Intrinsic CRF signaling within the lateral habenula

摘要 促肾上腺皮质激素释放因子(CRF)从下丘脑释放出来，其作用是 调节下丘脑-垂体-肾上腺(HPA)轴的神经内分泌应激介质。然而， 下丘脑外脑区的CRF信号也在调节正性和 通过不同的CRF神经元负强化应激源的激励行为 电路。此外，CRF信号中的性别偏见可能是女性易受焦虑和 抑郁症。最近，我们发现，外侧无顶核(LHb)，一个反奖赏的大脑区域也 与焦虑和抑郁有关，是一个对CRF高度反应的大脑区域，尽管这是 下丘脑外CRF对LHb的神经传递及其行为相关性在两性中仍然存在 未知。因此，在这份R21赠款提案中，我们的目标是探索一种新确定的 表达CRF(LHbCRF神经元)并提供局部抑制电路的LHB神经元亚群 在LHb内，LHb的活动和相关的焦虑相关行为在性和环路中的调节-- 具体的方式。我们的具体目标是确定LHbCRF→LHb回路在焦虑症相关疾病中的作用 LHb的行为和对CRF依赖的调节。我们的创新实验方法利用 老鼠遗传学，基于病毒的策略，电生理学的体外光遗传学，化学遗传学， GCaMP钙成像和雌性和雄性小鼠的行为将使我们能够发现 CRF在LHb功能和LHb相关焦虑行为的回路特异性调节中的作用及其意义 与压力相关的障碍和女性对压力的敏感性。

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.