The Synaptic Circuitry of the Lateral Habenula and Behavioral Depression

描述（由申请人提供）：外侧缰和行为抑制的突触回路。 情绪障碍的神经基础知之甚少。因此，开发更有效的抑郁症治疗方法的努力在很大程度上是不成功的。最近的研究表明外侧缰核（lateral habenula，LHb）内的神经元发出“失望”信号，可能在抑郁症中起重要作用，但LHb参与抑郁症的机制尚不清楚。在这里，我们将测试的中心假设，异常活动的突触回路的LHb的行为抑郁症的基础，LHb神经元活动的正常化是不可或缺的抗抑郁症治疗的疗效。这项研究计划的总体目标是更好地了解负责抑郁症发病机制的细胞变化。使用抑郁症的动物模型，将评估LHb中的异常神经元活动，并确定其潜在的突触机制。此外，通过选择性地操纵LHb神经元的活动并确定行为结果，将测试异常LHb神经元活动与行为抑郁之间的因果关系。重要的是，这项研究计划将导致开发允许调节动物抑郁样行为的方法。 将使用许多互补的方法，包括行为测定、电生理学、双光子成像、体内电路追踪、电脑深部刺激、分子遗传学和光遗传学技术。具体目的是：SA1：在抑郁症动物模型中确定过度活跃的LHb神经元的突触回路。 SA2：确定抑郁症动物模型中异常LHb神经元活动的突触机制。 SA 3：操纵LHb的突触回路以调节行为抑郁。） 开发更有效的抑郁症治疗方法是一个重要的目标。由于对抑郁症的病理生理学缺乏了解，目前的抗抑郁药受到严重的限制。这项研究的结果将为抑郁症的细胞和电路机制提供重要的见解，这可能导致能够改善某些形式的抑郁症的新颖有效的治疗方法。 公共卫生相关性：抑郁症的神经生物学机制尚不清楚，临床抗抑郁药物也远不能令人满意。在这项研究计划中，我们建议确定侧缰的作用，最近被认为是编码“失望”通过其调制多巴胺中心，在动物行为抑郁症的发病机制和治疗的大脑区域。通过这项研究，我们将对抑郁症的神经生物学变化获得新的见解，这可能会导致更有效的治疗方法。

DESCRIPTION (provided by applicant): The synaptic circuitry of the lateral habenula and behavioral depression. The neural basis of mood disorders is poorly understood. As a consequence, efforts to develop more effective therapies for depression have largely been unsuccessful. Recent studies indicate that neurons in the lateral habenula (LHb) signal "disappointment" and may play an important role in depression, however the mechanisms by which the LHb contributes to depression are unknown. Here, we will test the central hypothesis that aberrant activity in the synaptic circuitry of the LHb underlies behavioral depression, and that normalization of LHb neuronal activity is integral to the efficacy of anti-depression treatments. The overall goal of this research program is to gain a better understanding of the cellular changes responsible for the pathogenesis of depression. Using animal models of depression, aberrant neuronal activity in the LHb will be assessed and its underlying synaptic mechanisms will be determined. Furthermore, by selectively manipulating the activity of LHb neurons and determining the behavioral outcomes, the causal relationship between aberrant LHb neuronal activity and behavioral depression will be tested. Importantly, this research program will result in the development of methods that allow the modulation of depression-like behavior in animals. A number of complementary methodologies will be used, including behavioral assays, electrophysiology, two-photon imaging, in vivo circuit tracing, electrical deep brain stimulation, molecular genetics, and optogenetic techniques. The SPECIFIC AIMS are: SA1: To define the synaptic circuitry of hyperactive LHb neurons in animal models of depression. SA2: To determine the synaptic mechanisms underlying aberrant LHb neuronal activity in animal models of depression. SA3: To manipulate the synaptic circuitry of the LHb in order to modulate behavioral depression.) Developing more effective treatments for depression is an important goal. Current antidepressants suffer from critical limitations due to a lack of understanding of the pathophysiology of depression. Results from the proposed research will provide important insights into the cellular and circuit mechanisms of depression that may lead to novel and effective treatments capable of ameliorating some forms of depressive disorders. PUBLIC HEALTH RELEVANCE: The neurobiological mechanisms of depressive disorders remain poorly understood, and the clinical antidepressants are far from being satisfying. In this research program, we propose to determine the role of the lateral habenula, a brain region that was recently suggested to encode "disappointment" through its modulation of dopamine centers, in the pathogenesis and treatment of behavioral depression in animals. Through this research we will gain novel insights into the neurobiological changes underlying depressive disorders, which may lead to more effective therapeutic treatments.