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

5-HTergic DRN vCA1 回路与阿尔茨海默病

• 批准号: 10740050
• 负责人: Hesong Liu
• 金额: $ 11.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740050
• 关键词: Abeta clearance; Ablation; Aducanumab; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid beta-Protein; Antibodies; Behavior; Behavioral Symptoms; Benchmarking; Biosensor; Brain; Brain region; Combined Modality Therapy; Disease Progression; Drug Targeting; Electrophysiology (science); Excision; FDA approved; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Hippocampus; Image; Immunohistochemistry; Impaired cognition; Impairment; Knock-in; Knowledge; Lead; Learning Skill; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Monitor; Mus; Neurons; Neurosciences; Neurotransmitters; Pharmaceutical Preparations; Phase; Photometry; Physiological; Problem Solving; Research; Role; Senile Plaques; Serotonin; Serotonin Agonists; Symptoms; Synaptic plasticity; Techniques; Technology; Testing; Time; Training; Viral; Wild Type Mouse; abeta deposition; aged; aging population; associated symptom; career; cognitive benefits; cognitive process; design; dorsal raphe nucleus; drug development; experience; experimental study; genetic approach; improved; memory acquisition; memory retrieval; mortality; mouse model; neural circuit; neural correlate; new therapeutic target; novel; pharmacologic; real time monitoring; receptor; restoration; skills; spatial memory; therapeutic target; tool; training opportunity

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.

项目摘要 尽管在阿尔茨海默氏病（AD）研究方面做出了巨大努力，但我们在 了解AD的病理生理或抑制/纠正与AD相关的行为症状。最近 FDA批准的Aducanumab在还原淀粉样β（Aβ）方面表现出显着的效率。尽管如此，它显示了一个 在改善与广告相关的记忆障碍方面的影响有限。介导这些的特定神经回路 认知过程，但在广告大脑中逐渐改变，可以作为治疗目标 去除Aβ斑块。在我先前的研究中，我证明了背raphe核（DRN）5-羟色胺（5-- HT）神经元为海马腹CA1（VCA1）提供单突触输入。此外，遗传消融 在这些VCA1投影的DRN神经元中，5-HT合成幼体的空间记忆损害。在 另外，VCA1中5-HT 2C受体（5-HT2CR）的遗传缺失导致空间记忆定义 老鼠。我还观察到5-HT2CR的选择性激动剂Lorcasein可以改善空间记忆在 一个6个月大的敲入AD小鼠模型（APPNL-G-F），与VCA1中突触可塑性的恢复有关 神经元。我共同提出了一个假设，即5个矫正DRN到VCA1电路通过 5-HT2CR，是阿尔茨海默氏病记忆症状的治疗靶点。 K99阶段将重点放在 该电路的上游节点，即VCA1预测的5-HT神经元。纤维光度法实验将用于 监视这些VCA1投影5-HT神经元的实时活动，以及VCA1中的5-HT释放 对应于记忆采集和检索行为。交叉逆行化学发生 方法将用于进一步测试抑制VCA1投射5-HT神经元是否会抑制记忆 功能以及激活这些神经元是否会挽救AppNL-G-F小鼠的记忆障碍并老化 老鼠。在R00阶段，我将利用我从 K99相测试下游5-HT2CR的VCA1神经元的功能意义。我会用 纤维光度法监测记忆测试期间5-HT2CR的VCA1神经元的活性，并将 使用化学发生方法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-HT2CR激动剂的组合处理 （Lorcasein）在AppNL-G-F小鼠和老年小鼠中。拟议的研究将提高我们对电路的了解 记忆功能的基础机制，并评估5-HT2CR激动剂作为一种新型疗法的可能性 AD的靶标与减少Aβ的药物结合使用。此外，K99阶段将提供理想 培训机会，使我具备基本技术，知识和解决问题的技能。这些会 我为R00研究阶段和独立研究职业做好准备，重点是电路机制 不同的行为。