Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation

Abstract

Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified. Here we examine how lateral hypothalamic leptin receptor-expressing (LH LEPR ) neurons, a subset of GABAergic cells, regulate motivation in mice. We find that LH LEPR neuronal activation significantly increases progressive ratio (PR) performance, while inhibition decreases responding. Moreover, we mapped LH LEPR axonal projections and demonstrated that they target the ventral tegmental area (VTA), form functional inhibitory synapses with non-dopaminergic VTA neurons, and their activation promotes motivation for food. Finally, we find that LH LEPR neurons also regulate motivation to obtain water, suggesting that they may play a generalized role in motivation. Together, these results identify LH LEPR neurons as modulators within a hypothalamic-ventral tegmental circuit that gates motivation.

Basal forebrain parvalbumin neurons modulate vigilant attention

“…An additional control experiment used the progressive ratio operant task (a method commonly used to assess changes in motivation; e.g. drive to procure food) 25 to demonstrate that neither BF-PV excitation, nor BF-PV inhibition, altered motivation for food (Figure S4).…”

“…In the progressive ratio experiment, the FR1 session was followed by two sessions of FR3 (three presses per pellet). Then, mice were trained on a progressive ratio schedule according to the following formula: [Response Requirement = (5e 0.2 × Pellet Number ) -5] as in refs 25,57 , until the number of pellets earned was stable across three sessions (<10% change). Optogenetic manipulations of BF-PV activity used the same parameters as above and delivered laser for 1s every 30s throughout the 1hr test session.…”

Molecular profiling and targeting of brain cells and circuits related to energy balance and food reward

“…However, LH LepR neuron activation decreases food intake and increases locomotion and body temperature [103], while intra-LH leptin injections decrease feeding and body weight [104]. Furthermore, intracerebroventricular leptin decreases the rewarding effect of LH stimulation [105], whereas chemogenetic activation of LH LepR neurons increases motivation for food [106]. The regulation of food reward by LH LepR neurons is partly mediated by their projections to the VTA [106], which are Nts-but not Gal-expressing [107], [108], while there is also local inhibition of orexin neurons in the LH by LepR/Nts and LepR/Gal neurons [107], [109].…”

“…Furthermore, intracerebroventricular leptin decreases the rewarding effect of LH stimulation [105], whereas chemogenetic activation of LH LepR neurons increases motivation for food [106]. The regulation of food reward by LH LepR neurons is partly mediated by their projections to the VTA [106], which are Nts-but not Gal-expressing [107], [108], while there is also local inhibition of orexin neurons in the LH by LepR/Nts and LepR/Gal neurons [107], [109]. Alternative splicing of the leptin receptor gene generates six receptor isoforms (LepRa-f) that share a common extracellular and transmembrane domain, but differ in their intracellular segment [110].…”

“…LepR LH neurons are GABAergic [141] and mainly co-express the neuropeptides neurotensin (Nts) and galanin (Gal) [107], [336], [339]. Furthermore, intracerebroventricular leptin decreases the rewarding effect of LH stimulation [105], whereas chemogenetic activation of LH LepR neurons increases motivation for food [106]. The regulation of food reward by LepR LH neurons is partly mediated by their projections to the VTA [106], which are Nts-but not Gal-expressing [107], [108], while deleting LepR in Nts LH neurons blunts the effect of leptin on decreasing motivation [107], [339].…”