Characterizing the Inputs and Functionality of Stress- and Reward-Encoding Neuronal Ensembles in the Ventral Tegmental Area
Summary
Excessive amounts of stress can contribute to the development and exacerbation of various psychiatric diseases associated with maladaptive reward-driven reinforcement. The ventral tegmental area (VTA) is a mesolimbic brain region that is involved in the integration and processing of both stressful and rewarding experiences and is therefore believed to play a major role in stress-associated psychopathological manifestations. The VTA connectome comprises many synaptic inputs from numerous other brain regions, and it has been demonstrated that these inputs can differ in terms of the emotional valence that they encode. However, it remains elusive to what extent these inputs are engaged in response to a stressful and rewarding experience. The current study characterizes acute social defeat stress- and opioid-responsive neuronal ensembles within brain regions that project to the VTA. It also determines. First, we first quantified stress- and reward-related activation in VTA-projecting brain regions by using targeted recombination in active populations (TRAP2) and showed that acute social stress leads to increased activation in most brain regions whereas mu-opioid receptor agonist (D-Ala2,N-MePhe4,Gly-ol5 enkephalin (DAMGO) administration does not. By utilizing a retrogradely transported adeno-associated virus in combination with TRAP2 to identify monosynaptic VTA afferents responsive to acute social defeat and DAMGO, we found that the fraction of activated medial prefrontal cortex to VTA inputs is higher in the acute social defeat ensemble than in the DAMGO ensemble. Lastly, we sought to determine the functional role of social stress-responsive VTA neurons (VTASDS) in the expression of stress-driven cognitive effects. To that end, we induced the expression of an inhibitory DREADD in the VTASDS-ensemble and demonstrate that inhibition of these neurons during acute social stress precludes the expression of conditioned place aversion.