Sex-dependent effects of stress on aIC-NAc circuit neuroplasticity: Role of the endocannabinoid system

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Stress is a major risk factor for psychiatric disorders and affects neuroplasticity in brain areas like the nucleus accumbens core (NAcC) and the insular cortex (IC). This study examined neuroplasticity changes in the aIC-NAcC circuit after restraint stress in male and female rats, and explored the role of the endocannabinoid system. Male and female rats underwent 2 h of acute restraint stress. Behavioral tests and in vivo electrophysiological recordings were performed immediately and 24 h after stress exposure. cFos was performed immediately after stress. Since stress effects were observed only in males, we evaluated the systemic and intra-NAc blockade of CB1 receptors in male rats. We found increased c-Fos expression in the hypothalamus but not in the IC in both sexes after acute restraint stress, along with heightened anxiety and reduced exploratory behavior. Males and females exhibited different neuronal plasticity in the aIC-NAcC pathway. Under basal conditions, males showed equal proportions of long-term potentiation (LTP) and long-term depression (LTD), whereas females predominantly exhibited LTP. Stress disrupted synaptic plasticity in males by eliminating LTD in the aIC-NAcC pathway 24 h after exposure. This effect was reversed by systemic and local CB1 receptor blockade. These findings suggest that integration of aIC information into NAcC differs by sex, with stress-induced neuroplasticity changes occurring only in males, dependent on the endocannabinoid system. This study provides insight into sex differences in stress reactivity, which may relate to stress-related psychiatric disorders. • Acute stress increases c-Fos in the hypothalamus but not the IC. • Acute stress induces anxiety and decreases exploratory behavior in males and females. • Neuronal plasticity in the aIC-NAcC pathway is different between males and females under basal conditions. • Acute stress induces sustained changes in neuronal plasticity in the aIC-NAcC pathway only in males. • Stress-induced changes in neuronal plasticity in the aIC-NAcC pathway depend on CB1 receptor activation.

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