Arousal-induced noradrenergic signaling modulates cortical astrocyte-neuron circuits during ethanol consumption

唤醒诱导的去甲肾上腺素能信号在乙醇消耗过程中调节皮质星形胶质细胞-神经元回路

• 批准号: 10831585
• 负责人: Grayson Oren Sipe
• 金额: $ 24.9万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831585
• 关键词: Ablation; Adrenergic Receptor; Affect; Alcohol consumption; Alcohols; Anatomy; Animals; Anxiety; Arousal; Astrocytes; Axon; Behavior; Brain; Calcium; Cells; Clinical; Clinical Trials; Cognitive Science; Color; Communities; Consumption; Development; Diagnosis; Diameter; Disease; Drug Targeting; Ethanol; Event; Fellowship; Female; Functional disorder; Future; Genetic; Goals; Grant; Head; Human; Hyperactivity; Image; Lead; Locomotion; Longitudinal Studies; Measures; Mediating; Mentors; Methods; Modeling; Mus; Neurons; Norepinephrine; Norepinephrine Receptors; Optics; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiology; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Predisposition; Prefrontal Cortex; Process; Property; Pupil; Research; Research Infrastructure; Rewards; Role; Sex Differences; Signal Transduction; Stress; Structure; Substance abuse problem; Techniques; Testing; Therapeutic; Therapeutic Effect; Titrations; Training; Wakefulness; Work; alcohol behavior; alcohol use disorder; antagonist; anxiety symptoms; career; comorbidity; drinking; drinking behavior; experimental study; extracellular; genetic manipulation; in vivo; in vivo two-photon imaging; information processing; inhibitory neuron; insight; male; neural; neuronal circuitry; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; pharmacologic; programs; response; sensor; two photon microscopy; two-photon; Ablation; Adrenergic Receptor; Affect; Alcohol consumption; Alcohols; Anatomy; Animals; Anxiety; Arousal; Astrocytes; Axon; Behavior; Brain; Calcium; Cells; Clinical; Clinical Trials; Cognitive Science; Color; Communities; Consumption; Development; Diagnosis; Diameter; Disease; Drug Targeting; Ethanol; Event; Fellowship; Female; Functional disorder; Future; Genetic; Goals; Grant; Head; Human; Hyperactivity; Image; Lead; Locomotion; Longitudinal Studies; Measures; Mediating; Mentors; Methods; Modeling; Mus; Neurons; Norepinephrine; Norepinephrine Receptors; Optics; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiology; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Predisposition; Prefrontal Cortex; Process; Property; Pupil; Research; Research Infrastructure; Rewards; Role; Sex Differences; Signal Transduction; Stress; Structure; Substance abuse problem; Techniques; Testing; Therapeutic; Therapeutic Effect; Titrations; Training; Wakefulness; Work; alcohol behavior; alcohol use disorder; antagonist; anxiety symptoms; career; comorbidity; drinking; drinking behavior; experimental study; extracellular; genetic manipulation; in vivo; in vivo two-photon imaging; information processing; inhibitory neuron; insight; male; neural; neuronal circuitry; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; pharmacologic; programs; response; sensor; two photon microscopy; two-photon

