Chronic Stress-induced Behaviors Correlate with Exacerbated Acute Stress-induced Cingulate Cortex and Ventral Hippocampus Activation

Abstract

Altered activity of corticolimbic brain regions is a hallmark of stress-related illnesses, including mood disorders, neurodegenerative diseases, and substance abuse disorders. Acute stress adaptively recruits brain region-specific functions for coping, while sustained activation under chronic stress may overwhelm feedback mechanisms and lead to pathological cellular and behavioral responses. The neural mechanisms underlying dysregulated stress response and how they contribute to behavioral deficits are poorly characterized. Here, we tested whether prior exposure to chronic restraint stress (CRS) or unpredictable chronic mild stress (UCMS) in mice could alter neuronal response to acute stress and whether these changes are associated with chronic stress-induced behavioral deficits. More specifically, we assessed neuronal activation indexed by c-Fos+ cell counts in 24 stress-and mood-related brain regions, and determined if changes in acute stress-induced neuronal activation were linked to chronic stress-induced behavioral impairments. Results indicated that CRS and UCMS led to convergent physiological and anxiety-like deficits, whereas cognition was impaired only in UCMS mice. CRS and UCMS exposure exacerbated neuronal activation in response to an acute stressor in anterior cingulate cortex (ACC) area 24b and ventral hippocampal (vHPC) CA1, CA3, and subiculum. In dysregulated brain regions, levels of neuronal activation were positively correlated with principal components capturing variance across widespread behavioral alterations relevant to stress-related disorders. Our data supports an association between a dysregulated stress response, altered corticolimbic excitation/inhibition balance, and the expression of maladaptive behaviors.

Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation

“…Our approach did not distinguish SST vs. GABA roles, modeling evidence of both markers being reduced in MDD (Fee et al, 2017). However, corticolimbic hyperactivation is an expected outcome reflecting silencing both mediators given their shared roles in PN inhibition (Tallent and Siggins, 1997;Schweitzer et al, 1998;Stengel and Taché, 2017), and consistent with past chemogenetic SST+ cell silencing studies (Soumier and Sibille, 2014;Allen et al, 2017) and chronic stress studies wherein GABA and SST markers are selectively reduced (Lin and Sibille, 2015;Girgenti et al, 2019;Fee et al, 2020). Plasma corticosterone elevation also validated reduced SST function, given its role in inhibitory regulation of corticosteroid release (Engin and Treit, 2009;Prévôt et al, 2016Prévôt et al, , 2018.…”

“…However, region-specific manipulations may confer compensatory neural circuit adaptations that are not reflective of human pathology, wherein reductions in SST+ cell markers are evident across multiple brain regions in human and animal studies (Fee et al, 2017). Indeed, we found behavioral changes that closely paralleled past rodent chronic stress studies (Nikolova et al, 2018;Prevot et al, 2019c;Fee et al, 2020) that also found selective impingement upon SST+ cell functions via dysregulated cell integrity pathways (Lin and Sibille, 2015;Girgenti et al, 2019;Oh et al, 2019). These findings suggest that SST+ cell deficits are an intermediary causal factor between upstream risk factors (e.g., chronic stress, altered proteostasis and neurotrophic factor signaling) and MDD symptom emergence (Fee et al, 2017;.…”

“…In adulthood, anxiety-like behavior was assessed with the PhenoTyper test (PT), elevated plus- following past study designs (Fee et al, 2020). CNO was administered 30 min prior to test initiation, except for the PT where CNO was administered 30 min prior to the dark cycle (90 min prior to light challenge) to allow habituation.…”

Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex

“…The CRS paradigm is a well-documented rodent model of chronic stress that was shown to alter the physical animal’s state and produce behavioral deficits, including anxiety- and anhedonia-like behaviors [63-67]. Here, we confirmed previous findings from our lab and others demonstrating greater coat state deterioration [59, 60], reduction in sucrose intake [67] and increase in time spent in the shelter zone after the light challenge in the PhenoTyper test following CRS [60].…”

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

“…However, Z-score normalization of anxiety-like behavior, reflecting EPM, OFT, NSF, and NIH parameters, revealed an overall anxiogenic effect of UCMS. This test-specific behavioural variability is unsurprising as it has been noted using UCMS by our lab (Maluach et al, 2017;Nikolova et al, 2018;Prevot et al, 2019;Fee et al, 2020) and others (Ramos, 2008;Willner, 2017), whereas topdown dimension reduction via Z-scoring consistently increases the sensitivity and reliability of these same tests (Guilloux et al, 2011). Although this approach may improve the quality of conclusions about preclinical behavior changes, it is also important to mention that repeated testing is itself a source of variability (Voikar et al, 2004).…”