IDENTIFYING CELLULAR AND MOLECULAR SUBSTRATED OF TREATMENT- RESISTANT DEPRESSION

项目摘要 确定决定对药物的反应和抵抗的神经生物学机制 精神病治疗对于开发改进的药物至关重要， 治疗虽然来自人类和啮齿动物模型的大量证据表明， 证明了神经递质5-羟色胺（5-HT）在抗抑郁药中的关键作用。 行动，目前还不清楚为什么有些人对治疗有反应，而另一些人没有。 这种知识的缺乏限制了有效药物的开发， 靶向赋予治疗反应神经生物学底物。我们的研究揭示了 抑制海马齿状回区域可以保护大脑免受 在小鼠中出现焦虑样症状，这一机制可能是 被新型和改良的抗抑郁药使用。5-羟色胺1A受体（5-HT 1AR） 齿状回颗粒神经元是神经元抑制的关键介质， 对SSRIs的反应然而，5 HT 1ARs如何调节神经元功能， 引起抗抑郁反应仍然是难以捉摸的。根据这些发现，我们 假设抗抑郁反应是通过抑制齿状回介导的 活动为了验证这一点，我们将首先检查复杂的分子网络， 5-HT 1AR信号通路抑制小鼠和人死后脑齿状回活动 组织.然后，我们将使用化学遗传学技术来抵消或刺激神经元 抑制在转基因小鼠的齿状回，做或不响应 抗抑郁药。最后，我们将使用创新的体内显微镜成像， 自由行为反应者和无反应者齿状回中的神经元活动 在压力和焦虑相关的任务中。该项目将提供全面的 研究我们如何开发先进的抗抑郁治疗方法， 抑制齿状回活动。 !

PROJECT SUMMARY Identifying the neurobiological mechanisms that determine response and resistance to psychiatric treatment is of paramount importance for developing improved drugs and therapies. While substantial evidence from humans and rodent models has demonstrated a crucial role for the neurotransmitter, serotonin (5HT), in antidepressant action, it is unknown why some individuals respond to treatment with while others do not. This lack of knowledge limits the development of effective drugs that could specifically target neurobiological substrates that confer treatment response. Our work has revealed that inhibiting the dentate gyrus region of the hippocampus can protect from the development of anxiety-like symptoms in mice, a mechanism that could potentially be used by novel and improved antidepressants. The serotonin 1A receptor (5HT1AR) in dentate gyrus granule neurons is a crucial mediator for neuronal inhibition and behavioral responses to SSRIs. However, how 5HT1ARs regulate neuronal function to elicit an antidepressant response remains elusive. Leading on from these findings, we hypothesize that antidepressant responses are mediated by inhibition of dentate gyrus activity. To test this, we will first examine the complex molecular networks by which 5HT1AR signaling inhibits dentate gyrus activity in mice and in human postmortem brain tissue. Then, we will use chemogenetic techniques to counteract or stimulate neuronal inhibition in the dentate gyrus of transgenic mice that do or do not respond to antidepressants, respectively. Finally, we will use innovative in vivo microscopy to image neuronal activity in the dentate gyrus of freely behaving responders and non-responders during stress and anxiety-related tasks. This project will provide a comprehensive investigation into how we can develop advanced antidepressant treatments based on inhibition of dentate gyrus activity. !