Stress-induced neuronal hypertrophy decreases the intrinsic excitability in stress habituation

Abstract

We thank all members of Inoue lab for thoughtful inputs to the project. We are grateful to Ms. Irma Meteluch for her help with animal husbandry. We also thank Dr. Jaideep Bains (University of Calgary) for his constructive comments on early versions of the manuscript. Abstract:A rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark stress response to an imminent threat, but its chronic activation can be detrimental. Thus, the long-term survival of animals requires experience-dependent fine-tuning of the stress response. However, the cellular mechanisms underlying the ability to decrease the stress responsiveness of the HPA axis remain largely unsolved. Using a stress habituation model in male mice and slice patchclamp electrophysiology, we studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis. We found that the intrinsic excitability of these neurons substantially decreased after daily repeated restraint stress in a time course that coincided with their loss of stress responsiveness in vivo. This plasticity of intrinsic excitability co-developed with an expansion of surface membrane area, resulting in an increase in input conductance with minimal changes in conductance density. Moreover, multi-photon and electron microcopy data found that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that efficiently accommodates membrane area expansion with proportionally less expansion of gross cell volume. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response. Significance statement:The long-term survival of animals requires experience-dependent fine-tuning of stress response. Using a mouse model of repeated stress that develops habituation of the hypothalamic-pituitaryadrenal (HPA) axis, our study demonstrates a robust decrease in the intrinsic excitability of the output neuroendocrine neurons of the HPA axis. Mechanistically, we show that repeated stress increases the cell size of these neurons (i.e. surface membrane area). This cell-size change increases input conductance, and hence decreases excitability. Our findings challenge a conventional view that plasticity of intrinsic excitability relies on changes on membrane excitability resulting from up-and down-regulation of various voltage-gated ion channels. Our study reports a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.

Repeated exposure to multiple concurrent stressors alters visual processing in the adult posterior parietal cortex

“…The mature, adult circuitry may be more robust against stress-induced remodeling of synaptic connections in part due to the ability to habituate to repeated exposure to stressors. Such attenuation was noted across a multitude of chronic stress paradigms, including restraint ( Girotti et al, 2006 ; Grissom et al, 2007 ; Gray et al, 2010 ; Duarte et al, 2015 ; Matovic et al, 2019 ), social defeat stress ( Snyder et al, 2015 ), and audiogenic stress ( Armario et al, 1984 ; Campeau et al, 2002 ). Regularity of exposure and stress intensity are thought to be the key factors determining the activation of the HPA-axis in chronically stressed animals ( Martf and Armario, 1997 ; Grissom and Bhatnagar, 2009 ).…”