Garfield, Alastair S.Li, ChiaMadara, JosephShah, Bhavik P.Webber, EmilySteger, Jennifer S.Campbell, JohnGavrilova, OksanaLee, Charlotte E.Olson, DavidElmquist, Joel K.Tannous, BakhosKrashes, Michael J.Lowell, Bradford2016-01-042015Garfield, A. S., C. Li, J. C. Madara, B. P. Shah, E. Webber, J. S. Steger, J. N. Campbell, et al. 2015. “A neural basis for melanocortin-4 receptor regulated appetite.” Nature neuroscience 18 (6): 863-871. doi:10.1038/nn.4011. http://dx.doi.org/10.1038/nn.4011.1097-6256http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993471Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons are oppositely regulated by caloric depletion and co-ordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) within the paraventricular nucleus of the hypothalamus. Although this population is critical to energy balance the underlying neural circuitry remains unknown. Enabled by mice expressing Cre-recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVHMC4R→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development.en-USJournal Article2016-01-0410.1038/nn.4011