Activation of VTA GABA Neurons Disrupts Reward Seeking by Altering Temporal Processing

Abstract

The role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by scalloping over the 30s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.

Ventral pallidal GABAergic neuron calcium activity encodes cue-driven reward-seeking and persists in the absence of reward delivery

“…Rats received preoperative injections of carprofen (5 mg/kg) for analgesia and cefazolin (75 mg/kg) to prevent infection. To achieve cell-type specific calcium indicator expression we used a dual viral approach combining a glutamate decarboxylase 1 (GAD1) promoter virus for the expression of Cre recombinase with a virus for expression of GCaMP6f in a cre-dependent manner (Liu et al, 2013; Wakabayashi et al, 2019; Shields et al, 2021). Rats (n=19, 9 male, 10 female) received 0.8 uL of a 1:1 mixture of AAV9-Syn-Flex-GCaMP6f (2.1 * 10^13 GC/mL; Addgene) and AAV8-GAD1-cre (8.29×10^13 GC/mL; University of Minnesota Viral Vector Core) was injected unilaterally into VP.…”