Phosphoprotein Profile of Hypothalamic-Limbic Circuits Integral to Motivated Behavior and Addiction

Ralph DiLeone, Department of Psychiatry, Yale University

Addiction burdens our public health system and provides a dramatic example neural plasticity leading to maladaptive behavior. The long-term objectives of this proposed research are to understand the changes in proteins that occur in a key brain area that underlies motivated behavior and addiction. It is critical that we understand how reward and motivation circuits of the brain are integrated to develop a more complete view of drug addiction. Drugs of abuse have profound effects on the mesolimbic dopamine circuit, including the nucleus accumbens, while the hypothalamus has been better studies for control over food intake. The neuropeptide melanin-concentrating hormone (MCH) and its receptor serve as a molecular link between these two well-studied brain regions. The MCH peptide is produced in the lateral hypothalamus, a region that has been historically associated with reinforcing behavior, while the receptor is expressed in the nucleus accumbens. MCH in the nucleus accumbens inhibits neuronal firing and influences food intake and reward-related behavior. This proposal seeks to define the molecular mechanisms underlying these powerful behavioral effects. Specifically, proteomic analysis will allow for unprecedented sensitivity in detecting key molecular changes in the nucleus accumbens in response to MCH receptor signaling. The results from the proposed experiments will shed light on mechanisms of MCH action in the nucleus accumbens while also serving to provide a model for how neuropeptides regulate complex animal behaviors such as drug addiction.