Intrinsic CRF signaling within the lateral habenula

外侧缰核内的内在 CRF 信号传导

• 批准号: 10667070
• 负责人: Fereshteh S Nugent
• 金额: $ 22.78万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667070
• 关键词: Anti-Anxiety Agents; Anxiety; Applications Grants; Atlases; Axon; Behavior; Behavioral; Brain; Brain region; CRH gene; Calcium; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cyclic AMP-Dependent Protein Kinases; Darkness; Data; Drug Addiction; Electrophysiology (science); Exhibits; Female; Functional disorder; GABA Receptor; Genetic; Glutamate Receptor; Glutamates; Goals; Habenula; Hypothalamic structure; Image; Immunohistochemistry; In Vitro; Interneurons; Knowledge; Label; Lateral; Light; LoxP-flanked allele; Mediating; Mediator; Mental Depression; Mental disorders; Messenger RNA; Motivation; Mus; Negative Reinforcements; Neurons; Neuropeptides; Neurosecretory Systems; Phenotype; Play; Population; Positive Reinforcements; Predisposition; Proxy; Psychopathology; Publishing; Rattus; Regulation; Reporter; Research; Role; Sex Bias; Signal Transduction; Source; Stress; Synapses; System; Testing; Viral; anxiety-related behavior; anxiety-related disorders; behavioral outcome; behavioral response; brain reward regions; depressive symptoms; experimental study; gamma-Aminobutyric Acid; genetic approach; hypothalamic-pituitary-adrenal axis; innovation; male; motivated behavior; mouse genetics; neural circuit; neurochemistry; neuronal excitability; neuroregulation; neurotransmission; novel; optogenetics; postsynaptic; pre-clinical; presynaptic; receptor; release factor; response; reward processing; sex; sexual dimorphism; source localization; stress related disorder; stressor; virus genetics

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.

抽象的 从下丘脑释放的皮质激素释放因子（CRF）以其作用为 神经内分泌应激介体通过调节下丘脑 - 垂体 - 肾上腺（HPA）轴。然而， 偏射外丘脑脑区域中的CRF信号传导在调节正和 通过不同的CRF神经元响应压力源的成熟行为的负面增强 界。此外，CRF信号中的性偏见可能是女性对动画和动画的脆弱性的基础 沮丧。最近，我们表明外侧Ahebnula（LHB）也是一个反奖励大脑区域 在焦虑和抑郁中实施，是一个高度的CRF响应性大脑区域 在LHB上及其在男女中的行为相关性仍然是 未知。因此，在此R21赠款提案中，我们旨在探讨新确定的 表达CRF（LHBCRF神经元）并提供局部抑制作用的LHB神经元亚群 在LHB中，在性别和电路中，LHB活性和相关动画相关行为 具体方式。我们的具体目的是确定LHBCRF→LHB电路在焦虑相关的作用 行为和依赖CRF的LHB调节。我们利用创新的实验方法 小鼠遗传学，基于病毒的策略，具有电生理学，化学遗传学的体内光遗传学， 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角色 LHB功能和LHB相关的动画行为的特定电路调节中的CRF具有影响 在与压力有关的疾病和女性对压力的敏感性中。