Neurochemical Signaling of Reward and Aversion to Ventral Tegmental Area Glutamate Neurons

Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters of the nervous system. However, identifying how these neurotransmitters regulate motivated behavior has remained challenging because of a lack of tools (1) capable of measuring neurotransmission at the temporal scale of motivated behaviors and (2) capable of capturing chemical signaling onto genetically-distinct neuronal populations. We have overcome these obstacles by implementing genetically-encoded fluorescent indicators to monitor both glutamate and GABA input dynamics exclusively to ventral tegmental area (VTA) glutamate neurons during reward and aversion-based behaviors. We identify that glutamate and GABA inputs to VTA glutamate neurons differentially and dynamically signal reward and aversion-based cues and outcomes. This research provides foundational evidence that links distinct neurotransmitters to motivated behaviors regulated by VTA glutamate neurons. Ventral tegmental area (VTA) glutamate neurons signal and participate in reward and aversion-based behaviors. However, the neurochemical mechanisms that underlie how these neurons contribute to motivated behaviors is unknown. We used a combination of optical sensors to identify how distinct neurochemical inputs to VTA glutamate neurons participate in motivated behavior within female and male transgenic mice. Activity of glutamate inputs to VTA glutamate neurons increased for both reward-predicting and aversion-predicting cues and aversive outcomes, but subpopulations of glutamate inputs were increased or decreased by reward. For both reward and aversion-based cues and outcomes, activity of GABA inputs to VTA glutamate neurons mostly decreased. GCaMP recordings showed overall population increases in VTA glutamate neuron intracellular calcium during reward and aversion-based cues and outcomes. Electrophysiological recordings of VTA VGluT2 neurons showed that glutamate receptor activation increases firing while loss of excitation via glutamate receptor blockade decreases firing. GABA-A receptor activation decreased VTA glutamate neuron firing but GABA-A receptor blockade did not significantly change VTA glutamate neuron firing. Electrophysiological recordings in coordination with our sensor data suggest that glutamate inputs strongly regulate VTA glutamate neuron participation in diverse motivated behaviors.