Thalamic inputs modulate anxiety-related representations in the hippocampus

丘脑输入调节海马体中与焦虑相关的表征

• 批准号: 10464708
• 负责人: Mark M Gergues
• 金额: $ 2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464708
• 关键词: Adaptive Behaviors; Adult; American; Amygdaloid structure; Anatomy; Animals; Anterior; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Behavior; Brain; Calcium; California; Cells; Charge; Communities; Complex; Conflict (Psychology); Emotional; Environment; Equilibrium; Financial Hardship; Fright; Functional disorder; Generations; Heterogeneity; Hippocampus (Brain); Hypothalamic structure; Image; Lateral; Lead; Learning; Lesion; Medial; Mood Disorders; Moods; Mus; Neurons; Neurosciences; Optics; Output; Pathway interactions; Pharmacology; Population; Positioning Attribute; Prefrontal Cortex; Process; Publishing; Research Proposals; Rewards; Role; San Francisco; Shapes; Source; Stimulus; Structure of paraventricular nucleus of thalamus; Synapses; Techniques; Testing; Tetanus Toxin; Thalamic structure; Universities; Viral; Work; anxiety-related behavior; anxiety-related disorders; approach avoidance behavior; arm; avoidance behavior; base; behavioral response; brain cell; cell type; computerized tools; designer receptors exclusively activated by designer drugs; effective therapy; emotion regulation; emotional behavior; emotional stimulus; experimental study; field study; innovation; insight; maladaptive behavior; neural circuit; neurobiological mechanism; neuropsychiatry; novel; novel therapeutic intervention; optogenetics; tool; treatment of anxiety disorders

Project Abstract Almost one third of adult Americans suffer from an anxiety disorder, carrying an enormous personal, societal, and financial burden. Difficulty advancing novel more effective treatments for anxiety disorders is because they are complex circuit-based conditions, resulting from dysfunction in several distributed regions, connections, and cell types that generate normal adaptive behavior. Thus, a fundamental understanding of how neural circuits become disrupted to generate maladaptive behavior is crucial if we hope to generate impactful treatments. Recent work has revealed the hippocampus (HPC), which has classically been implicated in learning, for its role in encoding emotionally charged environments and generating appropriate behavioral responses. More specifically, emerging evidence from our lab has identified HPC neurons in the ventral pole that project to the hypothalamus encode anxiogenic environments and bidirectionally modulate avoidance behavior. Yet how and which inputs are involved in the generation of anxiety-related representations in the ventral HPC remain unknown. Using a whole-brain cell-type specific anatomical screen, we identified the anterior portion of the paraventricular nucleus of the thalamus (PVT), an area implicated in the processing of salient emotional stimuli, as a putative source of anxiety-related information to the HPC. Here, I will use a combination of cutting-edge optical, pharmacological, and computational tools to dissect and characterize the thalamic-hippocampal encoding of anxiogenic contexts and control of anxiety- related behaviors. Experiments done here will provide the first studies to interrogate how HPC encodes anxiogenic contexts and the thalamic contribution in classical tests of anxiety. All in all, this study will provide crucial insight into how circuits generate excessive avoidance (i.e., anxiety-related behavior) for new therapeutic interventions for anxiety-related disorders. All proposed experiments are well established techniques in the lab and part of a globally prestigious neuroscience community, including prominent leading experts of circuit function, at The University of California, San Francisco. Consequently, I am poised and positioned in an ideal world-class environment for completing a successful and impactful doctoral dissertation.

项目摘要 几乎三分之一的美国成年人患有焦虑症， 社会和经济负担。难以推进更有效的治疗焦虑症的新方法， 因为它们是复杂的基于回路的病症，由几个分布区域的功能障碍引起， 连接，以及产生正常适应行为的细胞类型。因此，一个基本的理解， 神经回路如何被破坏从而产生适应不良行为是至关重要的，如果我们希望产生 有影响力的治疗最近的研究揭示了海马体（HPC），它一直是经典的 与学习有关，因为它在编码充满情感的环境和产生适当的 行为反应更具体地说，来自我们实验室的新证据已经确定了HPC神经元， 投射到下丘脑的腹极编码焦虑环境并双向调节 回避行为然而，如何以及哪些输入参与了焦虑相关表征的生成 腹侧HPC的位置尚不清楚使用全脑细胞类型特异性解剖屏幕，我们确定了 丘脑室旁核（PVT）的前部，这是一个涉及处理 突出的情绪刺激，作为HPC的焦虑相关信息的假定来源。 在这里，我将结合使用尖端的光学、药理学和计算工具来 解剖和表征丘脑-海马编码的焦虑背景和控制焦虑- 相关行为。这里所做的实验将提供第一个研究，以询问HPC如何编码 焦虑情境和丘脑在经典焦虑测试中的贡献。总而言之，这项研究将提供 对电路如何产生过度回避的关键见解（即，焦虑相关的行为） 焦虑相关疾病的治疗干预。 所有拟议的实验都是实验室中成熟的技术，也是全球享有盛誉的 神经科学界，包括著名的电路功能的领先专家，在加州大学， 旧金山弗朗西斯科。因此，我在一个理想的世界级环境中完成了一个 成功和有影响力的博士论文。