ABSTRACTEndogenous neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF) modulate the responses of the Basolateral amygdala (BLA) to stress, and are associated respectively with the development of stress resilience and vulnerability. We characterized the persistent effects of repeated NPY and CRF treatment on the structure and function of BLA principal neurons (PN) in a novel organotypic slice culture (OTC) model of rat BLA, and examined the contributions of specific NPY receptor subtypes to these neural and behavioral effects. In BLA principal neurons within the OTCs, repeated NPY treatment caused persistent attenuation of excitatory input and induced dendritic hypotrophy via Y5 receptors; conversely, CRF increased excitatory input and induced hypertrophy of BLA PNs. Repeated treatment of OTCs with NPY followed by an identical treatment with CRF, or vice versa inhibited or reversed all structural changes in OTCs. These structural responses to NPY or CRF required calcineurin or CaMKII, respectively. Finally, repeated intra-BLA injections of NPY or a Y5 receptor agonist increased social interaction and recapitulated structural changes in BLA neurons seen in OTCs, while a Y5 receptor antagonist prevented NPY’s effects both on behavior and on structure. These results implicate the Y5 receptor in the long-term, anxiolytic-like effects of NPY in the BLA, consistent with an intrinsic role in stress buffering, and highlight a remarkable mechanism by which BLA neurons may adapt to different levels of stress. Moreover, BLA OTCs offer a robust model to study mechanisms associated with resilience and vulnerability to stress in BLA.Significance StatementWithin the basolateral amygdala (BLA), Neuropeptide Y (NPY) is associated with buffering the neural stress response induced by CRF, and promoting stress resilience. We used a novel organotypic slice culture (OTC) model of BLA, complemented with in vivo studies, to examine the cellular mechanisms associated with the actions of NPY. In OTCs, repeated NPY treatment reduces the complexity of the dendritic extent of anxiogenic BLA principal neurons, making them less excitable. NPY, via activation of Y5 receptors, additionally inhibits and reverses the increases in dendritic extent and excitability induced by the stress hormone, corticotropin releasing factor (CRF). This NPY-mediated neuroplasticity indicates that resilience or vulnerability to stress may thus involve neuropeptide-mediated dendritic remodeling in BLA PNs.
Mitogen-activated protein kinases support survival of activated microglia that mediate thrombin-induced striatal injury in organotypic slice culture
