Midbrain astrocytes controlling active avoidance learning

学会避免令人厌恶的结果有助于提高韧性并抑制普遍恐惧的表达 在人类身上。因此，人们对识别调节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做出积极的反应， 受腹侧被盖区(VTA)多巴胺神经元控制的过程。最近的研究表明 学习不是单纯由神经元驱动的，而是星形胶质细胞-神经元相互作用的结果。因此，一个人必须 确定VTA星形胶质细胞如何在厌恶情况下调节多巴胺神经元，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 传送器本身。特别是，星形胶质细胞上GQ偶联受体的激活促进了钙离子的释放。 依赖谷氨酸的释放。用分光光度法记录星形胶质细胞的钙离子水平，以检测 厌恶状态下VTA星形胶质细胞的细胞活动。初步研究结果显示VTA星形胶质细胞钙离子 在进行不可避免的足部电击任务的训练中，大鼠的水平会增加。此外，选择性刺激GQ VTA星形胶质细胞中的信号传递缩短了在不可避免的压力下启动行动的潜伏期，并提高了 伏核(NAC)中的多巴胺水平。总之，这些数据突出了VTA星形胶质细胞(1)经历了 厌恶情境中细胞活动的变化，(2)调节NAC中的多巴胺水平，(3)促进 在不可避免的压力下做出积极的行为反应。由于主动响应是必要的第一步 主动回避学习，VTA星形胶质细胞可能是控制回避学习的中枢节点。这个 这一建议的主要假设是，VTA星形胶质细胞通过 依赖于钙离子的VTA中谷氨酸的释放，以及随后NAC中多巴胺水平的升高。至 为了解决这个问题，本方案中的实验将通过病毒方式操纵VTA星形胶质细胞的钙信号，同时 记录VTA星形胶质细胞内钙离子水平、VTA内神经元谷氨酸信号和NAC内多巴胺水平。 总而言之，这项建议将描绘出VTA星形胶质细胞在主动回避学习中的作用。

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.