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UKnowledge > College of Medicine > Pharmacology and Nutritional Sciences > JPNS > Vol. 2 (2024) > Iss. 1

 

Abstract

Brain aging (BA) processes are complex, often affect multiple systems, and frequently lead to cognitive decline and increased susceptibility to insults. BA appears to be a primary risk for the development of many prominent neurodegenerative pathologies. The US Census Bureau predicts that the aging population (65+) will represent a greater proportion of the US population than children (under 18) by 2034, dramatically increasing the burden on health-care infrastructure.17 Several mechanisms of stress driven, aging-related neurologic dysfunction have been advanced in the past 50 years and include: Stress hormone exposure and glucocorticoid cascade;7, 16 calcium ion dyshomeostasis;8 allostatic load;10 and neuroinflammation.14 Taken together, these data suggest that many aspects of BA are accelerated, or even recapitulated, by stress. Here, the hippocampus (HIP) is an appropriate model structure based on its well-established role in cognition and memory, its manifestation of aging and stress-driven changes in gray (GM) and white matter (WM) transcriptional profiles, and its vulnerability to neurodegeneration; further, the HIP is a major target for stress hormones. It is well-recognized that stress’ influence on the limbic system is long-lasting. This may be due to its subcortical localization, evolutionarily conserved pathways, and potentially novel entrainment mechanism compared to the highly plastic neocortical memory processes ordinarily associated with cognition. Despite years of research clearly establishing a link between stress exposure and BA, no interventions targeting this interaction have been approved. We hypothesize that healthy BA and successful resilience to chronic stress would be indicated by improved hippocampal dependent, cognition, reduced stress-behavior, and reduced inflammatory transcriptional signatures; and not merely the persistence of youthful brain dynamics. Taken together, we refer to this constellation of beneficial responses in the aged and/or stressed subject as adaptive remodeling.

Psilocin (PSI), the active metabolite of psilocybin, has agonist or partial agonist activity at serotonin [5-Hydroxtryptamine (5-HT)] receptors, including the G-protein coupled receptor subtypes: 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C; functional interactions with central dopaminergic systems have also been demonstrated.12 Despite PSI’s known role in 5-HT and dopaminergic signaling, other agents engaging with these systems do not appear to exert similar effects; moreover, it is not clear to what extent PSI engages other glial and neuronal monoaminergic (e.g., serotonin, dopamine, epinephrine, and norepinephrine) systems. PSI has shown strong benefits in human studies and has twice been designated by the FDA as breakthrough therapy; first in 2018 for treatment resistant depression, and again in 2019 for major depressive disorder. Despite substantial interest in the therapeutic potential of PSI, little is known about the mechanisms through which it exerts its effects. An exhaustive search on the Gene Expression Omnibus revealed a single study using transcriptional profiling in ‘brain’ in conjunction with ‘PSI’ treatment (Donovan et al., 2021; GSE 172074). Our lab analyzed raw RNAseq data from this study and identified genes associated with myelin sheath, synapse, and neuron, among others, to be significantly down regulated (p < 0.001) one week after treatment in pig prefrontal cortex.

We propose a multi-level study in balanced groups of young and aged, male and female, Fischer 344 rats to investigate PSI’s effects on stress-accelerated BA. In Aim 1, using an ex-vivo hippocampal slice preparation, we will study the acute effects of PSI treatment on HIP. This model will be used to establish PSI concentration-effect relationships, identify responding HIP cell-types using immunohistochemistry or in situ hybridization, as well as to investigate, using RNA-seq, transcriptional profiles from laser capture microdissected hippocampal GM vs WM. Using this nonbiased approach to look at sub-region-specific profiles, will help establish a more complete account of PSI’s mechanism of action. In this prep, we will also measure PSI’s influence on basic electrophysiology properties like synaptic strength, conduction velocity and after-hyperpolarizing potential. PSI’s chronic effect on HIP-dependent cognitive behavior has also not been fully elucidated in prior studies. We will address this gap in Aim 2 of our study by using the Morris water maze test after 12-week chronic restraint [3hrs/day, 4days/week, using disposable DecapiCone restraint (or 3D printed ‘Restraint Device’ if approved)]. In human trials,1, 3, 5, 15 PSI has been used as an adjunct to guided psychotherapy (PT). To date, there are no recognized animal models of PT; though, enriched environments such as, social interaction, have been shown to be beneficial in animal models of neurodegenerative disease.9 We will attempt to mimic PT in our animal model with enriched group housing vs single housing. Regardless of whether results support our hypothesis, the significance of this project derives from its potential both for elucidating basic mechanisms of interactions between stress and BA, and for suggesting new therapeutic approaches to major health-related problems that widely affect the elderly.

References

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  17. United States Census Bureau. (2018). An Aging Nation. https://www.census.gov/content/dam/Census/library/visualizations/2018/comm/pop-projections-1.jpg.

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