Noradrenergic gating of astrocyte calcium-mediated homeostasis in vivo

星形胶质细胞钙介导体内稳态的去甲肾上腺素能门控

• 批准号: 10679269
• 负责人: Cameron Lewis Smith
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679269
• 关键词: Adrenergic Receptor; Affect; Animals; Area; Arousal; Astrocytes; Attention; Behavior; Behavioral; Brain; Ca(2+)-Transporting ATPase; Calcium; Calcium Oscillations; Calcium Signaling; Data; Ensure; Event; Exhibits; Generations; Glutamates; Goals; Heterogeneity; Homeostasis; Human; Impairment; Linear Models; Link; Literature; Locomotion; Machine Learning; Mammals; Measurement; Measures; Mediating; Methods; Microscope; Modeling; Mus; Mydriasis; Neuromodulator; Neuromodulator Receptors; Neurons; Neurophysiology - biologic function; Norepinephrine; Norepinephrine Receptors; Performance; Personal Satisfaction; Play; Population; Positioning Attribute; Primates; Process; Pupil; Regulation; Reporter; Rodent; Role; Running; Sensory; Shapes; Signal Pathway; Signal Transduction; Site; Stimulus; Techniques; Testing; Time; Visual Cortex; Wakefulness; Work; alertness; awake; experimental study; high dimensionality; in vivo; multiphoton imaging; neural; neuroregulation; neurotransmission; noradrenergic; novel; optogenetics; response; sensor; tool

PROJECT SUMMARY Humans and mice show various brain states which are integral for survival and well-being. In awake mice, alert brain states are distinguished by locomotion, whisking, or pupil dilation in the absence of overt behavior. These accompany changes in neural function within the cortex such as reduced population correlation, increased sensory response, and reduced oscillatory activity. In addition, norepinephrine (NE) levels are increased in cortex during these activated periods. These findings are consistent with a long literature linking NE to alertness, attention, and behavioral performance in primates and rodents. Our project is focused on understanding changes in cortical astrocyte activity during these aroused brain states. Astrocyte calcium activity increases during both running and pupil dilation, but the heterogeneity of this response and the relative contribution of neuromodulators or local changes in neural activity to these astrocytic calcium events is not well understood. Conversely, astrocyte calcium events may be important for regulating processes such as glutamate homeostasis that directly impact neural activity on short timescales, but these effects have not been well-characterized in vivo. Thus, the overall goal of this project is to understand the local and global factors contributing to changes in astrocyte calcium activity and the effect of astrocyte calcium on local networks of neurons. We hypothesize that noradrenergic neuromodulation drives calcium-mediated increases in glutamate homeostasis that facilitate and/or support changes in local neuronal brain state. To test this hypothesis, we will first investigate the heterogeneity of somatic and microdomain calcium waves in response to NE increases during alert brain states. We will then test the effects of artificially reducing astrocyte calcium on state changes in local populations of neurons, and whether reducing astrocyte calcium responses to NE locally affects glutamate homeostasis. Our final experiment will use optogenetics to test the sufficiency of NE signaling pathways for any observed changes and the necessity of astrocyte calcium for these induced changes. The results of this project will more clearly define the upstream and downstream mechanisms of calcium signaling within astrocytes across different brain states and their effect on neural populations.

项目概要 人类和小鼠表现出不同的大脑状态，这些状态对于生存和福祉至关重要。在清醒的小鼠中，警觉 在没有明显行为的情况下，大脑状态通过运动、快速运动或瞳孔扩张来区分。这些 伴随皮质内神经功能的变化，例如群体相关性降低、 感觉反应，并减少振荡活动。此外，去甲肾上腺素（NE）水平在 在这些激活时期的皮层。这些发现与将 NE 与 灵长类动物和啮齿动物的警觉性、注意力和行为表现。我们的项目专注于 了解这些唤醒的大脑状态期间皮质星形胶质细胞活动的变化。星形胶质细胞钙 在跑步和瞳孔扩张期间活动都会增加，但这种反应的异质性和相对 神经调节剂或神经活动的局部变化对这些星形细胞钙事件的贡献尚不清楚 明白了。相反，星形胶质细胞钙事件可能对于调节过程很重要，例如 谷氨酸稳态在短时间内直接影响神经活动，但这些影响尚未得到证实 体内特征良好。因此，该项目的总体目标是了解本地和全球因素 促进星形胶质细胞钙活性的变化以及星形胶质细胞钙对局部网络的影响 神经元。我们假设去甲肾上腺素能神经调节驱动钙介导的谷氨酸增加 促进和/或支持局部神经元大脑状态变化的稳态。为了检验这个假设，我们将 首先研究体细胞和微域钙波响应 NE 增加的异质性 在大脑警觉状态下。然后我们将测试人工减少星形胶质细胞钙对状态变化的影响 在局部神经元群体中，以及减少星形胶质细胞对 NE 的钙反应是否局部影响 谷氨酸稳态。我们的最终实验将使用光遗传学来测试 NE 信号传导的充分性 任何观察到的变化的途径以及星形胶质细胞钙对于这些诱导变化的必要性。这 该项目的结果将更清晰地定义钙信号传导的上下游机制 不同大脑状态的星形胶质细胞及其对神经群体的影响。