My career goal is to lead an independent research program studying astrocyte-neuron dynamics, arousal, and alcohol use disorder (AUD). I have benefitted from experimental training in numerous techniques including two-photon microscopy, neurophysiology, circuit anatomy, and behavior. During the mentored phase of this grant (K99), I will continue to work closely with my co-mentors, Drs. Mriganka Sur and Elena Vazey. Mriganka is an expert in cortical information processing, neuron- astrocyte circuits, and optical techniques. Elena Vazey is an expert in noradrenergic signaling, stress, alcohol-related behaviors, and chemogenetics. In addition, I will receive advice from my mentoring team consisting of Drs. Kerry Ressler, Heather Richardson, and Thomas Kash. Their combined expertise ranges across stress pathophysiology, alcohol-related processing, limbic and reward circuits, neuromodulation, and anxiety behaviors. The additional training from my mentoring team will equip me with the conceptual and technical acumen to become a significant contributor to the fields of alcohol behavior and stress. This training will be done within the Brain and Cognitive Sciences department at MIT, which provides both a vibrant intellectual research community and expansive research infrastructure support. During my postdoctoral fellowship, I developed novel methods of simultaneously imaging astrocyte-neuron networks to study astrocyte roles in information processing. This work led me to study how astrocytes affect neuromodulation of cortical circuits by norepinephrine (NE). I have found an intriguing astrocyte-neuron calcium signature that reflects a shift in cortical processing during periods of high arousal. Furthermore, the drugs that are currently being tested in arousal disorders and AUD block these signatures, suggesting that astrocyte-neuron interactions may provide crucial insight into the pathophysiology of stress and AUD. My immediate goals are to understand how these events relate to arousal and alcohol drinking behavior, and to determine the relationship with abnormal NE release. (Aim 1) I will study the astrocyte-neuron processing in the prefrontal cortex (PFC) while mice actively drink alcohol on using in vivo two-photon imaging. (Aim 2) I will determine the role of NE in affecting astrocyte-neuron physiology through pharmacological and chemogenetic manipulations of NE release. (Aim 3) Finally, during R00 phase, I will manipulate astrocyte-specific mechanisms to determine the role of astrocytes in arousal-mediated alcohol consumption. These experiments will clarify how astrocyte-neuron dysregulation in the PFC is related to NE release and AUD.

我的职业目标是领导一项独立的研究计划，研究星形胶质细胞神经动态， 唤醒和饮酒障碍（AUD）。我受益于许多实验培训 包括两光子显微镜，神经生理学，电路解剖学和行为的技术。期间 这笔赠款的指导阶段（K99），我将继续与我的联合委托人密切合作。 Mriganka Sur和Elena Vazey。 Mriganka是皮质信息处理的专家，神经元 - 星形胶质细胞电路和光学技术。埃琳娜·瓦泽（Elena Vazey 酒精相关的行为和化学遗传学。此外，我将收到我的指导团队的建议 由Drs组成。克里·雷斯勒（Kerry Ressler），希瑟·理查森（Heather Richardson）和托马斯·卡什（Thomas Kash）。他们的综合专业知识 跨压力病理生理学，与酒精相关的加工，边缘和奖励电路的范围， 神经调节和焦虑行为。我的指导团队的额外培训将使我装备 随着概念和技术敏锐度，成为酒精领域的重要贡献者 行为和压力。该培训将在大脑和认知科学系中进行 麻省理工学院既提供充满活力的知识研究社区，又提供广泛的研究 基础架构支持。在博士后奖学金中，我同时开发了新颖的方法 成像星形胶质细胞 - 神经元网络，以研究信息处理中的星形胶质细胞作用。这项工作带领 我研究星形胶质细胞如何影响去甲肾上腺素（NE）对皮质回路的神经调节。我有 发现一个有趣的星形胶质细胞神经元钙签名，反映了皮质加工过程中的变化 高唤醒的时期。此外，目前正在唤醒疾病和 AUD阻止这些签名，表明星形胶质细胞 - 神经元相互作用可能会提供至关重要的见解 进入压力和AUD的病理生理学。我的直接目标是了解这些事件是如何的 与唤醒和饮酒行为有关，并确定与异常NE的关系 发布。 （AIM 1）我将研究小鼠前额叶皮层（PFC）中的星形胶质细胞神经元加工 在使用体内两光子成像时积极喝酒。 （目标2）我将确定NE在 通过Ne 发布。 （目标3）最后，在R00阶段，我将操纵星形胶质细胞特异性机制 确定星形胶质细胞在唤醒介导的酒精消耗中的作用。这些实验会 阐明PFC中的星形胶质细胞 - 神经元失调与NE释放和AUD有关。