Early adversity promotes binge-like eating habits by remodeling a leptin-responsive lateral hypothalamus–brainstem pathway

Abstract

Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LHLepr) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LHLepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LHLepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity.

Lateral hypothalamic leptin receptor neurons drive hunger-gated food-seeking and consummatory behaviours in male mice

“…Based on the previous single-cell RNA sequencing data for the LH 26 , LH LepR neurons are mostly GABAergic (Supplementary Fig. 1l), consistent with previous results 21,23 . Further, LH LepR neurons constitute only 4% of LH GABA neurons (VGAT positive cells) (Supplementary Fig.…”

“…However, this paper did not provide a conclusion regarding different subpopulations among LH LepR neurons. Another previous micro-endoscope study on LH LepR neurons did not classify subpopulation heterogeneity of LH LepR neurons and did not differentiate the different phases of eating 23 . In contrast, applying our comprehensive eating behavioural paradigm, we could successfully distinguish the two distinct populations.…”

“…To elucidate which subpopulations in LH GABA neurons exclusively contribute to seeking and/or consummatory behaviours, several studies have been dedicated to identifying subpopulations and neural circuits 10,16,17,20 . LH leptin receptor expressing (LH LepR ) neurons are subpopulation of LH GABA neurons and has been reported to be associated with eating 10,16,[21][22][23] . However, the role of LH LepR neurons is controversial; no effect on eating 10,24 , decreased eating 16 , decreased eating after leptin treatment in the LH 22 , and increased eating by LH LepR -Ventrolateral Periaqueductal Grey (vlPAG) circuit 23 .…”

“…LH leptin receptor expressing (LH LepR ) neurons are subpopulation of LH GABA neurons and has been reported to be associated with eating 10,16,[21][22][23] . However, the role of LH LepR neurons is controversial; no effect on eating 10,24 , decreased eating 16 , decreased eating after leptin treatment in the LH 22 , and increased eating by LH LepR -Ventrolateral Periaqueductal Grey (vlPAG) circuit 23 .…”

Maternal overnutrition is associated with altered synaptic input to lateral hypothalamic area

“…Although we did not observe differences in litter size, HFD-fed dams did show reduced reproductive success. This may be driven by impaired pup care, which may contribute to changes in brain reward circuitry independently of those related to overnutrition per se [ 63 ]. Moreover, the present study has focused specifically on maternal diet.…”