The Influence of Acute Stress and Astrocytic GQ-Signaling on Dopamine-Dependent Behavior

The Influence of Acute Stress on Dopamine-dependent Behavior Mental health disorders, such as anxiety and depression, have been linked to disruptions in dopamine transmission (Zweifel et al., 2011; Tye et al., 2013). Studies have shown that stress can exacerbate symptoms of anxiety and depression (Sinha, 2001; Meyer et al., 2001). Therefore, determining how stress influences the dopamine system can potentially identify targets to minimize the impact of stress on mental health disorders. Research shows that acute stress induces long-lasting enhanced conditioned responding, and this effect depends on the dopamine system (Stelly et al., 2020). Here, I tested the hypothesis that corticotropin-releasing factor (CRF) is the stress signal mediating this behavioral effect. I found that antagonizing CRF receptors in the ventral tegmental area (VTA) attenuated the effect of stress on conditioned responding. CRF has been shown to enhance NMDA receptor currents in ventral tegmental area (VTA) dopamine neurons (Ungless, 2003). NMDA receptor activation in the VTA is critical for reward learning (Wanat et al., 2009). Therefore, I next examined if stress-enhanced conditioned responding involved NMDA receptor activation in the VTA. I found that antagonizing NMDA receptors attenuated head entries during the reward-predictive cue. This data suggests that CRF signaling and NMDA receptor activation in the VTA are involved with stress-enhanced conditioned responding. The Influence of Astrocytic Gq-signaling on Dopamine-dependent Behavior With at least 19.7 million adults having battled a substance use disorder (SUD) in 2017, SUDs are a significant problem within the United States (Hardey, 2021). Studies have shown that the mesolimbic dopamine system is involved with a variety of drug-dependent behaviors (Oliva & Wanat, 2016). Identifying strategies to regulate dopamine neuron activity is a potential strategy to modulate drug-dependent behaviors that involve the dopamine system. Increasing evidence highlights VTA astrocytes may be involved in modulating drug-dependent behavior as astrocytes facilitate excitation of local GABA neurons, which in turn inhibit dopamine neurons (van Zessen et al., 2012). One method for engaging this pathway is by using chemogenetics to selectively stimulate Gq-signaling in VTA astrocytes in order to determine how astrocytic regulation influences drug-dependent behavior. Here, I tested the hypothesis that midbrain astrocytes are a target for reducing drug-dependent behaviors. I found that Gq-pathway activation in VTA astrocytes elicited a conditioned place aversion. Prior research illustrated that decreasing dopamine neuron activity can similarly result in avoidance (Acquas et al., 1989). This data suggests VTA astrocytes could be targeted to regulate some drug-dependent behaviors that involve the dopamine system.