 

The MR-induced conversion of LTD to LTP in the VH could be due to the activation of VGCC, which will further facilitate the ventral route to the amygdale (Figure 1B).

 

In a previous study, we showed that, in the VH, application of DHPG, a group I mGluR agonist, increases the population spike amplitude in response to a baseline stimulation (Maggio and Segal, 2007a). Taken together, these observations suggest that in the VH, a decrease in GABAergic inhibition can shift LTD to a slow-onset LTP through a group I mGluR-mediated mechanism (Figure 1B).

 

End quote

 

 

 

 

D.LTD in DH:

 

In the DH, LTD is primarily facilitated through mGRs, and they increase LTD as the DH enters a decrease in LTP, and memories are consolidated.  This happens quickly pre first hour post stressor.

 

Quote

 

Conversely, LTD induction is facilitated by behavioral stress, through a mechanism that requires GR (Pavlides et al., 1995; Xu et al., 1997, 1998) and their effect on NMDA receptors (Kim et al., 1996; Yang et al., 2005). We replicated previous experiments where both stress and corticosterone facilitate LTD through a GR-dependent mechanism in the DH, but we have also shown that LTD is impaired in the VH through a MR-dependent mechanism (dm123: see above for VH)(Maggio and Segal, 2009b).

 

 

End quote

 

 

 

 

 

 

 

 

 

E.Joels citation

 

Joëls, M. (2008). Functional actions of corticosteroids in the hippocampus. Eur. J. Pharmacol. 583, 312–321.

 

 

Impairment of LTP is important to “give” the other regions of the brain a chance to route the information where they need to.  Unabated LTP is not good.  Balance is the key.

 

 

 

Quote

Corticosteroid hormones are released in high amounts after stress. The hormones enter the brain compartment and bind to high affinity mineralocorticoid receptors –particularly enriched in limbic regions– as well as to lower affinity glucocorticoid receptors which are more ubiquitous.

 

Shortly after the stressful event, corticosteroids (in concert with specific monoamines((dm123: catecholamines) and neuropeptides like CRH) have the potential to increase cellular excitability in subfields of the hippocampus, like the CA1 area. These effects are rapid in onset and occur via a nongenomic pathway.

 

At the same time, however, the hormones also start slower, gene-mediated processes. These cause attenuation of excitatory information flow through the CA1 hippocampal area. Induction of long-term potentiation at that time is impaired.(dm123: this is a good thing after sustained LTP)

 

This may help to normalize hippocampal activity some hours after the stressful event and preserve information encoded within the context of the event. (dm113: i.e., memory consolidation)

 

These adaptational effects of the hormones may become maladaptive if the stressful event is associated with other challenges of the network (like ischemic insults(dm123: i.e. Stroke, etc)) or when stress occurs repetitively, in an uncontrollable and unpredictable manner.(dm123: what I would term “negative  stress” in main section 4 below)

 

In that case,

 

i) normalization (dm123:via modulated or controlled LTP) of activity seems to be less efficient (particularly when other limbic areas like the amygdala nuclei are activated during stress),

 

ii) induction of long-term potentiation is hampered at all times and

 

iii) serotonin responses are attenuated. This may contribute to the precipitation of clinical symptoms in stress-related disorders such as major depression. A better understanding of the corticosteroid actions could lead to a more rational treatment strategy of stress-related disorders.

End quote

 

 

 

 

 

 

 

F.Summary

 

To summarize,

 

Given the above, it’s readily apparent that any pharmaceutical or stressor that distorts normal inhibitory post synaptic current frequencies and/or amplitudes (IPSCs) has the potential to disrupt a normal healthy physiological stress response.  Benzodiazaphines can do this via the GABAaRs, and corticosteroids can do this via MRs and GRs.  Pharmaceuticals that affect VGCCs also have the potential to do this (see the figure above and note that VGCCs affect LTP via mMRs and iGRs).  Metabotropic glutamate receptors and ionotropic glutamate receptors are also involved (NMDARs, see figure above).  Thus the glutamatergic and GABAergic systems are intimately tied together with the stress response system.  There are additional ways that these systems affect one another as well, but these are beyond the scope of this post.

 

Summary of the stress response relative to cortisol levels, receptor type, and brain region:

 

In the VH, initially after a stressor,  mMR activation predominates, resulting in a decrease in inhibitory signaling, a decrease in  LTD which then transitions to an increase in LTP  due to activation of VGCCs (voltage gated Calcium channels). 

