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

项目摘要 哺乳动物中脑/后脑中5-羟色胺（5-HT）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。选择性血清素再摄取 抑制剂（SSRIs）增加大脑5-HT水平，是最常见的治疗主要 人类的抑郁症然而，我们对5-HT影响突触的机制的理解， 细胞和电路是有限的，禁止抑郁症治疗的改进。5-HT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 （积极或消极）的行为。LHb是唯一一个显示出持续过度活跃的大脑区域， 慢性应激的啮齿动物模型和另外的研究最近已经改进了这一观察结果，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，使用单细胞转录组测序，我们从遗传学上定义了神经元亚类 首次揭示了5-HT受体和基因的细胞类型特异性表达 与爆炸有关我们的中心假设是，5-HT释放动态调节缰回路 尽管5-HT受体的神经元型特异性表达和在特定的、遗传定义的 LHb神经元类型是慢性应激后快感缺乏所必需的。本建议旨在：（1）确定 在体外和体内表现出爆发式放电的LHb中的神经元类型，2）决定5-HT如何调节 LHb内的神经元类型和局部连通性，以及3）定义LHb中的神经元类型， 慢性应激诱发的快感缺乏通过揭示5-HT如何调节缰回路， 将提供对这种重要神经调节剂的细胞和电路靶点的全面了解。 这些发现将为理解SSRIs影响的主要机制奠定基础。 突触和回路的LHb，揭示新的途径，治疗干预抑郁症 这些药物治疗的神经系统疾病和其他神经疾病。

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.