Molecules to Mental States: Psychological Stress and Cell Death

in #neuroscience7 years ago (edited)

Molecular Mechanisms that Underlie Psychological Stress

This post builds off my previous posts: Is Your Brain Too Excited?! Neurodegeneration By Over-Stimulation, and Neural Plasticity: Shaping How We View Ourselves. I will attempt to illustrate the balance that our biology manages between its capacity to learn and adapt and its resilience to deleterious phenomena. One concept that serves as an important on-ramp to this topic is the ‘Critical Period,’ which I describe in my post Manipulating Memories: Instantly Eliminate a Fear as the early stage in life “when our neurons can rapidly change by forming new connections and 'pruning' others through elevated neural plasticity.” This is responsible for children being able to acquire a new language, concept, or skill faster than an adult, but as I will explain in this article leaves them more susceptible to some forms of neuronal damage.


Cognitive Stress and Cell Death

Fear and anxiety functions have been passed down as favorable, survival promoting traits that help us sense and avoid danger. Although the environments that humans live in today are vastly divergent from those of our early ancestors, our genes are mostly conserved. While anxiety in the past might have helped someone prepare for a bear attack or battle with a rival tribe, today we usually experience anxiety in non-life-threatening situations. Perhaps because the threshold for scenarios to be anxiety inducing has significantly decreased over centuries, experiencing excessive anxiety has become increasingly common. Excessive anxiety response can lead to anxiety disorders, which have become the most common mental disorders within developed societies and cost the U.S. more than $42 Billion annually (Somers et al., 2006).

Understanding the underlying mechanisms and associated genes for anxiety is crucial to developing treatments and diagnostic tools. Extensive research has granted us insight into some of the biological and psychological components of fear and anxiety. The cholinergic and glutamatergic systems within the thalamus and pre-frontal cortex have been identified as key regions in the human brain that contribute to the processing of fear and anxiety related information (Davis, 2011; Tekinay et al., 2009; Yamamoto, 2008). These regions are highly conserved among different species, and are similarly involved in anxiety-like processing in mice (an animal with ~90% similar DNA). Utilizing these properties, we can make inferences based on tests conducted on mice to help build a better understanding of how anxiety is processed in humans.


LYNX2 Mediated Anxiety and Neuroprotection

Tekinay et al. (2009) used the mouse model to study the role of the protein LYNX2 (controlled by the Lynx 2 gene) in fear and anxiety like behavior. LYNX2 has been identified as a member of the Ly-6 prototoxin superfamily that has been shown to bind to and modulate nicotinic acetylcholine receptor (nAChR) function (Miwa et al., 1999; Miwa et al., 2006). These receptors are highly expressed in the central nervous system and have been shown to be involved in fear learning (Kutlu et al., 2016). Tekinay et al. (2009) compared Lynx 2 knock out (KO) mice to Wild Type (WT) mice in a fear conditioning task; a fear conditioning experiment involves pairing a neutral stimulus such as a tone to an adverse stimulus such as an electric shock. In mice, freezing behavior is expressed when afraid or anxious. By presenting the two stimuli together, a mouse will eventually exhibit freezing behavior when only presented by the previously neutral tone. The investigators showed that Lynx 2 KO mice exhibit increased associative fear learning and increased anxiety and fear like behavior; this result identified LYNX 2 as an anxiety limiting protein. Further, they found that administration of nicotine to the medial-dorsal thalamus (MDT) neurons evoked increased Layer V medial prefrontal cortex (mPFC) glutamatergic activity indicated by higher amounts of intracellular calcium. 

LYNX protein with 3 zinc finger motif (From Lyukmanova et al., 2011)  

Calcium (Ca2+) is a secondary messenger in neurons which is crucial to normal functioning. High intracellular levels of Ca2+ are associated with a plethora of signaling cascades, notably, many of which lead to cell death (Kang, B. N. et al, 2010). High intracellular levels of Ca2+ that accumulate, from overstimulation by glutamate specifically, trigger cell death processes. This form of degeneration is called excitotoxicity. For these reasons we suspect that Lynx 2 could play a neuroprotective role against excitotoxicity by mediating mPFC activity.

