Stress-induced plasticity of a novel CRH^GABA projection disrupts reward behaviors

Abstract

Disrupted operations of the reward circuit are thought to underlie major emotional disorders including depression and drug abuse. These disorders commonly arise following early life stress; however, how stress early in life enduringly impacts reward circuit functions to promote disease remains unclear. Here, we discover and characterize a novel stress-sensitive reward-circuit projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We then identify a crucial role for this projection in executing the disrupted reward behaviors provoked by early-life adversity (ELA): Chemogenetic and optogenetic stimulations of the CRHGABA BLA and NAc projection in typically reared mice suppressed several reward seeking behaviors, recapitulating deficits resulting from ELA and demonstrating a key contribution of this pathway in the normal operations of the reward circuit. Next, inhibition of the CRHGABA BLA and NAc projection in adult mice that experienced ELA restored typical reward behaviors in these mice, and, in contrast, had little effect in typically reared mice, indicating a selective ELA-induced maladaptive plasticity of this reward-circuit projection. We discover a novel, stress-sensitive, reward inhibiting projection from the BLA and NAc with unique molecular features, which may provide targets for intervention in disabling mental illnesses.

Amygdala-cortical collaboration in reward learning and decision making

“…The amygdala is a highly conserved, temporal lobe, limbic system structure with basolateral, central, and medial subcomponents Duvarci and Pare, 2014 ; Ehrlich et al, 2009 ; Janak and Tye, 2015 ; Sah et al, 2003 ; LeDoux, 2007 . I focus on the basolateral amygdala (BLA) which consists of lateral, basal, and basomedial nuclei and contains glutamatergic principle neurons, inhibitory interneurons, and potentially GABAergic projection neurons Birnie et al, 2022 . GABAergic intercalated cells flank the BLA Ehrlich et al, 2009 ; Marowsky et al, 2005 .…”