Opiate abuse is a major health concern and economic burden on society with overdose deaths rising dramatically in the past decade. Synaptic plasticity within the dopamine-rich ventral tegmental area (VTA) is a major target of addictive drugs, including opiates. Opioid exposure causes long-term potentiation at excitatory synapses and blocks it at inhibitory synapses on dopamine cells. The net result on synaptic strength is to increase dopamine cell firing, thought to be rewarding. For my dissertation, I use slice electrophysiology, optogenetics, and behavior techniques to characterize a previously unidentified form of long-term potentiation at inhibitory synapses in the VTA. Most reports describing synaptic plasticity in the VTA used nonspecific electrical stimulation of synaptic inputs in brain slices without consideration of circuit specificity. Given that separate VTA circuits mediate distinct behavioral responses, the consequences of synaptic plasticity depend on the circuit involved. I find that two inhibitory inputs to the VTA, the rostromedial tegmental nucleus (RMTg) and the periaqueductal gray (PAG) are oppositely regulated by the same patterning of afferent stimulation in brain slices: optogenetic low frequency stimulation induced long term depression of inhibitory RMTg inputs and unexpectedly induced long-term potentiation of inhibitory PAG inputs in the VTA. I also found that PAG inhibitory synapses were depressed more than RMTg synapses by opioid receptor activation, making the PAG inhibition perhaps the most opioid vulnerable synaptic population innervating the VTA described to date. Furthermore, optogenetic activation of the RMTg and PAG terminals in the VTA in behaving animals resulted in divergent outcomes. RMTg stimulation was aversive whereas PAG stimulation induced quiescence. The PAG stimulation-induced quiescent behavior was blocked by systemic morphine. Characterization of the heterogeneous properties of different VTA circuits via isolation of afferent populations places opioid effects into context for future studies involving therapeutic intervention for disorders involving the reward pathway.
St. Laurent, Robyn,
"Synaptic Plasticity and Behavior Profiles of Ventral Tegmental Area Inhibitory Circuits"
(2019).
Neuroscience Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/ay7v-xx26
