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Dorsal raphe dual serotonin-only and serotonin-glutamate neurons synapsing on VTA dopamine neurons drive dopamine release and reward Ph.D., Hui-Ling Wang1, , Ph.D., Shiliang Zhang1, Ph.D., Jia Qi1 , Ph.D., Roger Cachope2, Ph.D., Carlos A Mejias-Aponte1, Ph.D., Joseph F. Cheer2 and Ph.D., Marisela Morales1,*. 1 National Institute on Drug Abuse, Neuronal Networks Section, National Institutes of Health, Baltimore, Maryland, USA. 2 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA. Ventral tegmental area (VTA) dopamine neurons are theorized to play distinct roles in positive and negative reinforcement, decision-making, working memory, incentive salience, and aversion. This behavioral heterogeneity is reflected in part in the diverse phenotypic characteristics of VTA dopamine neurons and of the brain structures with which they are connected. The VTA receives a major innervation from the Dorsal Raphe (DR), which properties remain to be determined. By tracing studies, we found that within the total population of DR neurons innervating the VTA, a major population (≈46%) expresses the vesicular glutamate type 3, and a minor population (≈13%) expresses only serotonergic markers (serotonin-only neurons) or co-expresses serotonergic markers and VGluT3 (dual serotonin-VGluT3 neurons; ≈14%). By immunolabeling, we found that axon terminals from these three classes of DR neurons are present in the VTA with different proportions; axon terminals containing only VGluT3 (≈65%) are more abundant that than those containing only serotonergic markers (≈23%) or those co-expressing serotonergic markers and VGluT3 (≈12%). By electron microscopy, we found that within the VTA dopamine neurons are the major target of both VGluT3-only terminals and dual serotonin-VGluT3 terminals. The synapses establish between dopamine neurons and either VGluT3-terminals or dual serotoninVGluT3 terminals are asymmetric (putative) excitatory synapses, suggesting that these two types of terminals are capable to release glutamate on VTA dopamine neurons. By optogenetics, we found that VTA photoactivation of VGluT3-fibers elicits AMPAmediated excitatory currents in VTA dopamine neurons, promotes dopamine release in nucleus accumbens, reinforces instrumental behavior, and establishes conditioned place preference (CPP). VTA photoactivation of serotonin transporter (SERT) fibers promotes CPP, elicits excitatory currents on dopamine neurons, increases their firing rate, and evokes dopamine release in the nucleus accumbens. Dopamine release and CPP elicited by VTA SERT-fibers depend on local activation of AMPA- and serotonin type 3-receptors. By comparing CPP produced by VTA photoactivation of SERT-fibers or VGluT3-fibers, we found that the immediate rewarding effects mediated by SERT-inputs are less rewarding, but more resistant to extinction than those caused by VGluT3-inputs. Our findings provide evidence for a glutamatergic DR →VTA pathway from both serotonergic-only and serotonergic-glutamatergic neurons that participate in reward processing. The discovery of this brain pathway opens new avenues to examine its participation in a variety of mental disorders related to motivation. Biography of presenting author (about 100 words) Marisela Morales is a Senior Investigator in the Intramural Research Program at the National Institute on Drug Abuse in the National Institutes of Health. She has been investigating the molecules, cells and neuronal pathways central to the neurobiology of drug addiction through use of anatomical, biochemical, cell biological and electrophysiological approaches. The primary questions to be addressed by her research include: (a) what is the brain circuitry through which addictive drugs have their habit-forming actions and (b) what neuro-adaptations of this circuitry accompany the transition from recreational to compulsive drug-taking. Author Details: Full Name: Marisela Morales Contact Number: +1 (443) 315-9977 Country: USA Category: (Oral/Poster Presentation) Talk Session Name: Session on: Behavioral Neurology & Neuropsychiatry | Pediatric Neurology Email: [email protected]
