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）发展为阿尔茨海默病（AD）的危险因素，并且个体对痛苦的敏感性显着增加他们患 AD 的风险。这些发现表明，对行为压力的抵抗力差不仅仅是痴呆症的一个特征，而且可能反映了疾病病因学的机制。与压力相关的大脑回路的激活增加，例如基底外侧杏仁核 (BLA) 和海马体之间的回路，可能是海马体病理学某些方面的基础，并加剧 AD 中的记忆障碍。然而，正常和患病大脑中行为压力、杏仁核输出和海马功能障碍之间的机制联系仍不清楚。我们的初步结果利用光遗传学和药物遗传学技术表明，海马体特定 BLA 传入神经的激活模拟了行为压力对细胞病理学和认知功能的影响。重要的是，沉默这些通路可以防止重复行为压力后的认知障碍。此外，该回路的慢性失活似乎可以改善家族性 AD 小鼠模型中的 AD 样表型。因此，BLA-海马回路与压力对海马功能的影响密切相关，应该以只有通过使用细胞和回路特异性光遗传学技术才能实现的方式来仔细评估其对认知功能障碍和认知功能障碍的贡献。 AD 的细胞病理学。我们的初步数据还表明，BLA-海马压力回路并非由单独的通路组成，但该回路的腹侧和背侧组件可能在焦虑调节和行为压力对认知功能的影响中发挥不同的作用。该应用将测试以下假设：由于行为应激而激活 HPC 的 BLA 输入通路会导致 AD 病理恶化，并将确定该通路的腹侧和背侧成分的相对贡献。这些研究将探讨特定脑回路的靶向沉默如何减缓疾病进展和改善认知障碍，并可能为深部脑刺激技术在 AD 治疗中的应用提供理论依据。