The neurocircuitry of depression: Molecular and Cell Subtype Mechanisms

 描述(申请人提供)：抑郁症是世界范围内导致残疾的主要原因之一，许多患者没有得到充分的治疗，最糟糕的结果是自杀。因此，迫切需要新的治疗策略。这样的策略需要对抑郁症背后的准确神经元亚型和分子机制有一个整体的了解。成像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记。然而，将抑郁症中的适应不良神经元群与抑郁症的遗传学联系起来的信息还很缺乏。我们可以通过采用多学科的方法来研究严重抑郁障碍(MDD)的新危险基因，神经元氨基酸转运体SLC6A15，以及伏隔核微电路中的内源性阿片信号，从而克服这一局限性。我们的研究采用了多学科的方法，包括细胞亚型和回路选择性分子图谱、细胞亚型遗传靶向和光遗传学，以揭示抑郁症患者伏隔核微回路的新分子机制。我们有能力分析抑郁症临床前模型中选择性神经元群体中SLC6A15的水平。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SLC6A15的水平，并评估SLC6A15水平在啮齿动物抑郁相关行为中的影响。使用这些工具，我们将评估SLC6A15对内源性阿片信号的影响，并研究在这个伏隔核微回路内改变内源性阿片信号如何影响抑郁相关行为。这些拟议研究的结果可能会揭示多种治疗靶向的途径，这些途径可能会极大地影响这种慢性病患者的生活。

 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.