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Sources of Cholinergic Modulation of Cortical Microcircuits

皮质微电路胆碱能调节的来源

基本信息

批准号：
9760973
负责人：
Stephanie E. Myal
金额：
$ 5万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760973
关键词：
3-Dimensional Acetylcholine Analysis of Variance Anatomy Antipsychotic Agents Architecture Area Attention Attentional deficit Brain Cell Nucleus Cells Cerebral cortex Cholinergic Agonists Cholinergic Receptors Cognition Cognition Disorders Cognitive deficits Color Complement Complex Data Detection Diffuse Electrophysiology (science)Equilibrium Excitatory Synapse Feedback Fiber Future Goals Imaging Techniques Immunohistochemistry Impairment In Vitro Interneurons Label Learning Link Literature Medial Mediating Methods Modeling Molecular Target Mus Muscarinic Acetylcholine Receptor Neurobehavioral Manifestations Neurologist Neuromodulator Neurons Neurotransmitters Nicotinic Receptors Nonparametric Statistics Output Paper Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacology Study Physicians Physiological Physiology Principal Investigator Psychiatrist Resolution Rodent Role Schizophrenia Scientist Sensory Signal Transduction Site Slice Somatosensory Cortex Somatostatin Source Stimulus Suggestion Synapses Techniques Testing Thalamic Nuclei Thalamic structure Time Training Transgenic Mice Viral Whole-Cell Recordings Work basal forebrain base cell type cellular targeting cholinergic cholinergic neuron confocal imaging daily functioning experimental study fluorescence imaging in vivo insight nerve supply neural circuit neuropsychiatric disorder neuroregulation new therapeutic target novel optogenetics patch clamp postsynaptic presynaptic receptor expression reconstruction response sensory cortex sensory input sensory stimulus skills temporal measurement

项目摘要

PROJECT TITLE Sources of Cholinergic Modulation of Cortical Microcircuits PROJECT SUMMARY The neurotransmitter acetylcholine (ACh) is important for attention and implicated in the cognitive symptoms of schizophrenia. In the cerebral cortex, rapid release of ACh acts as an attention signal, activating a disinhibitory circuit that “frees” projection neurons to receive input from the thalamus and transmit information to other brain areas. Our lab uses the primary somatosensory cortex (S1) of mice to model basic, highly conserved aspects of cortical circuitry. In a recent paper, we showed that endogenously released ACh strengthens intra-cortical excitation in a cell type- and synapse-specific way in mouse S1. We also find intrinsic responses to ACh in different cell types, mediated distinctly by nicotinic and muscarinic receptors. To fully understand how ACh modulates circuits underlying cognition, we need to know the sources of ACh modulation of cortical excitability. The main source of cortical ACh is the basal forebrain. However, there are also cortical ACh neurons of unknown function which could potentially influence cholinergic signaling in a sparse, targeted manner. In Aim 1, we propose to anatomically assess the relative contribution of basal forebrain and cortically-derived ACh to cholinergic innervation of four neuron types, and functionally assess the contribution of these inputs to postsynaptic ACh responses using whole-cell recordings with optogenetics in brain slices. We hypothesize that cortical cholinergic cells get basal forebrain inputs and selectively target interneurons in deeper cortical layers, in contrast to the spatially diffuse, cell type-nonspecific inputs from the basal forebrain. We suspect that ACh selectively mediates thalamocortical excitation as well. In a recent paper, we found that endogenous Ach strengthens intra-cortical excitatory synapses onto somatostatin, but not PV, interneurons. However, activating cholinergic receptors pharmacologically strengthens both types of synapses, suggesting that physiologic ACh release is spatially segregated to target certain synapses. Prior pharmacological work suggests that thalamic inputs from the ventral posterior medial nucleus (VPM, a lower-order sensory thalamic nucleus) express nicotinic receptors, but it is unclear whether these inputs are strengthened by endogenous ACh, or whether inputs from a higher-order thalamic nucleus (the posterior medial nucleus, POm) could also be facilitated. Thalamic inputs show plasticity after attention-based learning, and we suspect that ACh may shift cortical circuits to favor different thalamic inputs during states of attention. In Aim 2, we will anatomically assess whether ACh release sites are located on VPM and POm thalamic inputs, and functionally assess whether endogenous ACh strengthens VPM and POm inputs using whole-cell recordings with dual-color optogenetics in brain slices. We hypothesize that ACh release sites are more commonly associated with POm inputs (to layers 2 and 5) than VPM inputs (to layer 4), and that endogenous ACh release has time-variable, facilitating effects on POm and VPM synapses.

项目名称大脑皮层微电路的胆碱能调制来源项目总结神经递质乙酰胆碱(ACh)对注意力很重要，并与认知症状有关精神分裂症。在大脑皮层，ACh的快速释放起到了注意信号的作用，激活了一种去抑制 “释放”投射神经元以接受来自丘脑的输入并将信息传递给其他大脑的回路区域。我们的实验室使用小鼠的初级躯体感觉皮层(S1)来模拟基本的、高度保守的方面大脑皮层回路。在最近的一篇论文中，我们证明了内源性释放的ACh可以增强皮质内的ACh 以一种细胞类型和突触特异的方式在小鼠S1中兴奋。我们还发现了ACh的内在反应不同的细胞类型，明显地由烟碱和毒扁豆碱受体介导。要充分了解ACH如何为了调制认知基础的回路，我们需要知道ACh调制皮层兴奋性的来源。皮质ACh的主要来源是基底前脑。然而，也有未知的皮层ACh神经元。可能以稀疏的、有针对性的方式潜在地影响胆碱能信号的功能。在目标1中，我们建议从解剖学上评估基底前脑和皮质来源的相对贡献。 ACh对四种类型神经元的胆碱能神经支配，并从功能上评估这些输入对用光遗传学全细胞记录的脑片突触后ACh反应。我们假设皮质胆碱能细胞获得基底前脑输入并选择性地靶向更深处的中间神经元皮质层，与来自基底前脑的空间弥漫的、细胞类型非特定的输入形成对比。我们怀疑ACh也选择性地介导了丘脑皮质的兴奋。在最近的一篇论文中，我们发现内源性Ach增强皮质内兴奋性突触至生长抑素，而不是PV，中间神经元。然而，激活胆碱能受体在药物上可以加强这两种类型的突触，这表明生理性ACh的释放在空间上是以某些突触为靶点的。前期药理工作提示丘脑从低阶感觉丘脑腹侧后内侧核(VPM)传入细胞核)表达尼古丁受体，但尚不清楚这些输入是否被内源性加强 ACh，或者来自更高阶丘脑核(后内侧核，POM)的输入是否也可能提供便利。丘脑输入在基于注意力的学习后表现出可塑性，我们怀疑ACh可能会发生变化大脑皮质回路在注意力状态下有利于不同的丘脑输入。在目标2中，我们将从解剖角度评估 ACh释放部位是否位于VPM和POM丘脑输入端，并从功能上评估内源性ACh利用双色光遗传学全细胞记录增强VPM和POM输入脑片。我们假设ACh释放部位更多地与POM输入有关(到层2和层5)而不是VPM输入(到层4)，且内源ACH释放具有时间变量，对POM和VPM突触的易化作用。