Current concepts suggest that electrical or optogenetic stimulation of lateral hypothalamus (LH) GABA neurons induces rapid and vigorous feeding in sated animals. Furthermore, mechanistic studies have shown that intact dopamine function is necessary for this phenomenon. Indeed, some LH GABA neurons have been shown to project to the ventral tegmental area (VTA) where they primarily target GABAergic neurons, thereby disinhibiting midbrain dopamine neurons. Here we explore the role of this circuitry in controlling feeding in sated mice. Surprisingly, we found that genetically-targeted lesion of VTA GABA neurons did not disrupt LH-stimulated feeding. Furthermore, direct stimulation of VTA and SNc dopamine neurons, though rewarding, did not induce feeding. Optogenetic manipulations of VTA glutamate and GABA populations also failed to produce feeding responses. We observed that a subset of GABAergic projections from the LH passed through the VTA and continued to dorsal and ventral brainstem targets. Feeding was induced by stimulation of the dorsal pathway as far posterior as the region of the locus coeruleus, where these fibers synapsed onto neurons medial to noradrenergic cell bodies. Finally, we targeted optogenetic stimulation and inhibition to noradrenergic, GABAergic, and glutamatergic cell bodies in tissue surrounding the locus coeruleus and found that feeding was uniquely induced by stimulation of GABAergic neurons. In conclusion, these findings appear to rule out a role for the GABAergic LH projection to the VTA as a feeding substrate and highlight a new player in the feeding system.
