Remediation of chronic immobilization stress-induced negative affective behaviors and altered metabolism of monoamines in the prefrontal cortex by inactivation of basolateral amygdala

Abstract

Exposure to chronic stress precipitates depression and anxiety. Stress-induced responses are differentially regulated by the prefrontal cortex (PFC) and basolateral amygdala (BLA). For instance, repeated stress leads to hypertrophy of BLA, resulting in the emergence of affective symptoms. Chronic stress-induced changes in the metabolism of monoamines are central in the manifestation of affective symptoms. Interestingly, BLA via its reciprocal connections modulates prefrontal cortical monoaminergic responses to acute stress. However, the effects of BLA inactivation on chronic stress-induced affective behaviors and monoaminergic changes in the PFC are relatively unknown. Thus, we hypothesized that inactivation of BLA might prevent chronic immobilization stress (CIS)-induced depressive-, anxiety-like behaviors, and associated monoaminergic alterations in the prelimbic (PrL) and anterior cingulate cortex (ACC) subregions of PFC. We used two different BLA silencing strategies, namely ibotenic acid lesion and reversible temporary inactivation using lidocaine. We found that CIS precipitates depressive- and anxiety-like behaviors. Further, CIS-induced negative affective behaviors were associated with decreased levels of 5-HT, DA, and NE, and increased 5-HIAA/5-HT, DOPAC + HVA/DA, and MHPG/NE ratio in the PrL and ACC, suggesting enhanced metabolism. Interestingly, BLA lesion prior to CIS blocked the emergence of depressive- and anxiety-like behaviors. Moreover, the lesion of BLA prior to CIS was sufficient to prevent alterations in levels of monoamines and their metabolites in the PrL and ACC. Thereafter, we evaluated whether the effects of BLA lesion could be mirrored by temporary inactivation of BLA, specifically during stress. Remarkably, temporary inactivation of BLA during stress recapitulated the effects of lesion. Our results have implications for understanding the role of BLA in chronic stress-induced metabolic alterations in prefrontal cortical monoaminergic systems, and associated mood and anxiety disorders. The current study supports the hypothesis that combating amygdalar hyperactivity might be a viable strategy for the management of stress and associated affective disorders.

Keywords: Chronic immobilization stress; Depression and anxiety; Inactivation of basolateral amygdala; Metabolism of monoamines; Prefrontal cortex.