 

After this, iGRs are activated as steroid concentrations rise, and LTP continues via VGCC activation. This facilitates emotional routing and regulation of the stress event, as the memory of the event is consolidated in the DH(see next paragraph)

 

Meanwhile, in the DH, mGRs are activated after the stressor,  quickly (Nongenomic), but this starts a bit after the VH mMR  activation above, because mGRs have low affinity for steroids. This mGR activation in the DH increases inhibitory conductance (amplitudes ), preventing the activation of NMDARs. This causes an increase in LTD and a decrease in LTP. This fosters consolidation of the memory of the stress event as the emotional routing by the VH occurs.  If inhibitory signaling is dysregulated, the stressor can’t be emotionally processed and anxiety spikes, as the stressor is perceived as completely overwhelming.  As the stress response system becomes more compromised, stress resiliency drops, and even minor stressors set off anxiety and panic…..

 

It’s important to note that the region specific differences of steroid response of the DH vs the VH are due, in part, to the VH MR density.  The VH has twice as many MRs as GRs, explaining why the early ramp up of cortisol affects VH LTP so dramatically.

 

 

 

 

 

 

[[ih...]]

Wow DM123, i just stumbled on this thread & want to add my appreciation for your sharing of this great body of work.

 

The complexity of the neurophysiology involved explains why such a range of symptoms occur in response to the ingestion of and withdrawal from benzos.

 

My own experience seems to be somewhat of an outlier on the curve of symptoms. From my initial CT from zopiclone, (then knowing nothing about z drugs or benzos), to the setback from Cipro, then a valium taper, i have had the same discrete set of symptoms, namely extreme fatigue & benzo flu. Even in the initial acute phase of z drug withdrawal, although bedridden for the best part of a year, I also had windows when I would be 100% as before.

 

Over the 5 years since last dose, the windows overall, (but not linearly), became more frequent & longer but consistently abrupt as if a switch has been thrown to switch from mode A to mode B.

 

There seems to be a loose correlation between the waves & psychological stress or too much exercise but there have also been periods where I could achieve multi day 200km hikes without consequence.

 

Conversely, one too many deaths of my sister & a close friend appears to have put me into the current wave just before Christmas. In a wave, i can barely stagger to the bathroom, that’s how extreme the switch is.

 

I have been operating on the theory that some stimulation albeit uncomfortable, may help to speed the reinstatement of healthy GABA receptors so have pushed exercise whenever possible & continued with coffee even though it can cause overstimulation.

 

I am extremely grateful for the windows & I know some BBs experience none for a long time. However the extreme shifts in functionality still do my head in & I am wondering if ketamine is worth a try. I am interested to see that you think it may be a plausible mechanism to help restore receptor homeostasis & would like to know if you have any further thoughts on this.

 

To others on this thread who are still tapering, please don’t think that my experience is typical. I am no doubt a hard case & the cold turkey followed by the Cipro no doubt cuased significant CNS shock.

 

Thanks again DM & other contributors.

[[Re...]]

-Are you able to psychologically handle stress?  You mentioned a strenuous bike ride causing relapse in the neuropathic pain.  Was your ability to handle negative stress or was your perception of everyday stressors detrimentally affected during this time shortly after the strenuous bike ride?

 

Hi dm123.

 

I am able to psychologically handle stress to some degree although this was increasingly impaired leading up to my prescriptions last year for effexor (depression/anxiety) and ativan (sleep).  I will say that one of the things that has been quite profound in your papers is the influence of corticosteroids.  I have for many years had cycles of severe eczema.  I have been regularly prescribed and used hydrocortisone ointments over the years.  Moreover, leading up to last year, I was using that ointment daily.  I've had to stop using it as it ramps up my symptoms.  Prior to the benzo exposure, I think the long-term use of hydrocortisone ointment was having a slow but progressively negative influence on my CNS.  Unfortunately, the correlation was not evident to me.  I had no idea that an ointment applied to the skin could make it's way past the BB barrier and influence CNS neuron LTP / LTD.

 

That being said, the anxiety I face from an identifiable source is manageable.  The more difficult form of anxiety is the kind that is a feeling of anxiety that arrives without any apparent stimulus and just exists.  This is the kind that arrived after my bike ride.  No reason, just an onset of anxiety.  I was able to handle it in that I could rationalize there was no actual stressor and that it must have been a function of my psychoactive medication.  Actually, the very first sensations I experienced after the bike ride were those of being almost drunk.  Not in a euphoric way, but in a dizzy and slightly confused way.  Then, about an hour later, spontaneous anxiety set in for a few days and then neuropathic pain increased significantly as well as the regular smorgasbord of other 'withdrawal' symptoms.

