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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要近三分之一的美国成年人患有焦虑症，承受着巨大的个人、社会和经济负担。推进新的更有效的焦虑症治疗方法的困难在于因为它们是复杂的基于电路的条件，是由几个分布式区域的功能障碍引起的，连接和产生正常适应性行为的细胞类型。因此，对如果我们希望产生适应不良行为，那么神经回路如何被破坏而产生适应不良行为就至关重要有效的治疗。最近的工作揭示了海马体（HPC），它通常被认为是与学习有关，因为它在编码充满情感的环境和产生适当的情绪方面发挥着作用行为反应。更具体地说，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对焦虑环境进行编码并进行双向调节回避行为。然而，如何以及哪些输入参与了与焦虑相关的表征的生成腹侧 HPC 的作用仍不清楚。使用全脑细胞类型特定的解剖屏幕，我们确定了丘脑室旁核 (PVT) 的前部，该区域涉及处理显着的情绪刺激，作为 HPC 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剖析和描述焦虑环境的丘脑-海马编码和焦虑控制相关行为。这里完成的实验将提供第一个研究来探究 HPC 的编码方式焦虑的背景和经典焦虑测试中丘脑的贡献。总而言之，这项研究将提供关于电路如何对新事物产生过度回避（即与焦虑相关的行为）的重要见解针对焦虑相关疾病的治疗干预。所有提出的实验都是实验室中成熟的技术，并且是全球享有盛誉的研究的一部分神经科学界，包括加州大学电路功能领域的杰出领先专家，旧金山。因此，我已准备好并处于理想的世界一流环境中，以完成成功且有影响力的博士论文。