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.

项目摘要 5-羟色胺（5-HT） - 哺乳动物中/后脑中的神经元释放神经元对于基本行为至关重要 认知过程，包括情绪控制，唤醒和运动控制。选择性5-羟色胺再摄取 抑制剂（SSRIS）增加了大脑5-HT水平，是最常见的主要处方治疗方法 人类的抑郁症。但是，我们对5-HT影响突触的机制的理解， 细胞和电路受到限制，禁止改善抑郁疗法。 5-HT的主要目标 神经元是外侧Habenula（LHB），这是一种主要与评估结果有关的皮层结构 动作的（正面或负面）。 LHB是唯一显示一致多动症的大脑区域 慢性压力和其他研究的啮齿动物模型最近完善了这种观察结果，表明“爆发” 在慢性应激之后，LHB中的发射”有时与几种行为表型（包括Anhedonia）有关。 最近，使用单细胞转录组宽测序，我们通常定义神经元子类 在LHB中首次揭示了5-HT接收器和基因的细胞类型的特异性表达 与爆发有关。我们的中心假设是5-HT释放动态调节了Habenula电路 虽然5-HT接收器的神经型特异性表达和特定于特定的，通常定义的爆发 慢性应激后，Anhedonia需要LHB神经类型。该提议寻求1）确定 LHB中的神经元型（S）在体外和体内暴露了爆发的爆发，2）确定5-HT如何调节 LHB内的神经元类型和局部连通性，3）定义LHB中的神经元类型 慢性应激诱发了Anhedonia。通过揭示5-HT如何调节Habenular电路，提议的工作 将对此重要神经调节剂的细胞和电路靶标提供全面的理解。 这些发现将构成理解SSRIS影响的主要机制的基础 LHB的突触和电路，揭示了针对主要抑郁症的治疗干预的新途径 这些药物治疗的疾病和其他神经系统疾病。