 

Unfortunately, each of the times my gabapentin taper has been interrupted by a severe set of symptoms, I've been unable to resume tapering at the same rate thereafter. 

 

At this point, I wonder about the possibility of using a low dose selective nmda or ampa receptor antagonist to help reduce the gabapentin.  That being said, would that just temporarily mask any damage being done by the spikes in Ca+ ions caused by a reduction in gabapentin?  Or, would it possibly interrupt the ability of the Ca+ surge to cause LTP by reducing the role of nmda or ampa receptors in such a process?  Much to consider.  I'm going to keep reading your posts to get a better handle on things.

 

THANK YOU SO MUCH.

 

-RST

 

[[cs...]]

Wow DM123, i just stumbled on this thread & want to add my appreciation for your sharing of this great body of work.

 

The complexity of the neurophysiology involved explains why such a range of symptoms occur in response to the ingestion of and withdrawal from benzos.

 

My own experience seems to be somewhat of an outlier on the curve of symptoms. From my initial CT from zopiclone, (then knowing nothing about z drugs or benzos), to the setback from Cipro, then a valium taper, i have had the same discrete set of symptoms, namely extreme fatigue & benzo flu. Even in the initial acute phase of z drug withdrawal, although bedridden for the best part of a year, I also had windows when I would be 100% as before.

 

Over the 5 years since last dose, the windows overall, (but not linearly), became more frequent & longer but consistently abrupt as if a switch has been thrown to switch from mode A to mode B.

 

There seems to be a loose correlation between the waves & psychological stress or too much exercise but there have also been periods where I could achieve multi day 200km hikes without consequence.

 

Conversely, one too many deaths of my sister & a close friend appears to have put me into the current wave just before Christmas. In a wave, i can barely stagger to the bathroom, that’s how extreme the switch is.

 

I have been operating on the theory that some stimulation albeit uncomfortable, may help to speed the reinstatement of healthy GABA receptors so have pushed exercise whenever possible & continued with coffee even though it can cause overstimulation.

 

I am extremely grateful for the windows & I know some BBs experience none for a long time. However the extreme shifts in functionality still do my head in & I am wondering if ketamine is worth a try. I am interested to see that you think it may be a plausible mechanism to help restore receptor homeostasis & would like to know if you have any further thoughts on this.

 

To others on this thread who are still tapering, please don’t think that my experience is typical. I am no doubt a hard case & the cold turkey followed by the Cipro no doubt cuased significant CNS shock.

 

Thanks again DM & other contributors.

 

Hi I hope,

 

Thanks for your detailed clinical experience.  It's quite revealing, if we take a closer look at your experience.  I'm sure you are more educated on Cirpo's potential adverse effects on inhibitory signaling than most.

 

Moderate Exercise is considered a positive stressor.  In general, positive stressors are

-controllable

-voluntary

-completely predictable,

-not continuous, providing we don't overdo it.

 

There's a lot of material in this thread on the differences between positive stressors and negative stressors.  It's hard to find topics in this thread, as it's not indexed     I want to keep it as a single thread because we are working towards a unified model for benzodiazaphine tolerance and withdrawal,

 

Negative stress has very distinct attributes:

-unpredictable

-constant and unrelenting

-uncontrollable

-involuntarily

 

These two very different types of stressors produce dramatically different physiological responses in the brain and central neurvous system.  This can be seen at the neuron level as well as at the level of neurogenesis, and also at the neuroplastic level.  Cortisol response in these two different types of stressors is distinctly unique.  Negative stress typically results in chronically elevated cortisone levels (prior to hypothalamic "exhaustion" ), and this clearly has detrimental effects on neurogenesis, on neuroplasticity (for example LTP and LTD balance, as well as morphological changes), on the GABAergic system, as well as on the glutamatergic system. Psychosocial stress is a very powerful negative stressor,

 

Positive stressors like moderate exercise promote healthy neurogenesis, and foster optimal GABAergic signaling through a variety of mechanisms.  The Neurogenesis paper above (PART 1) originally was written on the reference below, on exercise and its effects on the GABAergic system, but it ballooned into something much larger as I continued the research.  Here is the citation.  In it, ultimately we see that exercise fosters improved stress resiliency, which I mentioned above in the Neurogenesis paper and RST1 and RST2.  The improved stress resiliency is in large part due to the positive effects that exercise has on inhibitory signaling, and neuroplastic changes as well.

