Somatostatin-expressing neurons in the amygdala and their involvement in socio-affective behavior: early-life stress and functional manipulation studies in mice.

Abstract

Early postnatal development is crucial for configuring neural networks that support social and affective behaviors. Children exposed to stressful environments are at high risk for developing maladaptive behaviors, including anti-social and aggressive traits, due to poorly understood neurobiological mechanisms. In our model of early life stress (ELS) in mice, maternal separation with early weaning (MSEW) decreased somatostatin-expressing (SST) interneurons density in the basolateral amygdala (BLA) in both sexes and reduced their activity in the medial amygdala (MeA) of adult males. This hypoactivity correlated significantly with increased aggressive-like outcomes and decreased social interest. Importantly, after chronic chemogenetic activation of MeA-SST+ interneurons, MSEW adult males improved social interaction and reduced aggression, highlighting the role of these neurons in regulating socio-aggressive behaviors and the link of ELS with later maladaptive behaviors. We further demonstrated that ELS induced sex- and region-dependent changes in molecules related to plasticity and in the excitatory/inhibitory (E/I) balance, correlating with social and anxious outcomes. Specifically, in the BLA of MSEW females, transient increases in PSA-NCAM expression and the density of VGLUT2 puncta neuropil and decreases in the density of GAD67 perisomatic puncta were reported, normalizing in adulthood. BLA alterations in E/I markers were correlated with anxious traits and decreased sociability and social novelty preference. Males exhibited long-term increases in CBR1 expression in the BLA, positively correlated with increased sociability. Both sexes showed non-enduring increases in PSA-NCAM expression in the MeA, negatively correlated with social dominance. Additionally, modulation of social behaviors through the bidirectional pharmacogenetic manipulation of the MeA-SST+ neuronal activity provided further insights in the neural bases of male mice behavior. We found that chronic activation of SST+ neurons disrupted sociability and social novelty preference, and reduced offensive aggression toward males, while increased dominance and sexual interest toward female mice. In contrast, chronic MeA-SST+ neurons inactivation increased the social novelty preference for male mice and hampered coping strategies. These studies underscore the critical role of SST+ neurons in the MeA in behaviors affected by early-life stress and after their functional manipulation. They highlight the intricate role of MeA-SST+ neurons in modulating social behaviors and the profound impact of early life stress on later life outcomes, offering potential targets for therapeutic interventions.