A 5-HTergic DRN vCA1 circuit and Alzheimer's disease

项目摘要 尽管在阿尔茨海默病（AD）研究方面做出了巨大努力，但我们在以下方面没有取得太大进展： 了解AD的病理生理学或抑制/纠正AD相关的行为症状。近期 FDA批准的aducanumab在减少淀粉样蛋白β（Aβ）方面表现出显著疗效。尽管如此， 改善AD相关记忆障碍的效果有限。调节这些的特定神经回路 认知过程，但在AD大脑中进行性改变，可以作为治疗后的治疗目标。 去除Aβ斑块。在我以前的研究中，我证明了中缝背核（DRN）5-羟色胺（5-HT）， HT）神经元向海马腹侧CA 1（vCA 1）提供单突触输入。此外，基因消融 5-HT合成选择性地在这些vCA 1投射DRN神经元损害年轻小鼠的空间记忆。在 此外，vCA 1中5-HT 2C受体（5-HT 2CR）的遗传缺失导致年轻人的空间记忆缺陷， 小鼠我还观察到，氯卡色林，一种5-HT 2CR的选择性激动剂，可以改善空间记忆缺陷， 6月龄敲入AD小鼠模型（APPNL-G-F），与vCA 1中突触可塑性恢复相关 神经元总之，我提出了一个假设，即5-HTergic DRN到vCA 1回路通过以下途径调节空间记忆： 5-HT 2CR，阿尔茨海默病记忆症状的治疗靶点。K99阶段将侧重于 这个回路的上游节点，vCA 1投射5-HT神经元。光纤测光实验将用于 监测这些投射vCA 1的5-HT神经元的实时活动，以及vCA 1中的5-HT释放， 对应于记忆获取和提取行为。交叉逆行化学发生 方法将用于进一步测试vCA 1投射5-HT神经元的抑制是否会抑制记忆 功能以及激活这些神经元是否会挽救APPNL-G-F小鼠和老年人的记忆障碍 小鼠在R 00阶段，我将利用我从 K99期，以测试下游5-HT 2CR表达vCA 1神经元的功能意义。我会用 纤维光度法监测记忆测试期间表达5-HT 2CR的vCA 1神经元的活性， 使用化学发生学方法来评估这些神经元在记忆功能中的功能相关性。在 此外，我还将测试降低Aβ（aducanumab）和5-HT 2CR激动剂的联合治疗 （氯卡色林）在APPNL-G-F小鼠和老年小鼠中的作用。这项研究将促进我们对电路的了解 记忆功能的潜在机制，并评估5-HT 2CR激动剂作为一种新的治疗方法的可能性。 与降低Aβ药物联合治疗AD。此外，K99阶段将提供理想的 培训机会，使我掌握基本的技术、知识和解决问题的技能。这些将 准备我的研究R 00阶段和一个独立的研究生涯，专注于电路机制 不同的行为。

PROJECT SUMMARY Despite the tremendous efforts in Alzheimer’s disease (AD) research, we have not made much progress in understanding the pathophysiology of AD or inhibiting/correcting AD-related behavioral symptoms. The recent FDA-approved aducanumab demonstrated significant efficacy in reducing amyloid β (Aβ). Still, it showed a limited effect in improving AD-related memory impairments. The specific neural circuits that mediate these cognitive processes but are altered progressively in the AD brains may serve as a treatment target after the removal of Aβ plaques. In my previous studies, I demonstrated that dorsal Raphe nucleus (DRN) serotonin (5- HT) neurons provide monosynaptic inputs to the hippocampal ventral CA1 (vCA1). Further, genetic ablation of 5-HT synthesis selectively in these vCA1-projecting DRN neurons impaired spatial memory in young mice. In addition, genetic deletion of the 5-HT 2C receptor (5-HT2CR) in the vCA1 led to spatial memory deficits in young mice. I also observed that lorcaserin, a selective agonist of 5-HT2CR, can ameliorate spatial memory deficits in a 6-month-old knock-in AD mouse model (APPNL-G-F), associated with restoration of synaptic plasticity in vCA1 neurons. Together, I developed a hypothesis that a 5-HTergic DRN to vCA1 circuit regulates spatial memory via 5-HT2CR, a therapeutic target for memory symptoms in Alzheimer’s disease. The K99 phase will focus on the upstream node of this circuit, the vCA1-projecting 5-HT neurons. Fiber photometry experiments will be used to monitor the real-time activity of these vCA1-projecting 5-HT neurons, as well as 5-HT release in the vCA1, corresponding to memory acquisition and retrieval behaviors. The intersectional retrograde chemogenetic approach will be used to further test whether inhibition of the vCA1-projecting 5-HT neurons would inhibit memory function and whether activating these neurons would rescue memory impairments in APPNL-G-F mice and aged mice. During the R00 phase, I will utilize the techniques and the problem-solving experience I acquire from the K99 phase to test the functional significance of the downstream 5-HT2CR-expressing vCA1 neurons. I will use fiber photometry to monitor the activity of 5-HT2CR-expressing vCA1 neurons during the memory test and will use the chemogenetic approach to assess the functional relevance of these neurons in memory function. In addition, I will also test the combination treatment of Aβ-lowering (aducanumab) and 5-HT2CR agonism (lorcaserin) in APPNL-G-F mice and aged mice. The proposed studies will advance our knowledge of the circuitry mechanisms underlying memory function and evaluate the possibility of 5-HT2CR agonism as a novel therapeutic target for AD in combination with Aβ-reducing medications. In addition, the K99 phase will provide an ideal training opportunity to equip me with essential techniques, knowledge, and problem-solving skills. These will prepare me for the R00 phase of research and an independent research career focusing on circuitry mechanisms of different behaviors.