Intrinsic CRF signaling within the lateral habenula

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Abstract Corticotropin releasing factor (CRF) released from the hypothalamus is known for its role as the neuroendocrine stress mediator by regulating the hypothalamic-pituitary-adrenal (HPA) axis. However, CRF signaling in extrahypothalamic brain regions also plays a key role in regulation of positive and negative reinforcement of motivated behaviors in response to stressors through distinct CRF neural circuits. Moreover, sex biases in CRF signaling may underlie female vulnerability to anxiety and depression. Recently, we showed that the lateral ahebnula (LHb), an anti-reward brain region also implicated in anxiety and depression, is a highly CRF-responsive brain region although the source of this extrahypothalamic CRF neurotransmission to the LHb and its behavioral relevance in both sexes are still unknown. Therefore, in this R21 grant proposal, we aim to explore the contribution of a newly identified LHb neuronal subpopulation that expresses CRF (LHbCRF neurons) and provides a local inhibitory circuit within the LHb in regulation of LHb activity and related anxiety-related behaviors in a sex- and circuit- specific manner. Our specific aims are to identify the role of LHbCRF→LHb circuit in anxiety-related behaviors and in CRF-dependent regulation of LHb. Our innovative experimental approach utilizing mouse genetics, viral-based strategies, ex vivo optogenetics with electrophysiology, chemogenetics, GCaMP calcium imaging, and behavior in female and male mice will enable us to uncover novel roles for CRF in circuit-specific regulation of LHb function and LHb-related anxiety behaviors with implications in stress-related disorders and female susceptibility to stress.