Control of food approach and eating by a GABAergic projection from lateral hypothalamus to dorsal pons

Abstract

Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.

Lateral Hypothalamic GABAergic neurons encode and potentiate sucrose’s palatability

“…Although activation of LHA Vgat+ promotes substantial feeding behavior, it has become clear that LHA Vgat+ neurons are not directly involved in evoking hunger (Burnett et al, 2016;Navarro et al, 2016;Marino et al, 2020), as AgRP neurons in the arcuate do (Chen et al, 2016). In this regard, and unlike AgRP neurons, pre-stimulation of LHA GABAergic neurons did not trigger a sustained sucrose intake in the absence of continuous activation ( Supplementary Figure 4).…”

“…Thus, LHA Vgat+ neurons are the common neural substrate for evoking both feeding and reward. Though, it was recently shown that they do it by using two projection pathways; reward via a VTA projection and feeding via the peri-Locus Coeruleus nuclei (Marino et al, 2020).…”

“…Moreover, LHA Vgat+ neurons enhance the salience of the nearest stimulus and induce reward via stimulation of their projections to the ventral tegmental area (VTA) (Nieh et al, 2016). In addition, the evoked feeding is mediated by the modulation of terminals reaching a region adjacent to the locus coeruleus (Marino et al, 2020). On the contrary, inhibition of GABAergic LHA Vgat+ cell somas is aversive and stops feeding (Jennings et al, 2015;Navarro et al, 2016).…”

Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI)

“…Importantly, prototypic psychiatric diseases including treatment-resistant depression and severe schizophrenia are coupled to major derangements in appetite and body weight and often lead to a state of metabolic syndrome that negatively affects life expectancy [13][14][15] . Obviously, the GABAergic system composed by GABA and its receptors plays a major role in the central nervous system 16,17 as well as in the regulation of metabolism 18 and inflammation 19 .…”

REM sleep stabilizes hypothalamic representation of feeding behavior

“…Recent studies have highlighted a critical role for LH vgat neurons in food seeking ( 26 ), food intake ( 27 – 31 ), compulsive behavior ( 28 ) or hunting ( 32 ), and the induction of conditioned place preference in the absence of rewards ( 27 , 33 ). LH vgat neuron projections to the ventral tegmental area ( 30 , 33 ), the paraventricular hypothalamus ( 31 ), the ventrolateral peri-aquaeductal gray matter ( 32 ), and the dorsal pons ( 34 ) were shown to modulate feeding and motivation in mice. Taken together, these findings suggest that LH vgat neurons provide a link between sleep and the motivational, or consummatory, aspects of feeding behavior.…”