Cholinergic mechanisms of cortical activation

皮质激活的胆碱能机制

• 批准号: 8720452
• 负责人: William Javier Munoz Miranda
• 金额: $ 4.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720452
• 关键词: Ablation; Acetylcholine; Affect; Agonist; Alzheimer' s Disease; Animals; Attention; Basal Nucleus of Meynert; Bathing; Behavioral; Brain; Cell physiology; Cells; Cognitive; Data; Disease; Excitatory Synapse; Genetic; Goals; In Vitro; Interneurons; Label; Lead; Link; Maintenance; Mediating; Memory; Methods; Monitor; Muscarinic Acetylcholine Receptor; Muscarinics; Neurons; Parvalbumins; Pattern; Physiology; Property; Pyramidal Cells; Reporting; Role; Schizophrenia; Signal Transduction; Slice; Somatostatin; Structure; Subgroup; Synapses; System; Testing; Time; Wakefulness; Waxes; awake; base; cell type; cholinergic; improved; in vivo; neocortical; nervous system disorder; neuromechanism; neuropsychiatry; public health relevance; relating to nervous system; tool; vigilance

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.

描述（由申请人提供）：当我们在警觉状态和昏昏欲睡状态之间转换时，我们关注周围环境并成功互动的能力会时强时弱。这些状态反过来又表现为皮层中不同的电活动模式。尤其， 警惕性的提高与激活的、不同步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毒蕈碱乙酰胆碱受体，被认为提供了介导向这种激活状态转变的“供能”影响。这种转变对于我们提高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氏病和精神分裂症等神经系统疾病的背景下会退化或出现故障，从而可能损害新皮质回路的同步、振荡特性及其在高阶认知能力中的作用。基底核激活和相关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。对皮质状态转换的神经基质和机制的研究主要是通过沐浴或局部应用毒蕈碱受体激动剂后脑切片中的电生理记录来分离细胞和突触效应来研究的。这种还原论方法揭示了毒蕈碱信号传导可以增加或减少细胞活性，以及​​以细胞类型特异性方式增加或减少突触功效。然而，当整合在一起时，乙酰胆碱对皮质神经元和突触的影响显得矛盾且不一致。如果所有观察到的胆碱能毒蕈碱作用同时发生，它们将导致对皮质回路的矛盾影响。我假设皮质中乙酰胆碱释放的动态及时协调细胞和突触效应的多样性，以产生激活状态。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设。为了解决这个问题，我开发了一种光遗传学辅助方法，并将用它来记录基底核中的胆碱能细胞，当它们变得活跃并对皮质动力学产生调节影响时。当网络转变为激活状态时，我还将采用这种方法来探索 ACh 对皮层中已识别的 GABA 能中间神经元亚型的影响。最后，我建议采用特定毒蕈碱受体的细胞类型特异性基因消融来消除独立的胆碱能效应，以研究它们对激活皮质状态的转变、维持和特性的贡献。