Balancing motivation through VTA GABA/Glutamate co-transmission

Project Summary Updates: I am moving to a new position at Dartmouth College as an independent, tenure-track Assistant Professor in the Department of Psychological and Brain Sciences. Here I will conduct the R00 phase experiments and develop my own independent research program. The overall aims of the R00 phase have not changed from the K99 proposal. Identifying the neural circuit mechanisms underlying both homeostatic and uncontrolled motivation are crucial for developing more targeted and effective therapeutic treatments for neuropsychiatric disorders like major depression or bipolar disorder. Within mesolimbic brain reward circuitry, the ventral tegmental area (VTA) is a major regulator of both reward and aversion. While generally reduced to its dopamine projection neurons, the VTA also contains neurons that co-release inhibitory GABA and excitatory glutamate and, similar to dopamine projections, can modulate motivation. However, the functional role of this GABA/glutamate co-release is still not well understood, and major questions regarding their role in positive vs. negative reinforcement remain. In particular, why would neurons simultaneously send an inhibitory and excitatory signal? During the R00 phase, I will unify my prior expertise with newly acquired skills to determine the physiological and behavioral role of a newly-described VTA GABA/glutamate projection to amygdala. Using in vivo calcium imaging, I will first monitor activity of VTA GABA/glutamate terminals in amygdala during an effort-based instrumental sucrose task (Aim 1), and will then identify the net effect of optogenetically stimulating VTA GABA/glutamate terminals on cell-defined amygdala populations (Aim 2). These results will significantly expand our understanding of the role of VTA co-release in complex motivated behavior relevant to models of bipolar disorder and depression, and will crucially pave the way for more targeted approaches that form the basis my independent research program.