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
- 来源:
- 关键词:Abeta clearanceAblationAducanumabAgingAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAmyloid beta-ProteinAntibodiesBehaviorBehavioral SymptomsBenchmarkingBiosensorBrainBrain regionCombined Modality TherapyDisease ProgressionDrug TargetingElectrophysiology (science)ExcisionFDA approvedFiberFunctional Magnetic Resonance ImagingFunctional disorderGeneticHippocampusImageImmunohistochemistryImpaired cognitionImpairmentKnock-inKnowledgeLeadLearning SkillMediatingMemoryMemory LossMemory impairmentModelingMonitorMusNeuronsNeurosciencesNeurotransmittersPharmaceutical PreparationsPhasePhotometryPhysiologicalProblem SolvingResearchRoleSenile PlaquesSerotoninSerotonin AgonistsSymptomsSynaptic plasticityTechniquesTechnologyTestingTimeTrainingViralWild Type Mouseabeta depositionagedaging populationassociated symptomcareercognitive benefitscognitive processdesigndorsal raphe nucleusdrug developmentexperienceexperimental studygenetic approachimprovedmemory acquisitionmemory retrievalmortalitymouse modelneural circuitneural correlatenew therapeutic targetnovelpharmacologicreal time monitoringreceptorrestorationskillsspatial memorytherapeutic targettooltraining opportunity
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)
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