J Neurosci. 2024 Jul 18:e0228242024. doi: 10.1523/JNEUROSCI.0228-24.2024. Online ahead of print.

ABSTRACT

Neuropeptide Y (NPY) increases resilience and buffers behavioral stress responses in male rats in part through decreasing the excitability of principal output neurons in the basolateral amygdala (BLA). Intra-BLA administration of NPY acutely increases social interaction (SI) through activation of either Y₁ or Y₅ receptors, whereas repeated injections of NPY (rpNPY; once daily for 5 days) produce persistent increases in SI through Y₅ receptor-mediated neuroplasticity in the BLA. In this series of studies, we characterized the neural circuits from the BLA that underlie these behavioral responses to NPY. Using neuronal tract tracing, NPY Y₁ and Y₅ receptor immunoreactivity was identified on subpopulations of BLA neurons projecting to the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). Inhibition of BLA→BNST, but not BLA→CeA, neurons using projection-restricted, cre-driven DREADD-G_i expression increased SI and prevented stress-induced decreases in SI produced by a 30-minute restraint stress. This behavioral profile was similar to that seen after both acute and rpNPY injections into the BLA. Intracellular recordings of BLA→BNST neurons demonstrated NPY-mediated inhibition via suppression of H currents, as seen previously. Repeated intra-BLA injections of NPY, which are associated with the induction of BLA neuroplasticity, decreased the activity of BLA→BNST neurons and decreased their dendritic complexity. These results demonstrate that NPY modulates the activity of BNST-projecting BLA neurons, suggesting that this pathway contributes to the stress-buffering actions of NPY and provides a novel substrate for the pro-resilient effects of NPY.Significance statement Neuropeptide Y (NPY) is associated with resilience in humans and mitigates stress-related behaviors in animal models. Through the actions of different NPY receptor subtypes, NPY induces either acute (Y₁R) or long-term (Y₅R) changes in the activity of basolateral amygdala (BLA) principal neurons that result in the development of a persistent stress resistance. Here, we determined that BLA neurons projecting to the bed nucleus of the stria terminalis (BNST) are inhibited by NPY and demonstrate decreased excitability and dendritic hypotrophy to repeated application of NPY. Inhibiting BLA→BNST neurons elevated social interaction (SI) and prevented stress-induced decreases in SI similar to intra-BLA NPY injections. These findings are significant as they identify a neuronal circuitry associated with NPY-mediated stress resistance.

PMID:39025677 | DOI:10.1523/JNEUROSCI.0228-24.2024