Environmental Enrichment Confers Stress Resiliency to Social Defeat through an Infralimbic Cortex-Dependent Neuroanatomical Pathway

Abstract

Enriched environmental (EE) housing dampens stress-induced alterations in neurobiological systems, promotes adaptability, and extinguishes submissive behavioral traits developed during social defeat stress (SD). In the present study, we hypothesized that enrichment before SD can confer stress resiliency and, furthermore, that neuronal activity in the prefrontal cortex (PFC) is requisite for this resiliency. To test these hypotheses, mice were housed in EE, standard (SE), or impoverished (IE) housing and then exposed to SD. EE conferred resilience to SD as measured in several behavioral tasks. EE-housed mice expressed elevated FosB/ΔFosB immunostaining in areas associated with emotional regulation and reward processing, i.e., infralimbic, prelimbic, and anterior cingulate cortices, amygdala, and nucleus accumbens, and this expression was mostly preserved in mice receiving EE followed by SD. In contrast, in SE- or IE-housed animals, SD increased maladaptive behaviors and greatly reduced FosB/ΔFosB staining in the forebrain. We tested the putative involvement of the PFC in mediating resilience by lesioning individual regions of the PFC either before or after EE housing and then exposing the mice to SD. We found that discrete lesions of the infralimbic but not prelimbic or cingulate cortex made before but not after EE abolished the behavioral resiliency to stress afforded by EE and attenuated FosB/ΔFosB expression in the accumbens and amygdala while increasing it in the paraventricular hypothalamic nucleus. These data suggest that pathological ventromedial PFC outputs to downstream limbic targets could predispose an individual to anxiety disorders in stressful situations, whereas enhanced ventromedial PFC outputs could convey stress resilience.

Infralimbic cortex controls the activity of the hypothalamus–pituitary–adrenal axis and the formation of aversive memory: Effects of environmental enrichment

“…Based on the present study, we hypothesize that an enhanced capability of the infralimbic cortex to control the HPA axis contributes to the resilience of enriched animals to stress. In support of this hypothesis, it has been shown that EE increases the resilience of animals to social defeat stress by enhancing infralimbic cortical outputs to downstream limbic areas [9]. Also, in line with this possibility, it has been shown that an increased excitability in the PFC is associated with enhanced control over stress [33] and extinction learning [31].…”

“…These behavioural effects produced by environmental enrichment (EE) are, in part, mediated by changes in the activity of the HPA axis and the release of corticosterone [24]. Studies from our laboratory and others suggest that changes in the activity of the PFC, presumably infralimbic cortex, explain the reduced reactivity to stress that is observed in enriched animals [9,25,26].…”

“…However, most pharmacological and lesion studies are limited to the dorsal part of the medial PFC or do not distinguish between the dorsal and ventral parts [5][6][7][8] and, therefore, the role played by the infralimbic cortex in the regulation of the HPA axis and corticosterone concentrations is still uncertain. A dysfunctional regulation of the HPA axis as well as other limbic areas by the infralimbic cortex (ventral medial PFC in humans) is associated with stress mal adaptation and stress-related disorders [9][10][11][12].…”

“…Moreover, EE enhances the control that the infralimbic cortex exerts on the HPA axis. A stronger interaction between the infralimbic cortex and the HPA axis as well as other limbic areas might facilitate the extinction of fear-related memories [12,31,39] and protect enriched animals to stress-related disorders [9].…”

Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress

“…For example, the infralimbic subregion of the mPFC is required for stress resiliency conferred by environmental enrichment that suppresses induction of depressive and anxiety-like behaviors by repeated stress (6). The rapid antidepressant action of ketamine also requires the mTOR pathway in the mPFC (7).…”