A Functional Taxonomy of Cortical Astrocytes

皮质星形胶质细胞的功能分类

基本信息

批准号：
9215993
负责人：
Kira Poskanzer
金额：
$ 30万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215993
关键词：
Acute Address Affect Astrocytes Biological Brain Brain region CRISPR/Cas technology Calcium Categories Cells Cereals Chemicals Communities Complex Conflict (Psychology)Data Detection Electrophysiology (science)Event Feedback Future Genetic Glutamate Receptor Glutamates Hand Heterogeneity Image Imaging Device In Vitro Lead Light Maps Mediating Methods Molecular Monitor Morphology Neuraxis Neurobiology Neuroglia Neuromodulator Neurons Neurosciences Neurotransmitter Receptor Neurotransmitters Optics Outcome Pharmacological Treatment Phenocopy Photons Physiological Physiology Play Property Research Research Personnel Research Proposals Resolution Role Signal Transduction Slice Synapses System Taxonomy Techniques Testing Therapeutic Validation base cell type clinical application drug of abuse extracellular in vivo in vivo imaging neglect neural circuit neuronal circuitry neuroregulation neurotransmitter release novel presynaptic receptor receptor function receptor-mediated signaling response spatiotemporal technique development tool two-photon

项目摘要

A Functional Taxonomy of Cortical Astrocytes The vast majority of neural circuit studies neglect to take into account the non-neuronal cells in the brain, but in order to truly appreciate neural circuit function, we will need to monitor and manipulate activity in many cell types. Our understanding of astrocyte signaling is years behind that of neurons, because the appropriate tools have been lacking for these largely electrically silent cells. We don't know what extracellular signals astrocytes respond to, nor how they contribute to circuit function. This is due, in part, to the lack of methods that replicate the breadth of possible presynaptic activity in vivo, i.e. the release of neurotransmitter. The current proposal addresses gaps in our understanding of astrocytes in neural circuit function and harnesses the power of light-activatable tools to tackle them. We propose to apply a suite of optochemical tools that allow spatiotemporally precise and physiologically relevant release of neurotransmitter to astrocytes and neurons in cortical circuits. In Aim 1, we will test the hypothesis that astrocytes response acutely to the synaptic release of excitatory and inhibitory synaptic activity with differential and predictable activity. We will use simultaneous two-photon optochemical uncaging and calcium imaging in astrocyte branches to test their physiological response to glutamatergic and GABAergic synaptic events, and uncover the heterogeneity of molecular mechanisms that govern these responses. We will activate astrocytes in vivo using these optochemical techniques, and in Aim 2, genetically silence astrocyte-specific excitatory and inhibitory receptors during in vivo imaging and electrophysiology to determine the astrocytic signals that lead to downstream cortical state shifts. In Aim 3, we will validate novel optochemical tools to mimic the release of neuromodulators in the cortical circuit, testing their function in neurons and astrocytes. With these tools in hand, we will be able to probe the repertoire of signals to which astrocytes respond in the circuit.

皮质星形胶质细胞的功能分类学绝大多数神经回路研究忽略了不考虑非神经元的大脑中的细胞，但是为了真正欣赏神经电路功能，我们需要监视并操纵许多细胞类型的活动。我们对星形胶质细胞信号的理解是多年在神经元的背后，因为这些工具在很大程度上缺乏电静音细胞。我们不知道细胞外信号星形胶质细胞反应，也不它们有助于电路功能。这部分是由于缺乏复制的方法体内可能突触前活性的广度，即神经递质的释放。电流提案解决了我们对神经回路功能中星形胶质细胞的理解和利用可轻相机工具的力量来解决它们。我们建议使用一套光化学工具允许时空精确且在生理上相关的释放神经递质到皮质回路中的星形胶质细胞和神经元。在AIM 1中，我们将测试星形胶质细胞对突触的反应的假设释放具有差异和可预测活性的兴奋性和抑制性突触活性。我们将同时在星形胶质细胞中同时使用两光学的光化学未成纪录和钙成像分支以测试其对谷氨酸能和GABA能突触事件的生理反应，并发现控制这些反应的分子机制的异质性。我们将使用这些验光技术在体内激活星形胶质细胞，在AIM 2中，基因2 在体内成像期间沉默星形胶质细胞特异性兴奋性和抑制受体电生理学确定导致下游皮质状态的星形胶质细胞信号转移。在AIM 3中，我们将验证新颖的磁化学工具以模仿释放皮质回路中的神经调节剂，测试其在神经元和星形胶质细胞中的功能。和这些工具掌握了，我们将能够探测星形胶质细胞的信号曲目在电路中响应。