Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion

Abstract

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified.

Blunted leptin sensitivity during hedonic overeating can be reinstated by activating galanin 2 receptors (Gal2R) in the lateral hypothalamus

“…Our demonstration that PF ingestion does not impair proximal signalling of leptin, required formulation of an alternative hypothesis to explain how OX neurons might escape from the inhibitory control of leptin during consumption of PF. Furthermore, while our results may at first appear to be at odds with previous reports that Gal induces feeding 54 and food-seeking behaviour, 55 other work using mice in which leptin receptor (LepRb) expression was constitutively deleted in Gal neurons confirms that the inhibitory actions of leptin are mediated by GalR. While it is known that OX neurons do not express leptin receptors, it is worth noting that leptin receptor-expressing galanin (Gal) neurons (some of which co-express neurotensin/GABA) terminate in the vicinity of OX neurons 14,25,26 (see Figure 6A).…”

“…Notably, the finding that only low doses of M1145 could inhibit PF eating hints at the potential importance of the prevailing Gal-ergic tone. Furthermore, while our results may at first appear to be at odds with previous reports that Gal induces feeding 54 and food-seeking behaviour, 55 other work using mice in which leptin receptor (LepRb) expression was constitutively deleted in Gal neurons confirms that the inhibitory actions of leptin are mediated by GalR. 24 The precise mechanisms underlying the actions of Gal are unknown.…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…While we have focused on defining Nts-expressing afferents to the VTA, it is likely that these neurons also express other transmitters, whose release might produce differential effects in the VTA. For example, at least some LHA Nts neurons co-express the neuropeptide galanin, though they appear to predominantly project within the LHA and not to the VTA (Laque et al, 2015; Qualls-Creekmore et al, 2017). Different populations of Nts neurons might vary in classical neurotransmitter content, and hence release of Nts along with inhibitory GABA or excitatory glutamate could lead to very different effects within the VTA.…”

Preoptic galanin neuron activation is specific to courtship reproductive tactic in fish with two male morphs

“…Studies of neuropeptide regulation of social behavior in mammals have also traditionally focused on the nonapeptide family (27, 28). More recently, the neuropeptide galanin, which has established functions in pituitary hormone release and regulation of feeding (29–33), has received increased attention for its role as a regulator of social behavior (34, 35). Early studies of the POA-AH in mammals show a role for galanin in rat sexual behavior (36, 37) and identify populations of galanin neurons that is active during mating in male ferrets and mice (38, 39).…”