Midbrain astrocytes controlling active avoidance learning

中脑星形胶质细胞控制主动回避学习

• 批准号: 10621234
• 负责人: Matthew J. Wanat
• 金额: $ 21.85万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621234
• 关键词: Action Potentials; Address; Astrocytes; Avoidance Learning; Cell membrane; Cell physiology; Coupled; Data; Dopamine; Fright; Genetic; Glutamates; Goals; Human; Impairment; Learning; Mediating; Midbrain structure; Neurons; Neurotransmitters; Nucleus Accumbens; Outcome; Participant; Photometry; Physiological; Physiological Processes; Process; Pump; Rattus; Research; Role; Signal Pathway; Signal Transduction; Stress; Testing; Training; Ventral Tegmental Area; Viral; active control; behavioral response; designer receptors exclusively activated by designer drugs; dopaminergic neuron; experimental study; glutamatergic signaling; interest; mesolimbic system; neural circuit; optogenetics; prevent; promote resilience; receptor; transmission process

Learning to avoid aversive outcomes promotes resilience and suppresses the expression of generalized fear in humans. As such, there is great interest in identifying the cellular processes that mediate active avoidance learning. The first step in active avoidance learning is to actively respond during the aversive encounter, a process that is controlled by ventral tegmental area (VTA) dopamine neurons. Recent research indicates learning is not solely driven by neurons, but rather by astrocyte-neuron interactions. Therefore, one must determine how VTA astrocytes regulate dopamine neurons during aversive situations to delineate the cellular processes that control active avoidance learning. Astrocytes are active participants in local neural circuits as they respond to neurotransmitters and release transmitters themselves. In particular, activation of Gq coupled receptors on astrocytes promotes the Ca2+- dependent release of glutamate. Photometry recordings of astrocyte Ca2+ levels were performed to examine the cellular activity of VTA astrocytes during aversive situations. Preliminary findings illustrate VTA astrocyte Ca2+ levels increased in rats trained on an inescapable footshock task. Furthermore, selectively stimulating Gq signaling in VTA astrocytes reduced the latency to initiate actions during inescapable stress and elevated dopamine levels in the nucleus accumbens (NAc). Together, these data highlight VTA astrocytes (1) undergo changes in cellular activity during aversive situations, (2) regulate dopamine levels in the NAc and (3) promote active behavioral responses during inescapable stress. Since active responding is a necessary first step for active avoidance learning, VTA astrocytes are likely a central node for controlling avoidance learning. The overarching hypothesis of this proposal is that VTA astrocytes facilitate active avoidance learning through the Ca2+-dependent release of glutamate in the VTA and subsequent elevation of dopamine levels in the NAc. To address this, the experiments in this proposal will virally manipulate VTA astrocyte Ca2+ signaling while recording VTA astrocyte Ca2+ levels, neuronal glutamate signals in the VTA, and dopamine levels in the NAc. Collectively, this proposal will delineate the role of VTA astrocytes during active avoidance learning.

学会避免令人厌恶的结果可以增强复原力并抑制普遍恐惧的表达 在人类中。因此，人们对识别介导主动回避的细胞过程非常感兴趣 学习。主动回避学习的第一步是在厌恶的遭遇中积极做出反应， 该过程由腹侧被盖区（VTA）多巴胺神经元控制。最近的研究表明 学习不仅由神经元驱动，而且由星形胶质细胞与神经元的相互作用驱动。因此，人们必须 确定 VTA 星形胶质细胞在厌恶情况下如何调节多巴胺神经元，以描绘细胞 控制主动回避学习的过程。 星形胶质细胞是局部神经回路的积极参与者，因为它们对神经递质做出反应并释放 发射机本身。特别是，星形胶质细胞上 Gq 偶联受体的激活可促进 Ca2+- 谷氨酸的依赖性释放。进行星形胶质细胞 Ca2+ 水平的光度测定记录以检查 厌恶情况下 VTA 星形胶质细胞的细胞活动。初步结果表明 VTA 星形胶质细胞 Ca2+ 在接受不可避免的足部电击任务训练的老鼠中，该水平升高。此外，选择性刺激 Gq VTA 星形胶质细胞中的信号传导减少了在不可避免的压力和升高时启动行动的潜伏期 伏隔核 (NAc) 中的多巴胺水平。总之，这些数据强调了 VTA 星形胶质细胞 (1) 经历 厌恶情况下细胞活动的变化，(2) 调节 NAc 中的多巴胺水平，(3) 促进 在不可避免的压力下积极的行为反应。由于积极响应是必要的第一步 主动回避学习中，VTA 星形胶质细胞可能是控制回避学习的中心节点。这 该提案的总体假设是 VTA 星形胶质细胞通过 VTA 中谷氨酸的 Ca2+ 依赖性释放以及随后 NAc 中多巴胺水平的升高。到 为了解决这个问题，本提案中的实验将病毒式地操纵 VTA 星形胶质细胞 Ca2+ 信号传导，同时 记录 VTA 星形胶质细胞 Ca2+ 水平、VTA 中的神经元谷氨酸信号和 NAc 中的多巴胺水平。 总的来说，该提案将描述 VTA 星形胶质细胞在主动回避学习中的作用。