Unveiling the role and taking control of Cholinergic Tone in circuits of attentio

描述 摘要： 中枢胆碱能回路对注意力、焦虑和睡眠等各种行为都有强大的控制作用，尽管人们对此知之甚少。胆碱能信号的不平衡是神经退行性疾病中人格和记忆的根本变化的基础。事实上，阿尔茨海默病（AD）的认知下降和焦虑加剧的早期迹象被认为是由于基底前脑胆碱能核胆碱能信号的丢失。令人震惊的是，很少有人知道内源性乙酰胆碱介导的活动在中枢神经系统。胆碱能神经元数量很少，但在其皮质投射广泛。关于这种高度不稳定的调节性递质的非定向释放如何有效地调节回路活动以使警惕程度与任务相匹配并优化性能结果，人们甚至更不了解。由于对PNS功能的混杂作用和可用药物的选择性差，CNS胆碱能信号传导的药理学仍然不清楚。了解ACh的调节作用机制并有能力控制ACh的调节作用是开发神经退行性疾病（如AD）全新治疗方法的最后前沿。我将产生表达光遗传学探针的小鼠，用于选择性激活或抑制Meynert基底核中的胆碱能神经元，Meynert基底核是ACh输入皮质和杏仁核的主要来源。通过滴定光诱导的激活与抑制的NBM神经元植入光纤，我将确定在任务执行过程中的电路活动和内源性乙酰胆碱的调制的配置文件。我预测，通过调整胆碱能活动的范围和时间，我将能够控制与注意力相关的任务的准确性。我的目标是开发新的治疗方法来治疗阿尔茨海默氏症相关的认知能力下降。通过植入光学探针结合胆碱能激动剂的局部靶向场递送靶向刺激CNS胆碱能核将构成CNS退行性疾病治疗的新时代。

DESCRIPTION Abstract: Central cholinergic circuits exert powerful - though poorly understood - control over behaviors as diverse as attention, anxiety and sleep. Imbalances in cholinergic signaling underlie fundamental changes in personality and memory in neurodegenerative diseases. Indeed, the early signs of cognitive decline and heightened anxiety pathognomonic for Alzheimer's disease (AD) are thought to be due to loss of cholinergic signaling from the basal forebrain cholinergic nuclei. Shockingly little is known about endogenous ACh-mediated activity in the CNS. Cholinergic neurons are few in number, though extensive in their cortical projections. Even less is understood about how the non-directed release of this highly labile modulatory transmitter potently tunes circuit activity to match the degree of vigilance to the task and optimize performance outcome. The pharmacology of CNS cholinergic signaling remains obscure due to confounding effects on PNS function and poor selectivity of available drugs. Understanding the mechanisms of, and having the ability to control, the modulatory actions of ACh is the final frontier in the development of entirely new therapeutic approaches to neurodegenerative diseases such as AD. I will generate mice expressing optogenetic probes for selective activation or inhibition of cholinergic neurons in the Nucleus Basalis of Meynert, the major source of ACh inputs to cortex and amygdala. By titrating the light-induced activation vs. inhibition of NBM neurons with implanted fiber-optics, I will determine the profile of circuit activity and its modulation by endogenous ACh during task performance. I predict that by tuning the extent and timing of cholinergic activity, I will be able to control performance accuracy in attention-related tasks. My goal is to develop novel therapeutic approaches to Alzheimer's-associated cognitive decline. Targeted stimulation of CNS cholinergic nuclei via implanted optical probes combined with focal target-field delivery of cholinergic agonists will comprise a new era in treatment of CNS degenerative disorders.