Midbrain astrocytes controlling active avoidance learning

Learning to avoid stressful events promotes positive mental health outcomes. As such. there is significant interest to identify brain systems that mediate avoidance learning. While the cellular basis of learning has traditionally focused on neurons. accumulating evidence highlights learning depends on astrocyte-neuron interactions. Active avoidance learning depends on ventral tegmental area (VTA) dopamine neurons and their ability to promote active responses during aversive situations. Recent evidence highlights astrocytes in the VTA can modulate dopamine neurons. Determining how VTA astrocytes regulate dopamine transmission during aversive situations is therefore critical for identifying the cellular processes that underlie active avoidance learning.

Astrocytes are active participants in local neural circuits as they both respond to neurotransmitters and release transmitters. In particular. activation of Gq coupled receptors on astrocytes promotes the Ca2+-dependent release of glutamate. Preliminary experiments find that Gq pathway activation in VTA astrocytes reduced the latency to initiate active behavioral responses during inescapable stress and dopamine levels in the nucleus accumbens (NAc). Furthermore. photometry recordings of VTA astrocytes identified an increase in Ca2+ levels during the inescapable footshock task. 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 regulating 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. experiments will be performed to 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.