Time to drink: Activating lateral hypothalamic area neurotensin neurons promotes intake of fluid over food in a time-dependent manner

Abstract

The lateral hypothalamic area (LHA) is essential for ingestive behavior but has primarily been studied in modulating feeding, with comparatively scant attention on drinking. This is partly because most LHA neurons simultaneously promote feeding and drinking, suggesting that ingestive behaviors track together. A notable exception are LHA neurons expressing neurotensin (LHA^Nts neurons): activating these neurons promotes water intake but modestly restrains feeding. Here we investigated the connectivity of LHA^Nts neurons, their necessity and sufficiency for drinking and feeding, and how timing and resource availability influence their modulation of these behaviors. LHA^Nts neurons project broadly throughout the brain, including to the lateral preoptic area (LPO), a brain region implicated in modulating drinking behavior. LHA^Nts neurons also receive inputs from brain regions implicated in sensing hydration and energy status. While activation of LHA^Nts neurons is not required to maintain homeostatic water or food intake, it selectively promotes drinking during the light cycle, when ingestive drive is low. Activating LHA^Nts neurons during this period also increases willingness to work for water or palatable fluids, regardless of their caloric content. By contrast, LHA^Nts neuronal activation during the dark cycle does not promote drinking, but suppresses feeding during this time. Finally, we demonstrate that the activation of the LHA^Nts → LPO projection is sufficient to mediate drinking behavior, but does not suppress feeding as observed after generally activating all LHA^Nts neurons. Overall, our work suggests how and when LHA^Nts neurons oppositely modulate ingestive behaviors.

Keywords: ARC, Arcuate nucleus; CEA, Central amygdala; CNO, Clozapine N-Oxide; CPP, Conditioned place preference; DR, Dorsal raphe; DREADD; DREADD, Designer receptor exclusively activated by designer drugs; FR-1, Fixed ratio-1; LHA; LHA(Nts), Lateral hypothalamic area neuotensin-expressing; LHA, Lateral hypothalamic area; LPO, Lateral preoptic area; LT, Lateral terminalis; LepRb, Long form of the leptin receptor; MnPO, Median preoptic area; ModRabies, Genetically modified rabies virus, EnvA-∆G-Rabies-mCherry; NTS, Nucleus of solitary tract; Nts, Neurotensin; NtsR1, Neurotensin receptor-1; NtsR2, Neurotensin receptor-2; OVLT, Organum vasculosum lamina terminalis; PAG, Periaqueductal gray; PB, Parabrachial area; PR, Progressive ratio; PVH, Paraventricular nucleus of hypothalamus; SFO, Subfornical organ; SNc, Substantia nigra compacta; SO, Supraoptic nucleus; TVA, avian viral receptor protein; VEH, Vehicle; VTA, Ventral tegmental area; WT, Wild type; Water; aCSF, Artificial cerebrospinal fluid; body weight; feeding; homeostasis; lHb, Lateral habenula; lateral preoptic area (LPO); neurotensin receptor; reward.