Optogenetic dissection of brain network deficits in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种以记忆力和其他认知功能的进行性丧失为特征的神经退行性疾病。一些证据表明，神经网络损伤导致AD患者的认知和行为缺陷，但潜在的细胞和分子机制尚不完全清楚。阿尔茨海默病大脑中几种神经递质系统受损，尤其是胆碱能神经元。然而，药物，如乙酰胆碱酯酶抑制剂，开发针对个体神经递质系统已经遇到了有限的成功。因此，有人认为，长期和人为升高的环境神经递质水平可能干扰阶段性突触信号，导致突触外受体的异常张力激活。因此，系统机制的阐明可能为开发更有效的治疗方法提供新策略，包括更好地了解认知功能的远程电路和局部微电路，以及更好地理解由单个神经递质及其受体引发的突触传递的相位和张力模式的作用和分子基础。光遗传学的出现与自由运动动物进行认知任务的大规模体内记录相结合，为绘制功能电路和确定不同突触激活模式对改善AD认知缺陷的影响提供了极好的机会。前额叶皮层（PFC）与多种皮层和皮层下结构相互作用，在工作记忆、长期记忆巩固和行为执行中发挥重要作用。由于Meynert基底核（NBM）的神经元丢失是AD大脑的一个突出特征，NBM是基底前脑向皮层提供远程投射的一个组成部分，我们希望重点阐明NBM- pfc网络活动支持AD认知缺陷的细胞和分子机制。为了实现这一目标，我们提供的证据表明，APP41系AD小鼠在3个月大时皮层中表达高水平的淀粉样肽¿（A¿），表现出胆碱能和gaba能标记物减少，认知缺陷，theta和gamma振荡改变以及癫痫放电增加。此外，神经调节蛋白1 （NRG1）突变与精神病患者的晚发性家族性AD有关。我们的初步结果表明，NRG1改善了APP41小鼠的认知缺陷，与毒蕈碱乙酰胆碱受体M2形成复合物，并且是ach诱导的神经元兴奋性所必需的。胆碱能神经元缺乏NRG1的小鼠PFC神经元振荡受损。为了进一步阐明其分子和细胞机制，本研究提出了三个目标。目的1是表征AD小鼠认知任务期间PFC的网络活动。目的2是确定胆碱能和gaba能对AD小鼠网络病理生理和行为的贡献。目的3是确定NRG1在AD小鼠NBM-PFC回路、网络活动和认知功能发展中的作用。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of memory and other cognitive functions. Several lines of evidence suggest that neural network impairment leads to cognitive and behavioral deficits in AD, but the underlying cellular and molecular mechanisms are not completely understood. Several neurotransmitter systems are impaired in AD brain, in particular cholinergic neurons. However, drugs, such as acetylcholine esterase inhibitors, that are developed to target individual neurotransmitter systems have met with limited success. As a result, it has been suggested that prolonged and artificially elevated ambient levels of neurotransmitters may interfere with phasic synaptic signaling and lead to aberrant tonic activation of extrasynaptic receptors. Thus, elucidation of systems mechanisms may provide insights into novel strategies to develop more effective treatments for improving cognitive function, including better information on the long-range circuits and local microcircuits underlying cognitive function and better understanding of the roles and molecular basis of phasic and tonic modes of synaptic transmission elicited by individual neurotransmitters and their receptors. The advent of optogenetics coupled with large-scale in vivo recording of freely moving animals performing cognitive tasks provides an excellent opportunity to map functional circuitry and to determine the effect of different synaptic activation patterns to ameliorate cognitive deficits in AD. The prefrontal cortex (PFC) interacts with multiple cortical and subcortical structures and plays an important role in working memory, long-term memory consolidation and execution of actions. As neuronal loss in the nucleus basalis of Meynert (NBM), a component of the basal forebrain that provides long-range projections to the cortex, is a prominent feature in AD brain, we would like to focus on elucidating the cellular and molecular mechanisms of the NBM-PFC network activity underpinning cognitive deficits in AD. Toward this goal, we have provided evidence that APP41 line of AD mice, which express high levels of Amyloid peptide ¿ (A¿) in the cortex at 3 months of age, displays reduced cholinergic and GABAergic markers, cognitive deficits, altered theta and gamma oscillations and increased epileptic discharge. Furthermore, a neuregulin 1 (NRG1) mutation is associated with late-onset familial AD in patients with psychosis. Our preliminary results show that NRG1 improves cognitive deficits in APP41 mice, forms a complex with muscarinic acetylcholine receptor M2 and is required for ACh-induced neuronal excitability. Neuronal oscillations in the PFC are impaired in mice lacking NRG1 in the cholinergic neurons. To further elucidate the molecular and cellular mechanisms, three aims are proposed in the present application. Aim 1 is to characterize the network activity in the PFC during cognitive tasks in AD mice. Aim 2 is to determine the cholinergic and GABAergic contribution to network pathophysiology and behavior in AD mice. Aim 3 is to determine the role of NRG1 in the development of the NBM-PFC circuit, network activity and cognitive function in AD mice.