Midbrain astrocytes controlling active avoidance learning

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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.