Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice

Abstract

Disrupted operations of the reward circuit underlie major emotional disorders, including depression, which commonly arise following early life stress / adversity (ELA). However, how ELA enduringly impacts reward circuit functions remains unclear. We characterize a stress-sensitive projection connecting basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We identify a crucial role for this projection in executing disrupted reward behaviors provoked by ELA: chemogenetic and optogenetic stimulation of the projection in control male mice suppresses several reward behaviors, recapitulating deficits resulting from ELA and demonstrating the pathway’s contributions to normal reward behaviors. In adult ELA mice, inhibiting–but not stimulating–the projection, restores typical reward behaviors yet has little effect in controls, indicating ELA-induced maladaptive plasticity of this reward-circuit component. Thus, we discover a stress-sensitive, reward inhibiting BLA → NAc projection with unique molecular features, which may provide intervention targets for disabling mental illnesses.

Annual Research Review: The power of predictability – patterns of signals in early life shape neurodevelopment and mental health trajectories

“…We have shown that exposures to more unpredictable maternal mood predicts decreased flexibility in the salience network of their adolescents (Jirsaraie et al., 2023). Additional new work identifies an inhibitory basolateral amygdala to nucleus accumbens projection that is responsible for deficits in reward behavior resulting from early‐life unpredictability (Birnie et al., 2023). This exciting finding, in conjunction with human research linking unpredictable early life experiences to anhedonia and reward processes (Glynn et al., 2019; Spadoni et al., 2022), inspires our current cross‐species work evaluating impacts of unpredictability on anhedonia and reward behaviors and underlying processes and mechanisms.…”

Influence of chronic stress on network states governing valence processing: Potential relevance to the risk for psychiatric illnesses

“…Activation or inhibition of CRH neurons in the PVN is sufficient to induce a conditioned place aversion or preference, respectively 24 . The impact of early life stress on valence processing has been shown to involve activation of CRH neurons in the basolateral amygdala which project to the nucleus accumbens 15 . Stimulation of CRH projections from the basolateral amygdala to the nucleus accumbens impairs positive valence processing; whereas inhibiting CRH projections from the basolateral amygdala to the nucleus accumbens restores reward processing in mice subjected to early life stress 15 .…”

“…For example, reduced gray matter T A B L E 1 Summary of stress and neuroendocrine manipulations on valence processing. 15 ; Dedic et al 21 ; Füzesi et al 22 ; Hu et al 23 ; Kim et al 24 ; Yuan et al 25 volume has been demonstrated in the anterior cingulate cortex and amygdala in individuals with depression and comorbid anxiety (for review see 9,28 ). Similar reductions in gray matter volume have been observed in the amygdala, hippocampus, and anterior cingulate cortex associated with major depression (for review see 9,28 ).…”

Strain-specific changes in nucleus accumbens transcriptome and motivation for food reward in mice exposed to maternal separation

“…Finally, a growing body of evidence suggests that early-life stress impairs reward processes (Novick et al, 2018). While MS has been associated with reduced sucrose preference suggestive of an anhedonia phenotype (Rincel and Darnaudéry, 2020;Birnie et al, 2023), early-life adversity was found to exacerbate drug intake in rodents as well as in humans (Nylander and Roman, 2013;Walters and Kosten, 2019). MS has been associated with disruptions of the reward dopaminergic system (Rodrigues et al, 2011;Romaní-Pérez et al, 2017;Wendel et al, 2021).…”