Excitotoxicity is characterized by cytoplasmic vacuole formation causing acute swelling of the cells which leads to cell death. In my last post, Is Your Brain Too Excited?! Neurodegeneration By Over-Stimulation, I stated that as well as neurological disorders such as Alzheimer's, Parkinson's, or Huntington's, excitotoxity is implicated in “stroke, TBI (traumatic brain injury), alcohol or benzodiazepine withdrawal, hypoglycemia (a future article to look out for), and hearing loss.”

(from a presentation given to me by Adem Idrizi and Itzhak Mano at The CUNY School of Medicine)

Another piece of evidence that would suggest that Lynx 2 has neuroprotective properties is that the closely related Lynx 1 gene has been shown to have an important role in mediating cholinergic function to balance cell survival. Mice lacking Lynx 1 showed clear vacuolating degeneration from hyper-activity (Miwa et al., 2006). Since mice who lack the gene show degeneration, we would say that the gene and subsequent protein are neuroprotective. While the link between Lynx 1 and excitotoxic degeneration has been studied, Lynx 2 has yet to be investigated in any cell death processes. There is reason to believe that Lynx 2 could mitigate excitotoxicity, as it has been shown in previous reports to reduce glutamatergic activity in the mPFC via cholinergic modulation of MDT cells via binding to nAChRs.


TL;DR?

LYNX, through binding to nAChRs, reduces neuronal sensitivity to agonists (like nicotine) and enhance desensitization kinetics. This in turn reduces intracellular calcium levels, which lowers the spontaneous excitatory activity of the cell. This protects the cell from excitotoxicity, and has been shown through behavioral experiments to reduce fear and anxiety-like tendencies in mice. This allosteric modulator thereby plays a role to mediate the molecular balance for optimal plasticity and cell survival; it connects psychological phenomena to genetic and molecular mechanisms to help us better understand how cognitive stress can influence the health of our brains.

Thank you for reading! Be sure to post any comments, questions, or thoughts in the discussion below. I became aware of the Lynx genes in my "molecular neuroscience lab" at Lehigh University with Julie Miwa who is responsible for a bulk of our understanding of these regulatory proteins.


Recent Articles:

References:

