It is becoming increasingly recognized that alterations in the mesolimbic dopaminergic circuitry may underlie the development of obesity, and that obesity has more in common with drug addiction than previously thought. Specifically, alterations in the balance of activity of D1 and D2 dopamine receptor expressing medium spiny neurons of the nucleus accumbens (NAc) have been implicated. How exactly this alteration plays out in terms of the activity of the relevant circuitry, however, is still unknown. Observations made in the clinical as well as the laboratory over the past few decades have shown that dopamine agonists often cause weight loss and decreased food reward, whereas dopamine antagonists often lead to weight gain (and often the metabolic syndrome), and increased food reward. The proposed studies are in particular based on the observation that D2 and D1 expressing neurons in the striatum are antagonistic in their roles in mediating downstream motor outputs, as well as the recent observation by our colleagues that optogenetic activation of NAc D2 expressing neurons reduces reward whereas optogenetic activation of NAc D1 expressing neurons enhances reward. Furthermore, BDNF TrkB signaling has also been shown to attenuate both D1 and D2 expressing medium spiny neurons excitability. We hypothesize that optogenetic activation of D2 expressing NAc medium spiny neurons will cause decreased energy intake and decreased food reward, leading to reversal of obesity in a high-fat diet induced model of obesity. We hypothesize that TrkB deletion in these same neurons will cause a similar phenotype. Conversely, we hypothesize that optogenetic activation of D1 expressing NAc medium spiny neurons will increase feeding behavior and feeding-induced reward, and will lead to hyperphagia and weight gain. We also hypothesize that TrkB ablation specific to D1 expressing NAc medium spiny neurons will also mirror this phenotype. If successful, these studies will lead to novel therapeutic interventions for those who struggle with obesity. Additionally, further clarification of the regulation of reward by the balance of activation of these two neuronal subtypes of the nucleus accumbens can lead to development of new treatments for addictive behaviors.
The proposed project will test the hypothesis that optogenetic activation of D2 expressing medium spiny neurons in the nucleus accumbens will lead to decreased food intake and a reduction in glucose-induced reward, ultimately reversing obesity in a high-fat diet induced mouse model of obesity. We hypothesize that ablation of BDNF TrkB signaling will cause a similar phenotype. We further hypothesize that optogetentic activation of, as well as TrkB ablation in, D1 expressing NAc neurons will cause hyperphagia and an increase in glucose-induced reward.
