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

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个研究星形胶质细胞神经元动力学的独立研究项目， 性唤起和酒精使用障碍（AUD）。我从众多的实验训练中受益匪浅 技术包括双光子显微镜、神经生理学、电路解剖学和行为学。期间 在这笔资助（K99）的指导阶段，我将继续与我的共同导师 Drs. 密切合作。 姆里甘卡·苏尔和埃琳娜·瓦泽。 Mriganka 是皮质信息处理、神经元 星形胶质细胞电路和光学技术。 Elena Vazey 是去甲肾上腺素信号传导、压力、 酒精相关行为和化学遗传学。此外，我还会收到导师团队的建议 由博士组成。凯瑞·雷斯勒、希瑟·理查森和托马斯·卡什。他们的综合专业知识 范围涵盖应激病理生理学、酒精相关处理、边缘系统和奖励回路， 神经调节和焦虑行为。我的导师团队提供的额外培训将使我装备 凭借概念和技术敏锐性成为酒精领域的重要贡献者 行为和压力。该培训将在脑与认知科学系内进行 麻省理工学院，提供充满活力的知识研究社区和广泛的研究 基础设施支持。在我的博士后研究期间，我开发了同时 对星形胶质细胞-神经元网络进行成像，以研究星形胶质细胞在信息处理中的作用。这项工作导致 我的任务是研究星形胶质细胞如何通过去甲肾上腺素（NE）影响皮质回路的神经调节。我有 发现了一个有趣的星形胶质细胞-神经元钙特征，反映了皮质处理过程中的变化 高度兴奋的时期。此外，目前正在测试唤醒障碍和 AUD 阻断了这些特征，表明星形胶质细胞-神经元相互作用可能提供重要的见解 压力和 AUD 的病理生理学。我的近期目标是了解这些事件是如何发生的 与觉醒和饮酒行为相关，并确定与异常 NE 的关系 发布。 （目标 1）我将研究小鼠前额皮质 (PFC) 中的星形胶质细胞-神经元处理 使用体内双光子成像时积极饮酒。 （目标 2）我将确定 NE 的角色 通过 NE 的药理学和化学遗传学操作影响星形胶质细胞-神经元生理学 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饮酒中的作用。这些实验将 阐明 PFC 中星形胶质细胞神经元失调与 NE 释放和 AUD 的关系。