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

项目摘要 哺乳动物中脑/后脑5-羟色胺(5-羟色胺)释放神经元对基本行为和 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(SSRI)可提高脑组织5-羟色胺水平，是治疗严重脑出血的最常用药物。 人类的抑郁症。然而，我们对5-羟色胺影响突触的机制的理解， 细胞，而电路是有限的，阻碍了抑郁症治疗方法的改进。5-羟色胺的主要靶点 神经元是外侧缰核(LHb)，这是一种皮质下结构，主要参与评估结果 (积极的或消极的)一种行为。LHb是大脑中唯一一个显示出持续的多动的区域 啮齿类动物的慢性应激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”与慢性应激后的几种行为表型(包括快感缺乏)有因果关系。 最近，利用单细胞转录组广泛测序，我们从基因上定义了神经元亚类。 在LHb内首次揭示了5-羟色胺受体和基因的细胞类型特异性表达 与爆发式射击有关。我们的中心假设是5-羟色胺的释放动态地调节缰核回路 尽管5-羟色胺受体的神经元型特异性表达和突发性放电在特定的、基因定义的 慢性应激后的快感缺失需要LHB神经元类型。本提案旨在1)确定 体内外LHb中突发性放电的神经元类型(S)，2)决定5-羟色胺的调节方式 LHb内的神经元类型和局部连通性以及3)定义LHb中所需的神经元类型 慢性应激导致快感缺失。通过揭示5-羟色胺是如何调制缰核的，这项拟议的工作 将提供对这种重要神经调节剂的细胞和电路靶标的全面了解。 这些发现将为理解SSRIs影响的主要机制奠定基础 LHb的突触和环路，为重度抑郁症的治疗干预开辟了新途径 使用这些药物治疗精神障碍和其他神经疾病。

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.