Social isolation enhances calcium signaling and synaptic plasticity in dopamine neurons of the ventral tegmental area

Ramsey, Leslie Anne
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Environmental experiences play a critical role in an individualʼs risk of becoming addicted. Positive experiences may mitigate addiction vulnerability, whereas adverse experiences, particularly during adolescence, have been shown to increase addiction risk. Social isolation in rodents is a model system used to study the effects of such experiences, yet its impact on the learning and memory processes that underlie addiction remains elusive. Although social isolation is known to alter the functioning of the dopaminergic system, as well as reward processing and learning, its effect on dopamine (DA) neurons of the ventral tegmental area (VTA) is unknown. The data presented in this dissertation demonstrate that social isolation of rats during a critical period in adolescence (postnatal days 21-42) enhances long-term potentiation (LTP) of N-methyl D-aspartate receptor (NMDAR)-mediated glutamatergic transmission in the VTA. Activation of NMDARs is critical to the generation of DA neuron bursts that encode rewards and reward-predictive cues, and NMDARs are necessary for associative reward learning. The isolation-induced enhancement of NMDAR LTP results from augmentation of metabotropic glutamate receptor (mGluR)-dependent calcium (Ca²⁺) signaling via an increase in inositol 1,4,5-trisphosphate(IP3) sensitivity. Isolation-mediated effects on Ca²⁺ signaling and NMDAR plasticity were not reversed by a subsequent period of resocialization. Furthermore, social isolation during this critical period occludes the effect of repeated amphetamine exposure on mGluR/IP₃-mediated Ca²⁺ signaling and synaptic plasticity. Although corticotropin releasing factor (CRF) further facilitates mGluR/IP3-mediated Ca²⁺ signaling in DA neurons, alterations in CRF receptors are not responsible for the effects of isolation on Ca²⁺ signaling and synaptic plasticity. In addition, the learning of associations between environmental stimuli and drug rewards is acquired more quickly and is more resistant to extinction in isolated animals. Data presented in this dissertation lend support to the theory that enhanced mGluR/IP₃-mediated Ca²⁺ signaling and NMDAR plasticity facilitate the learning and memory of drug-associated stimuli. This dissertation provides the first demonstration of a cellular basis for the critical time window of social isolation during adolescence. NMDAR plasticity in the VTA may thus represent a neural substrate by which early life experiences regulate addiction vulnerability. (Note: Behavioral data were acquired by Mickael Degoulet)