The Synaptic Circuitry of the Lateral Habenula and Behavioral Depression

描述(申请人提供)：外侧缰核的突触回路和行为抑郁。人们对情绪障碍的神经基础知之甚少。因此，开发更有效的抑郁症疗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(LHb)中的神经元发出“失望”信号，并可能在抑郁中发挥重要作用，但LHb导致抑郁的机制尚不清楚。在这里，我们将检验这一中心假设，即LHb突触回路中的异常活动是行为抑郁的基础，LHb神经元活动的正常化是抗抑郁治疗效果所不可或缺的。这项研究计划的总体目标是更好地了解抑郁症发病机制的细胞变化。使用抑郁的动物模型，将评估LHb中异常的神经元活动，并将确定其潜在的突触机制。此外，通过选择性地操纵LHb神经元的活动和确定行为结果，将检验LHb神经元活动异常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方法的发展，允许在动物身上调节类似抑郁的行为。将使用一些互补的方法，包括行为分析、电生理学、双光子成像、体内电路跟踪、脑深部电刺激、分子遗传学和光遗传技术。具体目标是：SA1：确定抑郁症动物模型中过度活跃的LHb神经元的突触电路。SA2：确定抑郁症动物模型中LHb神经元活动异常的突触机制。SA3：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。由于缺乏对抑郁的病理生理学的了解，目前的抗抑郁药物受到严重的限制。这项拟议的研究结果将为抑郁症的细胞和回路机制提供重要的见解，这些机制可能导致能够改善某些形式的抑郁症的新颖和有效的治疗方法。 公共卫生相关性：抑郁障碍的神经生物学机制仍然知之甚少，临床抗抑郁药物也远远不能令人满意。在这项研究计划中，我们建议确定外侧缰核在动物行为抑郁的发病和治疗中的作用。外侧缰核是最近被认为通过调节多巴胺中心来编码“失望”的大脑区域。通过这项研究，我们将获得对抑郁症潜在的神经生物学变化的新见解，这可能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.