Melanocortin-4 receptor-expressing neurons in the nucleus accumbens and regulation of food preference

• Applicant: Henning Fenselau, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409551513

The melanocortin system, working through melanocortin-4 receptors (MC4Rs), controls body weight homeostasis by regulating food intake. The MC4R-dependent control of homeostatic feeding is strongly supported by the development of hyperphagia and massive obesity in both mice and humans lacking MC4Rs. Strikingly, MC4R deficient individuals, in addition to being hyperphagic, exhibit a markedly increased preference for high fat food. Their preference for high sucrose food, in contrast, is strongly reduced. Thus, MC4Rs in addition to controlling homeostatic feeding critically influence the rewarding aspects of food. The brain site mediating this is unknown. MC4Rs are expressed on hypothalamic neurons, which regulate homeostatic feeding, and in extra-hypothalamic brain regions associated with reward-related behavior including the nucleus accumbens (NAc). This is of particular interest because the NAc has been implicated in regulating fat and sucrose consumption. However, it is unknown whether MC4R-expressing NAc (NAcMC4R) neurons are a control point for food preference. This is due to the fact that neuroscience tools to target NAcMC4R neurons were missing. In the current proposal, we will directly assess the role of NAcMC4R neurons using recently generated MC4R-t2a-Cre knock-in mice. Using these mice in combination with Cre-enabled viral technology, we will target NAcMC4R neurons to i) selectively monitor their activity in vivo, ii) stimulate and inhibit them during behavioral food preference assays, and iii) investigate their afferents and efferents. Collectively, these studies will determine the necessity and sufficiency of NAcMC4R neurons in controlling food preference and define the underlying neurocircuitry.

• DFG Programme: Research Grants