Alterations to Taste Preference in MC4R Haploinsufficiency Manifest Prior to Dietary Induced Obesity and Are Accompanied by Dendritic Spine Alterations to Medium Spiny Neurons of the Nucleus Accumbens in Adulthood

Moran for their assistance in data collection and analysis. ABSTRACT Obesity has reached epidemic proportions in the United States and has become an increasing public health concern for developed nations. Haploinsufficiency of melanocortin receptor 4 has been identified as the single most common monogenetic cause of obesity in humans. Using the MC4R +/-haploinsufficient rat, we sought to determine potential alterations in body weight and morphology, locomotor activity, sucrose concentration preference, and progressive-ratio operant testing in a dietary-induced obesity environment. Rats were placed on four separate diets corresponding to 1.7% saturated fat with 12.2% total kcal/fat, 6% saturated fat with a 40% total kcal/fat, 12% saturated fat with a 40% total kcal/fat, and a 1.7% saturated fat with 12.2% total kcal/fat containing an inflammatory polyunsaturated fat ratio of 20:1 omega-6:omega-3 fatty acids. We found a significant interaction between genetic condition and diet in terms of body weight and waist circumference. Locomotor activity testing showed an increased level of activity for animals on the inflammatory diet, with lower levels of rearing for haploinsufficent animals on the high saturated fat diet. Normal PR schedules failed to produce significant results, but both varying the concentration and the addition of a distracting tone revealed significant effects on motivation for palatable rewards. Finally, we DiOlistically labeled medium spiny neurons in the nucleus accumbens to determine potential alterations to dendritic spine morphologies correlating to impulsive and compulsive behavior. Significant alterations in cumulative frequencies of spine length, spine head diameter, and spine volume are apparent and indicate functional iv alterations to the hedonic reward processing center of the brain under high fat, inflammatory, and haploinsufficient conditions. These findings provide insight to potential use of MC4R as a therapeutic target for early-onset dietary-induced obesity, and highlight the effects of inflammatory polyunsaturated fatty acids on hedonic motivational behavior.