Molecules to Mental States: Psychological Stress and Cell Death

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.

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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.

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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.

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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.

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Recent Articles:

• Is Your Brain Too Excited?! Neurodegeneration By Over-Stimulation
• Manipulating Memories: Instantly Eliminate a Fear
• GMOs: Addressing Environmental and Health Concerns
• Neural Plasticity: Shaping How We View Ourselves
• PTSD: The Psychology and Neurology of Trauma and Psychedelic Treatments

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.
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• 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.
• Somers J. M., Goldner E. M., Waraich P., Hsu L. (2006). "Prevalence and incidence studies of anxiety disorders: a systematic review of the literature". Can J Psychiatry. 51 (2): 100–13.
• Swanson, C. J., Bures, M., Johnson, M. P., Linden, A. M., Monn, J. A., & Schoepp, D. D. (2005). Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nature Reviews Drug Discovery, 4(2), 131-144.
• 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.