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

5-HTergic DRN vCA1 回路与阿尔茨海默病

基本信息

  • 批准号:
    10740050
  • 负责人:
  • 金额:
    $ 11.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Hesong Liu其他文献

Hesong Liu的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
  • 批准号:
    24K21101
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
  • 批准号:
    24K11201
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
  • 批准号:
    24K11281
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
  • 批准号:
    EP/Z001145/1
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
  • 批准号:
    2338890
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334777
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334775
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334776
  • 财政年份:
    2024
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
  • 批准号:
    515081333
  • 财政年份:
    2023
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
  • 批准号:
    2320040
  • 财政年份:
    2023
  • 资助金额:
    $ 11.19万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了