Serotonergic modulation of the circuits and cell-types of the lateral habenula

外侧缰核电路和细胞类型的血清素调节

• 批准号: 10713125
• 负责人: Michael L Wallace
• 金额: $ 62.04万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713125
• 关键词: Action Potentials; Acute; Affect; Anhedonia; Antidepressive Agents; Arousal; Axon; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Chronic stress; Color; Data; Disease; Dopamine; Electrophysiology (science); Emotional; Exhibits; Fire - disasters; Foundations; G-Protein-Coupled Receptors; Genes; Habenula; Head; Human; Hyperactivity; In Vitro; Individual; Ion Channel; Lateral; Learning; Link; Longitudinal Studies; Major Depressive Disorder; Measures; Mediator; Mental Depression; Mental disorders; Methods; Midbrain structure; Mus; Neuromodulator; Neurons; Norepinephrine; Optics; Outcome; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Prosencephalon; Psychiatric therapeutic procedure; Psychological reinforcement; Reporting; Rodent Model; Selective Serotonin Reuptake Inhibitor; Serotonin; Stress; Structure; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Work; behavioral phenotyping; cell type; cognitive process; common treatment; differential expression; fluorophore; hindbrain; improved; in vivo; memory process; motivated behavior; motor control; nervous system disorder; neural circuit; neuronal circuitry; receptor; sensor; serotonin receptor; spatiotemporal; transcriptome; transcriptomics

Project Summary Serotonin (5-HT)-releasing neurons in the mammalian mid/hindbrain are critical for fundamental behaviors and cognitive processes, including emotional control, arousal, and motor control. Selective serotonin reuptake inhibitors (SSRIs) increase brain 5-HT levels and are the most commonly prescribed treatment for major- depression in humans. However, our understanding of the mechanisms by which 5-HT influences synapses, cells, and circuits is limited, prohibiting improvement of depression therapeutics. A major target of 5-HT neurons is the lateral habenula (LHb), a subcortical structure principally implicated in evaluating the outcome (positive or negative) of an action. The LHb is the only brain region that shows consistent hyperactivity several rodent models of chronic stress and additional studies have recently refined this observation indicating “burst- firing” in LHb is causally related several behavioral phenotypes (including anhedonia) following chronic stress. Recently, using single-cell transcriptome wide sequencing, we genetically defined the neuronal subclasses within the LHb for the first time revealing cell-type specific expression of both 5-HT receptors and genes related to burst-firing. Our central hypothesis is that 5-HT release dynamically modulates the habenula circuit though neuron-type specific expression of 5-HT receptors and that burst-firing in specific, genetically defined LHb neuron-types is required for anhedonia following chronic stress. This proposal seeks to 1) identify the neuron-type(s) in the LHb that exhibit burst-firing in vitro and in vivo, 2) determine how 5-HT modulates neuron-types and local connectivity within the LHb and 3) define the neuron-types in the LHb required for chronic stress induced anhedonia. By revealing how 5-HT modulates habenular circuits, the proposed work will provide a comprehensive understanding of the cellular and circuit targets of this important neuromodulator. These findings will form the foundation for understanding the principal mechanisms by which SSRIs impact synapses and circuits of the LHb, uncovering new avenues for therapeutic intervention in major depressive disorder and other neurological disorders treated by these drugs.

项目概要 哺乳动物中脑/后脑中释放血清素 (5-HT) 的神经元对于基本行为和 认知过程，包括情绪控制、唤醒和选择性血清素再摄取。 抑制剂 (SSRIs) 会增加大脑 5-HT 水平，是治疗主要疾病最常用的药物。 然而，我们对 5-HT 影响突触机制的了解， 细胞和回路受到限制，阻碍了抑郁症治疗的改善，这是 5-HT 的主要目标。 神经元是外侧缰核 (LHb)，这是一种主要参与评估结果的皮层下结构 LHb 是唯一一个表现出持续多动的大脑区域。 慢性压力的啮齿动物模型和其他研究最近完善了这一观察结果，表明“爆发- LHb 中的“放电”与慢性压力后的几种行为表型（包括快感缺乏）存在因果关系。 最近，利用单细胞转录组全测序，我们从基因上定义了神经元亚类 首次揭示 LHb 内 5-HT 受体和基因的细胞类型特异性表达 我们的中心假设是 5-HT 释放动态调节缰核回路。 通过 5-HT 受体的神经元类型特异性表达以及特定的、基因定义的突发放电 LHb 神经元类型对于慢性压力后的快感缺失是必需的。该提案旨在 1) 确定 LHb 中在体外和体内表现出爆发放电的神经元类型，2) 确定 5-HT 如何调节 LHb 内的神经元类型和局部连接性，3) 定义 LHb 中所需的神经元类型 通过揭示 5-HT 如何调节缰核回路，提出的工作是慢性应激引起的快感缺失。 将提供对这种重要神经调节剂的细胞和电路目标的全面了解。 这些发现将为理解 SSRIs 影响的主要机制奠定基础。 LHb 的突触和回路，揭示重度抑郁症治疗干预的新途径 这些药物治疗的疾病和其他神经系统疾病。