, 2012). Specifically, the study establishes mechanisms by which stress can lead to reduced intake and anhedonia. The melanocortin agonist, alpha-MSH, is derived from the precursor peptide POMC. The POMC neurons of the arcuate nucleus form the “stop” side of the hypothalamic feeding equation whereby activation of this population reduces intake. The paraventricular

nucleus of the hypothalamus has been best studied as a site where the melanocortin MC4 receptor (MC4R) mediates these effects. However, the MC4R is broadly expressed in the brain, including the nucleus accumbens and dorsal striatum. Early work showed regulation of MC4R by opiates and a role for striatal MC4R signaling in cocaine reward (Alvaro et al., 2003; Hsu et al., 2005), and more recent studies Cobimetinib chemical structure have shown that selleck compound library MC4R is present on dopamine receptor-1 (D1)-expressing medium spiny neurons that are needed for procedural leaning (Cui et al., 2012). Previous findings implicate MC4R in stress responses and anxiety but did not identify brain regions involved (Chaki and Okuyama, 2005). Now, Lim et al. (2012) integrate this previous work and add a wealth of new mechanistic

and behavioral data. They start by establishing that POMC neurons project from the arcuate nucleus to the core region of the nucleus accumbens. This mapping sets the anatomical stage for a more detailed neuronal and functional analysis. Through brain-slice electrophysiology studies, the authors find similar effects of alpha-MSH and stress on medium spiny neurons (MSNs) of

the nucleus Non-specific serine/threonine protein kinase accumbens. Both reduce excitatory postsynaptic currents (EPSCs) via alterations of AMPA receptor subunit composition, as supported by observed changes in rectification. Strikingly, the effects of stress and MC4R agonism are only apparent on D1 neurons, whereas neither affects D2 neurons. Moreover, the effects of stress appear to depend on MC4R signaling in the region, which is significant because MC4R protein is upregulated during stress. Together, the findings support a physiological role for changes in MC4R signaling during stress-induced adaptation in the region. The changes in synaptic strength were then examined for effects on long-term depression (LTD). Pre-exposure to alpha-MSH occluded LTD, and this effect is shown to depend upon MC4R. This LTD appears also to be AMPAR subunit-dependent since it is sensitive to treatment with NASPM. To better relate the LTD to AMPA receptor dynamics, the authors used a virus expressing G2CT-pep, a synthetic peptide designed to prevent internalization of Glua2 expressing AMPARs. This in vivo manipulation caused a reduction in LTD while also blocking behavioral responses to stress. With the effects of MC4R on synaptic and neuronal signaling characterized, the authors asked how MC4R could have these effects on D1 neurons.