In a project that is highly complementary to project 1, Dr. Zweifel will lead a team of investigators asking how the Serotonergic and Dopaminergic systems of the brain interface to modulate affective state in the presence of stress and recovery from stress. Dopamine neurons located in the ventral tegmental area and serotonin neurons located in the dorsal raphe nucleus share common targets in the prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Each of these regions has been implicated in depression-related symptom domains and the balance of dopamine and serotonin in these regions is an important regulator homeostatic response to stress. Serotonin neurons of the DRN directly synapse onto dopamine neurons of the VTA, indicating a direct interaction between these systems. To establish the role of this circuit connection in behavioral regulation of stress and behavioral domains relevant to depression, this team will perform a detailed circuit analysis of serotonergic inputs from the DRN to dopamine neurons of the VTA and ask how this connectivity changes in response to social defeat stress in susceptible and resistance mice. To enhance the granularity of his circuit analysis, his group will measure excitatory and inhibitory coupling between serotonin and dopamine neurons in dopamine cells that project to specific areas of the brain. To ascertain how reward responding of serotonergic neurons change at the local circuit level of the DRN following social defeat in susceptible and resistant mice, they will monitor in vivo calcium dynamics in all serotonin producing neurons of the DRN and exclusively in those cells that synapse onto dopamine neurons. To establish the functional importance of serotonergic DRN input to the VTA in the mitigation of depression-related symptom domains following social defeat, in collaboration with Drs. Neumaier and Chavkin, he will selectively enhance the activity of DRN neurons that synapse onto dopamine cells using designer receptor (DREADD) technology. These studies, combined with the efforts described in the other projects of this center grant, will provide an unparalleled assessment the neural circuitry underlying susceptibility and resistance to social defeat stress, elucidate the therapeutic potential of an endogenous opioid system and define how it interfaces with these circuits, determine the impact of sex-specific differences in these circuits associated with stress-induced alterations in decision making, and provide detailed assessments of transcriptional and translational changes in treatment resistant females suffering from depression and in rodents susceptible to depression-related symptoms.
