| The nucleus accumbens shell (AcbSh) contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. Here I demonstrate that MCH action in the AcbSh is sufficient to drive free feeding behavior, whereas a peptide antagonist of the MCH receptor (MCHR1) reduces food intake. In an effort to understand the mechanisms that mediate this phenomenon, I use a combination of biochemical and electrophysiological techniques to find that MCH reduces excitability of AcbSh neurons via two distinct but complementary mechanisms. First, MCH receptor-1 (MCHR1) functions through a Gi/o signaling pathway to reduce phosphorylation of GluR1 at Serine-845 (pSer845). As a consequence, cell surface expression of GluR1-containing AMPARs was reduced along with amplitude of AMPAR-mediated synaptic events (miniature excitatory postsynaptic currents (mEPSCs)). Second, MCH suppresses action potential firing of medium spiny neurons (MSNs) through K+ channel activation. In agreement with in vitro data, MCH is found to reduce neuronal activity in the AcbSh in vivo. As an extension of these findings, a role for AMPAR-mediated neuronal excitability in the AcbSh-mediated feeding behavior was examined. Moreover, studies looking at the role of MCH in other AcbSh-mediated behaviors are presented. In conclusion, MCH-MCHR1 defines a hypothalamic-limbic feeding circuit that acts by reducing excitatory synaptic activity and membrane excitability in the AcbSh. These studies support a general excitability hypothesis for the AcbSh in the control of food intake and related behaviors. |