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865561/

 

Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus

J Neurosci. 2013 May 1; 33(18): 7770–7777.

doi:  10.1523/JNEUROSCI.5352-12.2013

PMCID: PMC3865561

Timothy J. Schoenfeld, Pedro Rada, Pedro R. Pieruzzini, Brian Hsueh, and Elizabeth Gould

 

Quote

 

-Running increases the number of new neurons in the dentate gyrus and decreases anxiety-like behavior

-Running prevents stress-induced activation of new neurons in the ventral dentate gyrus

-Running prevents stress-induced activation of hippocampal granule cells and pyramidal cells

-Running enhances stress-induced activation of inhibitory interneurons and GABA release

End quote

 

 

In earlier posts, I discussed an "enriched environment ", as it is referred to in the clinical research.  This involves spacious living arrangements, learning and spatial naviagation tasking, amicable social interaction, and of course exercise.

 

Some of the stressors that you mention above, like deaths of loved ones are clearly negative stressors.    200km multiday hike, although physically very strenuous, does not necessarily have to be a negative stressor, especially if it's perceived as enjoyable.  If physical stamina has acclimated to that type of stress level, and you are recovered, it shouldn't be an issue.

 

 

-----------------

Regarding ketamine, I have researched this, but not enough.  I did post the below in October in this very thread.  I hope it helps you.  If you do decide to try this therapy please seek a knowledgeable MD, and preferably do it in a hospital setting.  The article below refers to neuroplasticity, and we also know that chronically high levels of cortisol are detrimental to healthy neurogenesis as well.

 

From the article below, anecdotally ketamine appears to affect neuroplasticity, i.e. The dendrites morphological changes mentioned in the article below  I hope this helps..,,,

 

October post

 

 

Very very interesting post on ketamine IV infusions. 

 

Please read the article below in its entirety ; it's one woman's fascinating  jouney into the effects of PTSD on the glutamatergic system and thus neuroplastic changes in the brain,  and how she rectified it through ketamine infusions.

 

https://vanwinkles.com/ketamine-treatment-chronic-insomnia-trauma-therapy-celia-farber

 

 

Her viewpoint is from PTSD, but the pathway to the neuroplastic changes that occurred , as she admits, were through the stress system, ultimately.  Whether or not it's benzodiazaphines, stress or PTSD that created the neuroplastic changes really doesn't matter.  As the article states, ketamine doesn't care about the origin.  Some quotes are below.  Please read the whole article

 

 

Quote

 

As Dr. Brooks explained it, the brain can heal — the word is “neuro-plasticity.” He told me to imagine our brain’s dendritic system, at birth, as a forest with lush trees. This forest allows all the parts of the brain to communicate; it produces stable moods as well as joy, hope, inspiration and aspiration. Trauma releases cortisol, which begins to strip the dendrites of their foliage.

 

“Somebody like you,” he said, “with a lot of early childhood trauma, has no trees.”

 

“What do I have?” I asked.

 

“Nothing but stubs.”

 

Ketamine causes the dendrites to grow back and flourish again. Some patients experience relief within just a few hours of their first treatment. For my part, the day after my first ketamine treatment, I woke up, made coffee and looked around. Something was different. Something was missing. I was lighter. I’d shrugged of the bodysuit of psychic quicksand I’d been carrying for so long.

 

The change was subtle and also dramatic. I felt normal. The fear was gone. And because I felt normal, I soon felt elated. That feeling of being frozen was over.

 

Two days later, I went back for another session. And then I went back for another.

 

In each session, waves of blocked pain were dislodged and dealt with. Once, it was my mother. Then, my father. I often emerged with tears streaming down my face (in a good way). Once, I called my father right from the chair and tried to explain the epiphany I’d had. “There was never anything wrong,” I said through the tears.

 

Clinically speaking, my breakdowns and epiphanies were of no interest to Dr. Brooks. “That’s fine,” he said after one session, “but it’s not what ketamine is about.” It works no matter what you experience, he explained. The healing that follows occurs independently on the patient’s emotional experience.

 

In the days to follow, the changes continued. Dramatic changes. I wanted to do things. I was suddenly going to parties and poetry readings, talking to people, reconnecting with my fellow writers. Once again, finally, I felt part of life.

 

Hearing this, Dr. Brooks said, “I wish you and I had found each other sooner.”

 

With that, he turned off the light. Sixty seconds later, the ketamine took hold, sending me back to that faraway world that allowed me, mysteriously, maybe even miraculously, to come back to this, the real world — once so crippling and cruel.

 

I sleep just fine now, with no chemicals, and every day is a shimmering gift.

