Intrinsic CRF signaling within the lateral habenula

摘要 从下丘脑释放的促肾上腺皮质激素释放因子（CRF）以其作为促肾上腺皮质激素释放因子的作用而闻名。 神经内分泌应激介质通过调节下丘脑-垂体-肾上腺（HPA）轴。然而，在这方面， 下丘脑外脑区的CRF信号传导也在正性和负性调节中起关键作用。 通过不同的CRF神经元对应激源的激励行为进行负强化 电路.此外，CRF信号中的性别偏见可能是女性易受焦虑和焦虑影响的基础。 萧条最近，我们发现外侧无感觉核（LHb），一个抗奖赏的大脑区域，也 与焦虑和抑郁有关，是一个高度CRF反应的大脑区域，尽管这种反应的来源是 下丘脑外CRF神经传递到LHb及其在两性中的行为相关性仍然是 未知因此，在这项R21赠款提案中，我们的目标是探索一种新发现的 表达CRF（LHbCRF神经元）并提供局部抑制回路的LHb神经元亚群 在LHb内调节LHb活性和相关的焦虑相关行为，在性别和电路中， 具体方式。我们的具体目标是确定LHbCRF→LHb回路在焦虑相关的 行为和CRF依赖的LHb调节。我们的创新实验方法利用 小鼠遗传学，基于病毒的策略，具有电生理学的离体光遗传学，化学遗传学， GCaMP钙成像，以及雌性和雄性小鼠的行为，将使我们能够发现新的作用， CRF对LHb功能和LHb相关焦虑行为的回路特异性调节及其意义 与压力有关的疾病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.