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施加强大的控制--尽管人们对此知之甚少。胆碱能信号的失衡是神经退行性疾病人格和记忆发生根本变化的基础。事实上，阿尔茨海默病(AD)认知功能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团的胆碱能信号丢失所致。令人震惊的是，人们对中枢神经系统内源性ACh介导的活动知之甚少。胆碱能神经元的数量很少，尽管它们的皮质投射很广泛。对于这种高度不稳定的调制发射器的非定向释放如何有效地调整电路活动，以匹配对任务的警惕程度并优化性能结果，人们了解更少。由于PNS功能的混杂作用和现有药物的低选择性，CNS胆碱能信号转导的药理学仍不清楚。了解ACh的调节作用机制，并有能力控制ACh的调节作用，是开发全新的神经退行性疾病治疗方法(如AD)的最终前沿。我将产生表达光遗传探针的小鼠，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。通过滴定植入光纤的NBM神经元的光诱导激活与抑制，我将确定在任务执行过程中电路活动的轮廓及其内源性ACh的调制。我预测，通过调整胆碱能活动的范围和时间，我将能够在与注意力相关的任务中控制表现的准确性。我的目标是开发新的治疗方法来治疗阿尔茨海默病相关的认知衰退。植入光学探针结合焦点靶场传递靶向刺激中枢胆碱能核团

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 deliver