Cholinergic mechanisms of cortical activation

描述(由申请者提供)：当我们在警觉和昏昏欲睡状态之间转换时，我们参与并与周围环境成功互动的能力起伏不定。这些状态反过来又表现为大脑皮层中不同的电活动模式。特别是， 增强的警觉性与激活的、去同步化的皮质网络活动相关。基底核中的胆碱能细胞，通过激活皮质中的M胆碱型乙酰胆碱受体，被认为提供了“能量”的影响，介导了向这种激活状态的转变。这种转变对于提高我们快速处理不断变化的任务需求的能力至关重要。重要的是，这种神经调节系统在阿尔茨海默病和精神分裂症等神经疾病的背景下退化或出现故障，从而潜在地损害新皮质回路的同步、振荡特性及其在高级认知能力中的作用。基底核的激活和相关的乙酰胆碱释放如何改变皮质状态？几十年来，了解皮质状态转换的神经机制一直是神经科学家的中心目标，对于了解影响注意力和记忆的众多神经精神疾病的病理生理学基础，以及开发适当的治疗方法至关重要。寻找皮质状态转换的神经底物和机制的研究主要是通过电生理记录来分离细胞和突触效应，然后在脑片上沐浴或局部应用M受体激动剂。这种简约主义的方法揭示了毒碱信号可以增加或减少细胞的活性，以及以细胞类型特有的方式增加或减少突触的效率。然而，当ACh结合在一起时，对皮质神经元和突触的影响似乎是自相矛盾和不一致的。如果所有观察到的胆碱能毒碱能活动同时发生，它们将导致对皮层环路的相互矛盾的影响。我推测，大脑皮层ACh释放的动力学在时间上协调了这种细胞和突触效应的多样性，以便产生激活状态。我将在动物清醒时发生的自然状态转换期间皮质神经元和网络的胆碱能调节的背景下测试这一假说。为了解决这个问题，我开发了一种光遗传学辅助方法，并将使用它来记录基底核中的胆碱能细胞，因为它们变得活跃，并对皮质动力学施加调制影响。我还将使用这种方法来探索ACh对大脑皮质中已识别的GABA能中间神经元亚型的影响，因为网络转换到激活状态。最后，我建议使用特定细胞类型的特定M受体的遗传消融来减去独立的胆碱能效应，以调查它们对激活的皮质状态的转换、维持和特性的贡献。

DESCRIPTION (provided by applicant): Our ability to attend and interact successfully with our surroundings waxes and wanes, as we transition between alert and drowsy states. These states are, in turn, represented as distinct patterns of electrical activity in the cortex. In particular, enhanced vigilance is correlated with activated, desynchronized cortical network activity. Cholinergic cells in the nucleus basalis, through the activation of muscarinic acetylcholine receptors in the cortex, are thought to provide the 'energizing' influence that mediates the transition to this activated state. Such transition is crucial to our improved ability to rapidly handle changing task demands. Importantly, this neuromodulatory system degenerates or malfunctions in the context of neurological disorders, such as Alzheimer's disease and schizophrenia, thus potentially compromising the synchronizing, oscillatory properties of neocortical circuits and their role in higher order cognitive abilities. How does nucleus basalis activation and associated acetylcholine release alter cortical states? Understanding the neural mechanisms of cortical state transition has been a central goal of neuroscientists for decades, and is of crucial importance to understand the pathophysiological basis of numerous neuropsychiatric disorders affecting attention and memory, and to develop appropriate treatments. The search for the neural substrates and mechanisms of cortical state transition has been mostly studied by isolating cellular and synaptic effects through electrophysiological recordings in brain slices following bath or locally applied muscarinic receptor agonists. This reductionist approach has revealed that muscarinic signaling can increase or decrease cellular activity, as well as increase or decrease synaptic efficacy in a cell type- specific fashion. However, when integrated together, the effects of ACh on cortical neurons and synapses appear paradoxical and inconsistent. If all of the observed cholinergic muscarinic actions occurred simultaneously they would lead to contradictory effects on cortical circuits. I hypothesize that the dynamics of ACh release in the cortex coordinates in time this diversity of cellular and synaptic effects in order to give rise to the activated state. I will test this hypothsis in the context of cholinergic modulation of cortical neurons and networks during the natural state transitions that occur when an animal is awake. To tackle this problem, I have developed an optogenetically assisted method and will employ it to record from cholinergic cells in the nucleus basalis, as they become active and exert modulatory influences on cortical dynamics. I will also employ this method to explore ACh effects on identified GABAergic interneuron subtypes in the cortex, as the network transitions to the activated state. Finally, I propose to employ cell-type-specific genetic ablation of specific muscarinic receptors to subtract independent cholinergic effects, in order to investigate their contribution to the transition, maintenance, and properties f the activated cortical state.