Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

Abstract

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions.

Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving

“…Stamatakis et al (2016) have confirmed those findings in transgenic mouse preparations in which LH neurons were transfected with photosensitive excitatory or inhibitory ion channels controlled by the VGluT2 promoter. Optogenetic stimulation of the VGluT2 controlled pathway produced mostly glutamate-mediated excitatory postsynaptic potentials.…”

Lateral hypothalamic circuits for feeding and reward

“…Intriguingly, optogenetic stimulation of glutamatergic projections from the neighboring endopeducular nucleus (EP) is also aversive 140 , suggesting that glutamatergic neuronal populations in the LHA, the zona inserta, and EP may share a common behavioral/circuit function. In our studies, we have also observed substantially weaker LHb innervation from LHA GABAergic neurons 113 . However, LHA VGat neurons appear to innervate midline thalamic structures just ventral to the LHb such as the periventricular thalamus (PVT), a brain region shown to produce GABA-mediated feeding 141 .…”

“…4). Consistent with this, optogenetic inhibition of the LHA Vglut2 -LHb pathway enhances licking for a caloric reward and produces aversion when optogenetically activated 113 . Intriguingly, optogenetic stimulation of glutamatergic projections from the neighboring endopeducular nucleus (EP) is also aversive 140 , suggesting that glutamatergic neuronal populations in the LHA, the zona inserta, and EP may share a common behavioral/circuit function.…”

“…Interestingly, optogenetic stimulation of VGlut2 expressing LHA neurons has the opposite effect; it reduces feeding in hungry mice, as well as producing an aversion to locations where stimulation of these cells occurs 112 . Consistent with the idea that VGat and VGlut2 expressing LHA neurons exert opposing behavioral effects, selective genetic ablation of VGat expressing LHA neurons reduces feeding, body weight gain, and motivation to obtain palatable caloric rewards 111 , while ablation of VGlut2 expressing LHA neurons enhances both feeding and body weight gain 113 . Thus, perhaps Vgat and Vglut2 expressing LHA neurons produce a bidirectional output signal, which is then directly and indirectly conveyed to VTA dopamine neurons to homeostatically invigorate behavioral output (Fig.…”

“…In addition to the glutamatergic projection to the VTA, Vglut2-expressing neurons in the LHA also project to the lateral habenula to excite LHb neurons that likely project to VTA/RMTg GABAergic neurons, which in turn can inhibit VTA dopamine neurons 113,138,139 (Fig. 4).…”