Effect of chronic ethanol exposure on synaptic organization in the rostromedial tegmental nucleus

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PROJECT SUMMARY In 2009 two laboratories independently discovered the rostromedial tegmental nucleus (RMTg) – a small GABAergic nucleus that encodes negative reward prediction error via the inhibitory control it exerts over midbrain dopamine neurons. Together with subsequent studies demonstrating a role for the RMTg in responding to aversive stimuli, this work sparked new research investigating involvement of this region in the neurobiological mechanisms underlying alcohol use disorder. The medial prefrontal cortex (mPFC) plays a key role in regulating alcohol seeking and taking behavior. Interestingly, our recent work revealed the presence of dense input from the mPFC to the RMTg that spans both the prelimbic (PL) and infralimbic (IL) subregions. Studies manipulating PL and IL activity at the subregional level suggest that these two regions exert opposing control over alcohol seeking. However, the application of circuit-specific approaches is beginning to suggest a more complex picture with differing roles across discrete cortico-subcortical projections. Combined with only a very superficial understanding of the heterogeneity / uniformity of RMTg neurons, these conflicting data make it difficult to develop hypotheses regarding circuit motifs in RMTg and the potential synergistic or dichotomous functions of RMTg-projecting PL and IL mPFC neurons. Given the impact that recent data demonstrating the previously unappreciated heterogeneity of the ventral tegmental area has had on functional understanding of this region, a rigorous investigation of the RMTg is warranted. The aims described in the current proposal will combine circuit- specific labeling with state-of-the-art connectomics approaches to characterize the effects of chronic ethanol exposure on the RMTg and its cortical afferents at nanometer resolution. Acquisition of an RMTg connectome will provide crucial insight into cell structure and synaptic patterns as well as a precise neuronal map of dense cortical input to RMTg thought to play a critical role in top-down control over alcohol seeking. The resulting circuit data will provide a foundation for future studies investigating the functional consequences of dependence- induced synaptic reorganization by integrating subcellular anatomical findings with physiology and behavior.