Examination of neural circuits underlying mood disorders in Alzheimer?s disease

阿尔茨海默病情绪障碍的神经回路检查

基本信息

批准号：
8711599
负责人：
Li-Huei Tsai
金额：
$ 169.45万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711599
关键词：
Acute Alzheimer&apos s Disease Alzheimer&apos s disease risk Amygdaloid structure Amyloid deposition Anterior Anxiety Area Attenuated Aversive Stimulus Behavior Behavioral Brain Brain region Cells Characteristics Chronic Chronic stress Cognition Disorders Cognitive deficits Data Deep Brain Stimulation Dementia Development Diagnosis Disease Disease Progression Distress Dorsal Emotions Etiology Functional disorder Future Hippocampus (Brain)Hydrocortisone Impaired cognition Impairment Incidence Individual Link Major Depressive Disorder Mediating Memory impairment Mental Depression Mood Disorders Output Pathology Pathway interactions Patients Perception Pharmacogenetics Phenotype Plasma Play Predisposition Relative (related person)Research Risk Factors Role Stress Symptoms Synapses Techniques Testing Therapeutic Translations Wild Type Mouse biological adaptation to stress cellular pathology cingulate cortex cognitive function depressive symptoms emotional distress entorhinal cortex excitatory neuron familial Alzheimer disease improved mild cognitive impairment mouse model neural circuit neuropsychiatry optogenetics prevent public health relevance resilience tool

项目摘要

DESCRIPTION (provided by applicant): Recent research suggests that the presence of neuropsychiatric symptoms is a risk factor for progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), and an individual's susceptibility to distress significantly increases their risk of AD. These findings imply that poor resilience to behavioral stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. The increased activation of stress-related brain circuits, such as that between the basolateral amygdala (BLA) and the hippocampus, may underlie aspects of hippocampus pathology and exacerbate memory impairment in AD. However, the mechanistic link between behavioral stress, amygdala output, and hippocampal dysfunction in the normal and diseased brain remains unclear. Our preliminary results utilize optogenetic and pharmacogenetic techniques to show that activation of specific BLA afferents to the hippocampus mimics the effects of behavioral stress upon both cellular pathology and cognitive function. Importantly, silencing these pathways prevents cognitive impairment following repeated behavioral stress. Moreover, chronic inactivation of this circuit appears to ameliorate AD-like phenotypes in a mouse model of familial AD. Therefore, the BLA- hippocampus circuit, so heavily implicated in the impact of stress upon hippocampal function, should be closely evaluated, in a manner only achievable via the use of cell- and circuit-specific optogenetic techniques, for its contribution to cognitive dysfunction and cellular pathology in AD. Our preliminary data also show that the BLA- hippocampal stress circuit is not comprised of a solitary pathway, but that the ventral and dorsal components of this circuit may play differential roles in the modulation of anxiety and the impact of behavioral stress upon cognitive function. This application will test the hypothesis that the activation of BLA input pathways to the HPC as a result of behavioral stress leads to the exacerbation of AD pathology, and will determine the relative contribution of the ventral and dorsal components of this pathway. These studies will examine how the targeted silencing of specific brain circuits can slow disease progress and ameliorate cognitive impairment, and may provide rationale for the application of deep brain stimulation techniques in the treatment of AD.

描述（由申请人提供）：最近的研究表明，神经精神症状的存在是从轻度认知障碍（MCI）到阿尔茨海默氏病（AD）进展的危险因素，并且个体对困扰的易感性显着增加他们的广告风险。这些发现表明，对行为压力的韧性不佳不仅是痴呆的特征，而且可能反映了疾病病因涉及的机制。与压力相关的脑回路的激活增加，例如基底外侧杏仁核（BLA）和海马之间的激活可能是海马病理学的基础，并加剧了AD中的记忆障碍。但是，在正常和患病的大脑中，行为应力，杏仁核输出和海马功能障碍之间的机械联系尚不清楚。我们的初步结果利用光遗传学和药物遗传学技术表明，特定BLA传入对海马的激活模仿了行为应激对细胞病理学和认知功能的影响。重要的是，沉默这些途径会防止反复行为应力后的认知障碍。此外，该电路的慢性失活似乎可以改善家庭AD小鼠模型中的AD样表型。因此，应以一种仅通过使用细胞和电路特异性光遗传技术来实现的方式对压力对海马功能的影响的严重影响的蓝光电路应进行仔细评估，以便其对AD中的认知功能障碍和细胞病理学的贡献。我们的初步数据还表明，海马应力回路不是由孤立途径组成的，而是该回路的腹侧和背部成分在调节焦虑和行为应力对认知功能的影响中起着不同的作用。该应用将检验以下假设：由于行为应力，BLA输入途径对HPC的激活导致AD病理的加剧，并确定该途径的腹侧和背部成分的相对贡献。这些研究将研究特定脑回路的靶向沉默如何减缓疾病进展并改善认知障碍，并可能为在AD治疗中应用深脑刺激技术的应用提供理由。