The neurocircuitry of depression: Molecular and Cell Subtype Mechanisms

 描述（由申请人提供）：抑郁症是全球残疾的主要原因之一，许多患者治疗不当，最严重的结果是自杀。因此，迫切需要新的治疗策略。这些策略需要对抑郁症的精确神经元亚型和分子机制有全面的了解。影像学和遗传学研究已经确定了抑郁症患者的关键神经生物学标志物。然而，抑郁症的遗传学与适应不良的神经元群体的信息是缺乏的。我们可以通过采用多学科的方法来研究一种新的重度抑郁症（MDD）的风险基因，神经元氨基酸转运蛋白Slc6a15，和内源性阿片类药物信号传导在延髓核微电路，这是已知的介导负面情绪状态。我们的研究采用了多学科的方法，包括细胞亚型和电路选择性分子分析，细胞亚型遗传靶向，以及光遗传学，以揭示抑郁症中这种神经核微电路的新分子机制。我们有能力在抑郁症的临床前模型中的选择性神经元群体中分析Slc6a15水平。与此同时，我们开发了新的遗传工具来操纵选择性神经元群体中的Slc6a15水平，并评估Slc6a15水平对啮齿动物抑郁相关行为的影响。使用这些工具，我们将评估Slc6a15对内源性阿片信号传导的影响，并研究如何改变内源性阿片信号传导，在这个核内的微回路，影响抑郁症相关的行为。这些拟议研究的结果可以揭示多种治疗靶向途径，这些途径可以极大地影响患有这种慢性疾病的个体的生活。

 DESCRIPTION (provided by applicant): Depression is one of the leading causes of disability worldwide, with many patients inadequately treated, and at its worst results in suicide. Thus, new therapeutic strategies are critically needed. Such strategies require a holistic understanding of the precise neuronal subtypes and molecular mechanisms underlying depression. Imaging and genetic studies have identified key neurobiological markers in depressed patients. However, information relating maladaptive neuronal populations in depression with the genetics of depression is lacking. We can overcome this limitation by employing a multidisciplinary approach to investigate a novel risk gene for major depressive disorder (MDD), the neuronal amino acid transporter Slc6a15, and endogenous opioid signaling in a nucleus accumbens microcircuit, which is known to mediate negative emotional states. Our studies employ a multidisciplinary approach including cell subtype and circuit selective molecular profiling, cell subtype genetic targeting, and optogenetics to uncover novel molecular mechanisms in this nucleus accumbens microcircuit in depression. We have the ability to profile Slc6a15 levels in selective neuron populations in preclinical models of depression. In parallel we have developed novel genetic tools to manipulate Slc6a15 levels in selective neuronal populations and assess the impact of Slc6a15 levels in depression related behaviors in rodents. Using these tools we will assess the effects of Slc6a15 on endogenous opioid signaling and study how altering endogenous opioid signaling, within this nucleus accumbens microcircuit, impacts depression related behaviors. Findings from these proposed studies could uncover multiple avenues of therapeutic targeting that can greatly impact the lives of individuals suffering from this chronic disease.