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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轻度认知障碍（MCI）发展为阿尔茨海默病（AD）的危险因素，并且个体对痛苦的易感性显着增加