Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding of food intake and body weight regulation may lead to effective strategies to combat obesity and diabetes. Serotonin (5-HT) neurons in the dorsal Raphe nucleus (DRN) play an essential role in regulating feeding behavior. Enhanced brain 5-HT actions robustly inhibit food intake and body weight but little is known about how firing activity of 5-HTDRN neurons is regulated. Based on pilot observations, the Xu and Tong labs put forward a general hypothesis that 5-HTDRN neurons integrate dopamine (DA) and GABA inputs to promote food intake. The first objective is to determine whether DA released by neurons in the ventral tegmental area inhibits 5-HTDRN neurons to promote food intake. In vivo optogenetic studies will be carried out to determine whether photostimulation of the DADRN circuit increases food intake while photoinhibition of the same circuit inhibits eating; a DA receptor (DRD2) will be deleted in 5-HT neurons to test whether this deletion decreases food intake and body weight and block effects of DADRN activation in mice. The second objective is to determine whether GABA released by neurons in the lateral hypothalamus inhibits 5-HTDRN neurons to promote food intake. Similar optogenetic studies will be carried out to determine whether photostimulation of the GABADRN circuit increases food intake while photoinhibition of the same circuit inhibits eating; a GABA receptor (?2) will be deleted in 5-HT neurons to test whether this deletion decreases food intake and body weight and block effects of GABADRN activation in mice. The third objective is to determine whether DA and GABA signals converge on the same or distinct subsets of 5-HTDRN neurons and whether stimulation of both DA and GABA-originated circuits produce redundant or synergistic effects on food intake. Thus, accomplishment of these experiments may advance our understanding about the physiological roles of brain 5-HT system in the regulation of feeding and energy balance, we may also identify novel targets (e.g. DRD2 and ?) for therapeutic development of human diseases, e.g. obesity.
Obesity is now recognized as a serious global health problem due to its increasing prevalence and comorbidities, but effective therapies for obesity are limited. We propose to determine if two neural signals, dopamine and GABA, converge on brain 5-HT neurons to regulate food intake and body weight balance.