 

End quote

 

 

[[ih...]]

Thanks for your considered response.  The last week has unfortunately included a lot of uncontrollable negative stress & I really look forward to being less sensitised to it.

 

The article you cited about ketamine is promising but I know full well not to expect miracles for our busted brains. At least a partial reset would be welcome & if I proceed, it will be with a reputablle clinic.

 

Thanks again for your time in responding to os all.

[[cs...]]

Thanks for your considered response.  The last week has unfortunately included a lot of uncontrollable negative stress & I really look forward to being less sensitised to it.

 

The article you cited about ketamine is promising but I know full well not to expect miracles for our busted brains. At least a partial reset would be welcome & if I proceed, it will be with a reputablle clinic.

 

Thanks again for your time in responding to os all.

 

I just read your signature.  The good part about all of this is that it's due to negative stress, and it's reversible and recoverable,,,,

[[ih...]]

I mostly know that iwill recover. I think that I am just exhausted for now. It would be great if we could just pause the rest of life momentarily while we heal.

[[cs...]]

-Are you able to psychologically handle stress?  You mentioned a strenuous bike ride causing relapse in the neuropathic pain.  Was your ability to handle negative stress or was your perception of everyday stressors detrimentally affected during this time shortly after the strenuous bike ride?

 

Hi dm123.

 

I am able to psychologically handle stress to some degree although this was increasingly impaired leading up to my prescriptions last year for effexor (depression/anxiety) and ativan (sleep).  I will say that one of the things that has been quite profound in your papers is the influence of corticosteroids.  I have for many years had cycles of severe eczema.  I have been regularly prescribed and used hydrocortisone ointments over the years.  Moreover, leading up to last year, I was using that ointment daily.  I've had to stop using it as it ramps up my symptoms.  Prior to the benzo exposure, I think the long-term use of hydrocortisone ointment was having a slow but progressively negative influence on my CNS.  Unfortunately, the correlation was not evident to me.  I had no idea that an ointment applied to the skin could make it's way past the BB barrier and influence CNS neuron LTP / LTD.

 

That being said, the anxiety I face from an identifiable source is manageable.  The more difficult form of anxiety is the kind that is a feeling of anxiety that arrives without any apparent stimulus and just exists.  This is the kind that arrived after my bike ride.  No reason, just an onset of anxiety.  I was able to handle it in that I could rationalize there was no actual stressor and that it must have been a function of my psychoactive medication.  Actually, the very first sensations I experienced after the bike ride were those of being almost drunk.  Not in a euphoric way, but in a dizzy and slightly confused way.  Then, about an hour later, spontaneous anxiety set in for a few days and then neuropathic pain increased significantly as well as the regular smorgasbord of other 'withdrawal' symptoms.

 

Unfortunately, each of the times my gabapentin taper has been interrupted by a severe set of symptoms, I've been unable to resume tapering at the same rate thereafter. 

 

At this point, I wonder about the possibility of using a low dose selective nmda or ampa receptor antagonist to help reduce the gabapentin.  That being said, would that just temporarily mask any damage being done by the spikes in Ca+ ions caused by a reduction in gabapentin?  Or, would it possibly interrupt the ability of the Ca+ surge to cause LTP by reducing the role of nmda or ampa receptors in such a process?  Much to consider.  I'm going to keep reading your posts to get a better handle on things.

 

THANK YOU SO MUCH.

 

-RST

 

I agree, stress  and cortisol are critical.  As we've seen , cortisol in excess can disrupt LTP/LTD balance (neuroplastic) as well as slow the healthy rate of neurogenesis if it's chronically elevated.  Negative stress induces chronic elevations.  I'm not sure how much hydrocortisone is absorbed systemically through the skin.

 

It's ironic that you ask about NMDAR and/or AMPAR antagonists,  I just posted a bit on ketamine to ihope.  I haven't had a chance to research ketamine in depth to answer your question, but I hope the link above helps.  Ketamine appears to affect neuroplasticity .  The article above is not a clinical citation, but anecdotally it's implying stress related changes can be reverted via ketamine infusions that supposedly foster healthy dendritic neuroplastic changes.,,,,,  It can at least get us in the right direction in terms of research.    Please seek a knowledgeable MD, and do in a hospital setting if you are considering this approach.

 

I've researched it in the context of CRPS(or reflex sympathetic dystrophy), and it appears to help in some of those cases.  You don't have CRPS, but CRPS has neuropathic pain as one of its symptoms,(you don't fit the full criteria for CRPS).