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

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）进展为阿尔茨海默病（AD）的危险因素，个体对痛苦的易感性显著增加 AD的风险。这些发现意味着，对行为压力的适应能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中的机制。应激相关脑回路的激活增加，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AD的记忆障碍。然而，在正常和患病的大脑中，行为应激、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，激活特定的BLA传入海马模仿行为应激对细胞病理和认知功能的影响。重要的是，沉默这些通路可以防止重复行为应激后的认知障碍。此外，该回路的慢性失活似乎改善了家族性AD小鼠模型中的AD样表型。因此，BLA-海马回路，如此严重地涉及应激对海马功能的影响，应该以仅通过使用细胞和回路特异性光遗传学技术可实现的方式密切评估其对AD中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，BLA-海马应激回路不是由一个孤立的途径，但腹侧和背侧的组件，这个电路可能发挥不同的作用，在焦虑的调制和行为应激对认知功能的影响。本申请将检验以下假设：行为应激导致BLA输入途径激活至HPC导致AD病理恶化，并将确定该途径的腹侧和背侧成分的相对贡献。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和改善认知障碍，并可能为脑深部电刺激技术在AD治疗中的应用提供理论基础。

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.