  • Chou, J. H., Bargmann, C. I., & Sengupta, P. (2001). The Caenorhabditis elegans odr-2 gene encodes a novel Ly-6related protein required for olfaction. Genetics, 157(1), 211-224.
  • Danbolt, N. C. (2001). Glutamate uptake. Progress in neurobiology, 65(1), 1-105.
  • Davis, Michael (2002). Neuropsychopharmacology: the fifth generation of progress: an official publication of the American College of Neuropsychopharmacology, 931-951.
  • Davis, Michael (2011). "NMDA receptors and fear extinction: implications for cognitive behavioral therapy." Dialogues Clinical Neuroscience 13.4: 463-74.
  • Del Rosario, J. S., Feldmann, K. G., Ahmed, T., Amjad, U., Ko, B., An, J., ... & Mano, I. (2015). Death Associated Protein Kinase (DAPK)-mediated neurodegenerative mechanisms in nematode excitotoxicity. BMC neuroscience, 16(1), 25.
  • Dembrow, N. C., Chitwood, R. A., & Johnston, D. (2010). Projection-specific neuromodulation of medial prefrontal cortex neurons. Journal of Neuroscience, 30(50), 16922-16937.
  • Dessaud, E., Salaün, D., Gayet, O., & Chabbert, M. (2006). Identification of lynx2, a novel member of the ly6/neurotoxin superfamily, expressed in neuronal subpopulations during mouse development. Molecular and Cellular Neuroscience, 31(2), 232-242. 
  • Falls, W. A., Miserendino, M. J., & Davis, M. (1992). Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. Journal of Neuroscience, 12(3), 854-863.
  • Giocomo, L. M., & Hasselmo, M. E. (2007). Neuromodulation by glutamate and acetylcholine can change circuit dynamics by regulating the relative influence of afferent input and excitatory feedback. Molecular Neurobiology, 36(2), 184-200.
  • Kang, B. N., Ahmad, A. S., Saleem, S., Patterson, R. L., Hester, L., Doré, S., & Snyder, S. H. (2010). Death associated protein kinase-mediated cell death modulated by interaction with DANGER. Journal of Neuroscience, 30(1), 93-98.
  • Kutlu, M. G., Holliday, E., & Gould, T. J. (2016). High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction. Neurobiology of learning and memory, 128, 17-22.
  • Miwa, J. M., Freedman, R., & Lester, H. A. (2011). Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron, 70(1), 20-33.
  • Miwa, J. M., Iban̆ez-Tallon, I., Crabtree, G. W., Sánchez, R., S̆ali, A., Role, L. W., & Heintz, N. (1999). lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron, 23(1), 105-114.
  • Miwa, J. M., Stevens, T. R., King, S. L., Caldarone, B. J., Ibanez-Tallon, I., Xiao, C., ... & Heintz, N. (2006). The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron, 51(5), 587-600.
  • Miwa, J. M., Lester, H. A., & Walz, A. (2012). Optimizing cholinergic tone through lynx modulators of nicotinic receptors: implications for plasticity and nicotine addiction. Physiology, 27(4), 187-199.
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  • Tekinay, A. B., Nong, Y., Miwa, J. M., Lieberam, I., Ibanez-Tallon, I., Greengard, P., & Heintz, N. (2009). A role for LYNX2 in anxiety-related behavior. Proceedings of the National Academy of Sciences, 106(11), 4477-4482.
  • Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S. (2008). Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology, 33(9), 2108-2116.
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Very indepth description ! Thanks for the TL;DR tho

Thank you for the support :)

I enjoy the scientific details and credibility of your posts. In my experience with GAD, the treatments with the best efficacy are GABA receptor agonists and CB receptor agonists. SSRI's, SNRI's, buspirone never helped. I hope a CRF inhibitor can be discovered.

OK, so this is a pretty interesting piece. Thanks for sharing it. I like your intro to excitotoxic pathways and how they contribute to cell death. It's a critical pathway to know about and it plays a role in many pathologies, as you included.

I want to share with you a caution I've learned going from a basic science lab into drug development and clinical practice. Basic science is inherently reductionist in nature. We try to distill a process down to one protein, one gene, one root cause. While you may see an effect in a KO mouse its translatability to humans and to clinical medicine MAY not pan out. Mother nature is one smart complex lady. We all know that a mechanism may make sense or work in a lower mammalian model but when tried in humans it doesn't work or cause harm. I caution anyone that anyone hangs their hat on one protein or gene to fix a neurologic problem, unless it's a problem having to do with a miscoded protein/lack there of and you are using a gene therapy to replace that missing gene.

This is the challenge of neuroscience and therapeutics. We still don't fully understand how the brain works. We are trying to solve a puzzle that we don't even have all the pieces to yet. It's exhilarating and frustrating. You talk a lot about memory, LTP and LTD, but what physically, in the brain, is a memory. It's a philosophical question because no one really has a definitive answer (I have my own thoughts on this).

At the end of the day modulating Lynx 2 MAY be of benefit. I'd bet it helps people who are lacking it or have lower levels to tolerate normal stresses. Do I think that upregulating it will prevent cell death in a stroke? Doubtful

Again, thanks for sharing this. I just caution anyone from hanging their hat on any one mechanism as the therapy to fix everyone with a particular disease. It can work in some cases, but not in most.

Be inquisitive, skeptical and always curious

Yes, I too share such a caution. I certainly do not intend to suggest that Lynx 2 could be fully responsible for the grand sum of cell death and plasticity, but rather I wanted to show how a single gene and its protein can have behavioral and cognitive implications.

