Astrocyte-neuron circuits underlying cortical mechanisms of learned behavior

星形胶质细胞-神经元回路是学习行为皮质机制的基础

• 批准号: 10709012
• 负责人: MRIGANKA SUR
• 金额: $ 42.83万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709012
• 关键词: Acute; Address; Affect; Astrocytes; Beds; Behavior; Brain Diseases; CRISPR/Cas technology; Calcium; Calcium Signaling; Complex; Computer Analysis; Cues; Data; Development; Forelimb; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Glutamates; Goals; Individual; Learning; Mediating; Methods; Modeling; Molecular; Motor; Motor Cortex; Motor Neurons; Movement; Mus; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Pattern; Physiological; Process; Role; Shapes; Sodium; Specific qualifier value; Stereotyping; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Training; Viral; brain dysfunction; cell type; differential expression; gamma-Aminobutyric Acid; high resolution imaging; in vivo; insight; knock-down; learned behavior; motor behavior; motor learning; neuronal circuitry; neurotransmission; neurotransmitter uptake; novel; optogenetics; prevent; response; skills; spatiotemporal; tool; transmission process; uptake

Astrocytes are the major non-neuronal cell type in the cortex and are increasingly recognized as key contributors to the development, plasticity and function of neuronal circuits. Yet, how they participate with neurons in learned behavior and dynamically shape the underlying cortical circuits is poorly understood. The primary motor cortex is required for learning and executing voluntary movements: the acquisition of a cued, stereotyped, movement in mice is accompanied by synaptic remodeling of motor cortex neurons and the emergence of coordinated movement-related ensemble neuronal activity. Here, we propose to examine functional astrocyte mechanisms in motor cortex that mediate synaptic plasticity and neuronal dynamics during motor learning. Astrocytes have highly ramified fine processes that contact nearly all synapses in the cortex, where they modulate synaptic transmission and plasticity by mechanisms that include uptake of glutamate and GABA, primarily via the transporters GLT1 and GAT3 respectively. Astrocytes also respond to, as well as modulate, synaptic activity with spatiotemporally heterogeneous calcium transients in their processes, termed microdomains. We will examine the role of astrocytes in shaping motor cortex circuits as mice learn a forelimb lever push movement, including cued response onset and reliable movement trajectory, using a range of cutting-edge approaches: simultaneous high-resolution imaging of astrocytes and neurons in vivo, computational encoding-decoding models of astrocyte and neuronal activity, astrocyte-specific gene expression analyses, and novel astrocyte optogenetic and CRISPR tools alongside established chemogenetic and viral knockdown methods. Building on our preliminary data, which demonstrate parallel learning-related changes in astrocyte microdomain responses and neuronal responses, along with gene expression changes in astrocyte GLT1 and GAT3, in Aim 1 we will determine functional astrocyte calcium signatures in motor cortex during learning and their relationship to neuronal activity and behavior. We hypothesize that astrocytes shape neuronal plasticity during task learning with corresponding plasticity in their microdomain calcium responses, which we will specify computationally. In Aim 2, we will determine the effect of astrocyte calcium signaling on motor learning and neuronal responses. We hypothesize that disruption of calcium transients alters the emergence of neuronal ensembles and expert behavior, potentially by altering astrocyte gene expression of transporter mechanisms. In Aim 3, we will determine the role of astrocyte neurotransmitter transporter function in motor cortex circuits and learning. We hypothesize that disrupting astrocytic modulation of excitatory transmission via GLT1, and inhibitory neurotransmission via GAT3, disrupts astrocytic calcium responses together with neuronal circuit plasticity and behavior. Together, these studies will provide a mechanistic, computational view of astrocyte involvement in the function and plasticity of cortical circuits, reveal their task-specific contributions to neuronal responses and learned behavior, and provide the basis for understanding their role in a range of brain disorders and diseases.

星形胶质细胞是皮质中主要的非神经元细胞类型，越来越被认为是关键因素 神经元电路的发展，可塑性和功能。然而，他们如何与神经元一起参与学习 行为并动态塑造基本的皮质回路知之甚少。主要运动皮层 学习和执行志愿运动所必需 在小鼠中，运动皮层神经元的突触重塑和配位的出现 与运动相关的集合神经元活性。在这里，我们建议检查功能性星形胶质细胞机制 在运动皮层中，在运动学习过程中介导突触可塑性和神经元动力学。星形胶质细胞具有 高度分支的精细过程，几乎接触皮层中的所有突触，它们调节突触 通过包括吸收谷氨酸和GABA的机制的传播和可塑性，主要是通过 转运蛋白GLT1和GAT3。星形胶质细胞还响应以及调节突触活动 在其过程中，时空异质钙瞬时，称为微域。我们将检查 随着老鼠学习前肢杠杆推动运动，星形胶质细胞在塑造运动皮层电路中的作用，包括 提示响应发作和可靠的运动轨迹，使用一系列尖端方法：同时 体内星形胶质细胞和神经元的高分辨率成像，计算编码模型的星形胶质细胞模型 和神经元活性，星形胶质细胞特异性基因表达分析以及新型星形胶质细胞光遗传学和 CRISPR工具以及已建立的化学发生和病毒敲低方法。基于我们的初步 数据表明，星形胶质细胞微域反应和神经元的平行学习相关的变化 反应，以及星形胶质细胞GLT1和GAT3的基因表达变化，在AIM 1中，我们将确定 运动皮质中的功能性星形胶质细胞钙在学习过程中及其与神经元活动的关系 和行为。我们假设在任务学习过程中，星形胶质细胞塑造神经元的可塑性，相应 其微区钙反应中的可塑性，我们将通过计算指定。在AIM 2中，我们将 确定星形胶质细胞信号传导对运动学习和神经元反应的影响。我们假设 钙瞬变的破坏改变了神经合奏和专家行为的出现，可能会改变 通过改变转运蛋白机制的星形胶质细胞基因表达。在AIM 3中，我们将确定 星形胶质细胞神经递质转运蛋白在运动皮层电路和学习中的功能。我们假设这一点 通过GLT1和通过GAT3抑制性神经传递的兴奋性传播的星形细胞调节， 与神经元电路的可塑性和行为一起破坏星形胶质性钙反应。在一起，这些 研究将提供星形胶质细胞参与功能和可塑性的机械计算视图 皮质回路，揭示其对神经元反应的特定任务贡献和学习的行为，并提供 理解它们在脑部疾病和疾病范围内的作用的基础。