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.

学会避免厌恶结果会促进韧性并抑制广义恐惧的表达 在人类中。因此，人们非常有兴趣识别介导主动回避的细胞过程 学习。积极回避学习的第一步是在厌恶性相遇期间积极回应 由腹侧对盖区（VTA）多巴胺神经元控制的过程。最近的研究表明 学习不仅是由神经元驱动的，而是由星形胶质细胞 - 神经元相互作用驱动的。因此，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 控制主动避免学习的过程。 星形胶质细胞是当地神经回路的积极参与者，他们对神经递质做出反应并释放 发射器本身。特别是，星形胶质细胞上的GQ耦合受体的激活促进了Ca2+ - 谷氨酸的依赖释放。进行了星形胶质细胞CA2+水平的光度计记录以检查 VTA星形胶质细胞在厌恶情况下的细胞活性。初步发现说明了VTA星形胶质细胞CA2+ 接受不可避免的脚垫任务训练的大鼠的水平增加。此外，选择性刺激GQ VTA星形胶质细胞中的信号传导降低了在不可避免的应力和升高期间启动动作的潜伏期 伏隔核（NAC）中的多巴胺水平。这些数据共同突出了VTA星形胶质细胞（1）进行 在厌恶情况下细胞活性的变化，（2）调节NAC中的多巴胺水平，（3）促进 不可避免的应力期间的主动行为反应。由于主动响应是必要的第一步 积极的避免学习，VTA星形胶质细胞可能是控制回避学习的中心节点。这 该提议的总体假设是，VTA星形胶质细胞有助于通过 谷氨酸在VTA中的Ca2+依赖性释放以及NAC中多巴胺水平的随后升高。到 解决这个问题，该提案中的实验将病毒操纵VTA星形胶质细胞CA2+信号传导 记录VTA星形胶质细胞Ca2+水平，VTA中的神经谷氨酸信号和NAC中的多巴胺水平。 总的来说，该建议将描述VTA星形胶质细胞在积极回避学习中的作用。