While insulin?s effects in the periphery has been studied extensively, insulin?s effects on neural function in the adult brain are poorly understood. Infusion of insulin directly into the brain reduces food intake in rodents, and intranasal insulin reduces food intake in humans, though the mechanism(s) of this effect is unknown (Brown et al. 2006; Benedict et al., 2008; Figlewicz et al. 2006). In addition, insulin decreases excitatory transmission onto dopamine neurons in adult rodents (Labouebe et al. 2013; Liu et al., 2013) and enhances dopamine release in the nucleus accumbens (NAc; Stouffer et al., 2015). However, no studies have examined insulin?s effects on neurotransmission in brain circuits that influence feeding in lean or obese individuals. Our objective is to determine how insulin regulates excitatory glutamatergic transmission in the NAc in the normal and obese state. The NAc influences both the initiation of feeding and the consumption of food through regulation of distinct sub-circuits (Kelley, 2004; Everitt and Robbins, 2005; Figlewicz and Sipols, 2010). For example, increases in excitatory transmission in the NAc core increases food-seeking (Brown et al., 2015), whereas decreases in the NAc shell can induce feeding (Maldonado-Irizarry et al., 1995; Peters and Kalivas, 2006). Excitatory drive to the NAc is provided by glutamatergic inputs from several brain regions including the medial prefrontal cortex (mPFC; Ding et al., 2001) and disruption of these inputs perturbs feeding (Land et al., 2014). Our preliminary data show that insulin bi-directionally influences excitatory transmission in the NAc. However, the mechanism underlying this effect is unknown. Furthermore, in obese rats, insulin receptor-induced increases in excitatory transmission are absent. This is consistent with the idea that obesity produces central insulin resistance. We will combine electrophysiology, biochemical and optogenetic approaches in normal and obese rats to determine the mechanisms by which insulin modulates glutamatergic transmission in the NAc, and will examine the specific role of prefrontal cortical inputs to the NAc in effects of insulin.
Over 30% of the U.S. population is struggling with obesity, which contributes to the development of type 2 diabetes, cardiovascular disease, and many cancers. Obesity produces chronic elevations in circulating insulin and peripheral insulin reaches the brain. However, how insulin affects the function of brain reward circuits is poorly understood. The goal of the proposed work is to determine how insulin regulates communication between neurons critical for feeding by studying the mechanisms by which insulin modulates glutamatergic transmission in the nucleus accumbens in lean and obese individuals.
