Optogenetic dissection of brain network deficits in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，以记忆和其他认知功能的进行性丧失为特征。一些证据表明，神经网络损伤会导致AD患者的认知和行为障碍，但其潜在的细胞和分子机制尚不完全清楚。阿尔茨海默病的几个神经递质系统受损，尤其是胆碱能神经元。然而，针对单个神经递质系统开发的药物，如乙酰胆碱酯酶抑制剂，取得的成功有限。因此，有人认为，环境中神经递质水平的延长和人为升高可能干扰突触时相信号，并导致突触外受体的异常紧张性激活。因此，阐明系统机制可能为开发更有效的改善认知功能的治疗方法提供新的策略，包括更好地了解认知功能背后的长程回路和局部微回路的信息，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时相和紧张性模式的作用和分子基础。光遗传学的出现，加上对自由活动的动物进行认知任务的大规模活体记录，为绘制功能电路图和确定不同突触激活模式对改善AD认知缺陷的效果提供了一个极好的机会。前额叶皮质(PFC)与多种皮质和皮质下结构相互作用，在工作记忆、长期记忆巩固和动作执行中发挥重要作用。Meynert基底核(NBM)是阿尔茨海默病(AD)脑内的一个重要特征，它是基底前脑的一个组成部分，向大脑皮质提供长程投射。因此，我们将重点探讨NBM-PFC网络活动在AD认知功能障碍中的细胞和分子机制。为了达到这一目标，我们提供了证据表明，APP41系AD小鼠在3月龄时大脑皮质中表达高水平的淀粉样多肽，表现出胆碱能和GABA能标志的减少，认知障碍，改变了theta和Gamma振荡，增加了癫痫放电。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小鼠的认知障碍，与M受体M2形成复合体，是ACh诱导的神经元兴奋性所必需的。在胆碱能神经元中缺乏NRG1的小鼠，PFC中的神经元振荡受到损害。为了进一步阐明分子和细胞机制，本申请提出了三个目标。目的1是研究AD小鼠认知任务过程中前额叶皮质的网络活动。目的2确定胆碱能和GABA能在AD小鼠网络病理生理和行为中的作用。目的3确定NRG1在AD小鼠NBM-PFC回路、网络活动和认知功能发育中的作用。

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.