Neural adaption in midbrain GABAergic cells contributes to high-fat diet–induced obesity

Abstract

Overeating disorders largely contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet–induced obesity (DIO) mice. This was associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing CACNA2D1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment.

Tonically active GABAergic neurons in the dorsal periaqueductal gray control the initiation and execution of instinctive escape

“…While modulation of threat processing and escape behaviour can be accomplished through a variety of different circuits (40–46), the network of excitatory neurons in the dPAG stands out as a key control node (24, 29, 31, 47–50). Previous work has demonstrated the presence of an inhibitory tone in the PAG (51–53) that could in principle control the excitability of the excitatory network to modulate escape. For example, local application of a GABA A receptor antagonist in the PAG elicits responses to a previously sub-threshold stimulus (23, 24).…”