Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex

Abstract

Background: Neuromorphological changes are consistently reported in the prefrontal cortex (PFC) of patients with stress-related disorders and in rodent stress models, but the effects of stress on astrocyte morphology and potential link to behavioral deficits are relatively unknown. Methods: To answer these questions, transgenic mice expressing green fluorescent protein (GFP) under the glial fibrillary acid protein (GFAP) promotor were subjected to 7, 21 or 35 days of chronic restraint stress (CRS). CRS behavioral effects on anhedonia- and anxiety-like behaviours were measured using the sucrose intake and the PhenoTyper tests, respectively. PFC GFP+ or GFAP+ cells morphology was assessed using Sholl analysis and associations with behavior were determined using correlation analysis. Results: CRS-exposed mice displayed anxiety-like behavior at 7, 21 and 35 days and anhedonia-like behavior at 35 days. Analysis of GFAP+ cell morphology revealed significant atrophy of distal processes following 21 and 35 days of CRS. CRS induced similar decreases in intersections at distal radii for GFP+ cells, accompanied by increased proximal processes. Additionally, the number of intersections at the most distal radius step significantly correlated with time spent in the shelter zone in the PhenoTyper test (r=-0.581, p<0.01) for GFP+ cells and with behavioural emotionality calculated by z-scoring all behavioral measured deficits, for both GFAP+ and GFP+ cells (r=-0.400, p<0.05; r=-0.399, p<0.05). Conclusion: Chronic stress exposure induces a progressive atrophy of cortical astroglial cells, potentially contributing to maladaptive neuroplastic changes associated with stress-related disorders.

Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation

“…Other tests measuring anxiety and anhedonia exist however most cannot be repeated hindering longitudinal analysis (Nollet et al, 2013; Planchez et al, 2019). Secondly, in our attempt to avoid ceiling effects of CRS and detect susceptibility, we used a less severe protocol for a shorter duration than our previous studies (Codeluppi et al, 2021; Misquitta et al, 2021; Prevot et al, 2019). It is possible that a longer CRS protocol is needed to observe greater susceptibility associated with cHOA.…”

“…In previous studies, we identified that CRS-exposed and control animals spend equivalent amounts of time avoiding the food zone in favor of the shelter during the spotlight challenge. However, CRS animals subjected to chronic stress continue to avoid the food zone after the challenge (Codeluppi et al, 2021; Misquitta et al, 2021; Prevot et al, 2019). This is a behavior, is highly specific of chronic stress exposure, defined as “residual avoidance” (RA).…”

“…The next day, bottles were placed back on the cages at 10am, and sucrose consumption was measured for a 1-hour period. Bottles with no sucrose are then given to the mice and the same procedure (fluid deprivation and 1h test) is performed the next day with water to control for fluid intake (Codeluppi et al, 2021; Duric et al, 2017; Misquitta et al, 2021). Sucrose preference is calculated as percent of the ratio of sucrose consumption over total fluid consumption of the two 1hr-test.…”

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

“…Chronic stress-induced elevated or sustained Glu levels causes excitotoxic effects via enhanced extrasynaptic signaling activity (Hardingham and Bading, 2010;Popoli et al, 2011;Pál, 2018). These alterations were linked to maladaptive changes to the structure and function of neurons (Musazzi et al, 2015;Lener et al, 2017) and glial cells (Banasr et al, 2010;Sanacora and Banasr, 2013;Mayegowda and Thomas, 2019;Codeluppi et al, 2021). Homeostatic glial cells such as astrocytes play a pivotal role in regulating stress-induced glutamatergic dysfunction (Popoli et al, 2011;Rajkowska and Stockmeier, 2013;Sanacora and Banasr, 2013;Abbink et al, 2019) as are accountable for over 80% of Glu reuptake, Glu synthesis and metabolism (Chen et al, 2014;Baek et al, 2019;Fullana et al, 2020).…”

“…Elevated or sustained Glu levels induced by chronic stress can causes excitotoxic effects via enhanced extrasynaptic signaling activity [48, 51, 52]. These alterations have been linked to maladaptive changes in the structure and function of neurons [53, 54] and glial cells [55–58]. Glial cells such as astrocytes play a pivotal role in the homeostatic response to the stress-induced increases in glutamatergic neurotransmission [48, 57, 59, 60] as they are responsible for over 80% of Glu reuptake, Glu synthesis and metabolism [61–63].…”