This modulator is a particularly good example in my opinion, as it is:

  • Up regulated during the critical period
  • Causes the physiology of MDT cells which project to the mPFC to exhibit kinetics which reduce LTP downstream
  • Deletion causes excitotoxicity in the mPFC cells after nicotine infusion to MDT projections
  • And it is conserved well across rodents and humans

Also, they are doing some human assessments for certain things which I am not at liberty to disclose as they are yet to be published.

Exciting! do let us know when they are published. apoptosis is a fascinating topic. What's your next article going to be on?

Not sure yet, but I plan to write one tomorrow when I have a free moment!

Hey all. I started taking proposals for topics people are interested in. See the post for what topics I can explain off the cuff. More in-depth ones will take longer but I look forward to interacting.

https://steemit.com/health/@toxdocx/community-interest

"Although the environments that humans live in today are vastly divergent from those of our early ancestors, our genes are mostly conserved."

Such a great point. We are still adapting to an increasingly and rapidly changing world. If I'm understanding your point here...our genetics have yet to "catch up" to the new stressors we face today.

This reminds me of Robert Sapolsky's description of the changing nature of stress. We've gone from living in a world of acute short-term stress related to real physical dangers...and into a world of long-term periods of stress that are (mostly) psychological/imaginary in nature.

"Perhaps because the threshold for scenarios to be anxiety inducing has significantly decreased over centuries, experiencing excessive anxiety has become increasingly common."

This is something I hadn't considered, and it makes total sense. We are more easily triggered into an anxious (fight-or-flight) state than before.

Do you think this has mostly do with the new environment we find ourselves in (work, traffic, Internet, etc.) or has something changed in the way we psychologically respond to stress...or perhaps both?

Thanks for the great response!

Yes, that was the point I was trying to convey; we are living in a modern world with somewhat primitive brains, designed to navigate environments that are quite distinct from the cities and societies we live in.

Its hard to completely tease these things apart, but it does seem clear that our ancestors never experienced the stress-inducing stimuli that many of us face everyday. I am usually one to be sympathetic to the "a little bit of both" argument. With all of these novel stimuli comes novel adaptation and psychological conceptualization!

Be sure to check out the posts that this one builds on if your interested in delving further into this line of thought!
Is Your Brain Too Excited?! Neurodegeneration By Over-Stimulation
Manipulating Memories: Instantly Eliminate a Fear

Thanks for the info. I'll check out the posts you linked to.

Thank you for the post.
I like these type of in-depth posts that force my brain to fire all cylinders.
I don't understand all of it but most of it.
Great job.

Glad that it was a stimulating read! Many of my other posts are less technical, are require little to no previous knowledge. I suggest that you check out the first posts that this one builds off of:
Is Your Brain Too Excited?! Neurodegeneration By Over-Stimulation
Manipulating Memories: Instantly Eliminate a Fear

Thanks for the support!!!

Excellent because my brain still hurts, I think I pulled a muscle.

In a sense, cell death is a good thing, it's called Autophagy.

If autophagy doesn't occur frequently and properly you'll get cancer. 

There's a bunch of different fancy biohacks, technologies and supplements for autophagy but one of the simplest and most effect ways is habituating fasting, there's two fasting strategies

Intermittent fasting - Spending 16 hours a day NOT eating.

2-3 day fasts - Start at lunch, the 1st day is the hardest

This interview goes deeper

ngans - another interesting and well-informed piece. I am able to make practical clinical connections (to be applied in my psychotherapy practice) as a result to reading this and other ngans posts. Very interesting to see the biological and adaptive roots of disorders that plague so many people. Thank you for writing these articles, ngans.

Thanks! Glad you enjoyed this one!

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Another fantastic piece @ngans...
My question is, is this anxiety in a way associated with the adrenaline that sets off the fight or flight response centres in the brain?

Thanks!

They are certainly related. In this article, I do not get into hormonal systems, but there are certainly some interesting connections!

You got a 6.56% upvote from @postpromoter courtesy of @ngans!

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