UC Berkeley

The activity of ventral tegmental area dopamine neurons (VTA DA) in the midbrain is central to the generation of motivated behaviors, such as feeding. Drugs of abuse, such as nicotine, are capable of “hijacking” this system by artificially driving VTA DA activity to promote reinforcement, but high doses of nicotine are aversive. Many brain regions send inputs to the VTA to influence DA activity, including those independently sensitive to food or nicotine consumption, which can strongly modulate behavior. In Chapter 2, I describe how a high dose of nicotine can promote aversive behavior in mice by employing in vivo fiber photometry with nicotine and/or nicotinic acetylcholine receptor (nAChr) blockers, a computational model of nAChr activation and sensitization, and optogenetic behavior experiments. I reveal that a high dose of nicotine inhibits DA release in the canonical reward pathway, from VTA DA neurons that project to the lateral shell of the nucleus accumbens (NAcLat). Using a computational model as a guide, I show that the inhibition of NAcLat dopamine release arises from an alpha7 nAChr sensitive laterodorsal tegmentum (LDT) GABA projection to the VTA, which is activated by aversive nicotine. Finally, by suppressing activity of LDT GABA during delivery of an aversive dose of nicotine, I show diminished inhibition of NAcLat dopamine and that conditioned place aversion is prevented. In Chapter 3, I introduce the role of NAcLat inputs to the VTA which are sensitive to and can impose hedonic feeding behavior. Using in vivo and ex vivo electrophysiology, RNA sequencing, imaging with a novel peptide fluorescent sensor, and optogenetic behavior experiments, I reveal that NAcLat→VTA releases neurotensin and requires neurotensin receptor availability to drive hedonic feeding behavior. I find that in a high fat diet-induced obese mouse model, neurotensin release is diminished, which correlates with reduced hedonic feeding behavior and an inability to increase VTA DA firing and hedonic feeding behavior from optogenetic activation. Finally, by specifically overexpressing neurotensin in the NAcLat→VTA pathway in mice on high-fat diet (HFD), I will show that mice gain less weight and exhibit more locomotion and hedonic feeding behavior compared to control mice on HFD, partially ameliorating the negative impact of the obesogenic food environment. Together, these results highlight the power of inputs to VTA DA neurons to modify responses to nicotine and hedonic feeding, which can translate to targeted therapeutics for nicotine dependence and obesity in the future.