Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation

Abstract

The habenula (Hb) is a bilateral, evolutionarily conserved epithalamic structure connecting forebrain and midbrain structures that has gained attention for its roles in depression, 1 addiction, 2-5 rewards processing, 6 and motivation. 7,8 Of its two major subdivisions, the medial (MHb) and lateral Hb (LHb), MHb circuitry and function are poorly understood relative to LHb. 9 Prkar2a codes for cAMP-dependent protein kinase (PKA) regulatory subunit IIα (RIIα), a component of the PKA holoenzyme at the center of one of the major cell-signaling pathways conserved across systems and species. Type 2 regulatory subunits (RIIα, RIIβ) determine the subcellular localization of PKA, and unlike other PKA subunits, Prkar2a has minimal brain expression except in the MHb. 10 We previously showed that RIIα knockout (RIIαKO) mice resist diet-induced obesity (DIO). 11 In the present study, we report that RIIαKO mice have decreased consumption of palatable, "rewarding" foods and increased motivation for voluntary exercise. Prkar2a deficiency led to decreased habenular PKA enzymatic activity and impaired dendritic localization of PKA catalytic subunits in MHb neurons. Re-expression of Prkar2a in the Hb rescued this phenotype confirming differential roles for Prkar2a in regulating the drives for palatable foods and voluntary exercise. Our findings show that in the MHb decreased PKA signaling and dendritic PKA activity decrease motivation for palatable foods, while enhancing the motivation for exercise, a desirable combination of behaviors.

Activation of basal forebrain-to-lateral habenula circuitry drives reflexive aversion and suppresses feeding behavior

“…For example, cues that indicate spoiled food or a nearby predator may drive overriding avoidance or escape behavior, respectively, to ensure survival. While it is generally appreciated that the hypothalamus regulates key aspects of homeostatic feeding [4][5][6][7][8] , and that homeostasis, reward, and aversion pathways converge to govern feeding [9][10][11] , the circuits, neuronal constituents, and patterns of functional connectivity that mediate non-homeostatic feeding behavior remain largely unknown.…”

A Chinese indicine pangenome reveals a wealth of novel structural variants introgressed from otherBosspecies

“…( Supplemental Table S18 ; Supplemental Fig. S20 ; London et al 2020 ; Gu et al 2022 ). We additionally performed SV-eQTL mapping and identified 250 SVs with genotypes that correlate with expression levels of a nearby gene ( P value < 0.05, Benjamini–Hochberg adjust) ( Supplemental Table S19 ), of which 15 introgressed SVs.…”

Expression of olfactory receptor genes in non-olfactory tissues in the developing and adult zebrafish

“…It is noteworthy that all ORs assessed in the adult brain in this study show expression in the habenula and the hypothalamus. The hypothalamus has long been implicated in controlling food intake 27,28 and recent studies have implicated the habenula in food-related behaviors [29][30][31] . One interesting possibility is that the odors during food intake is transported into the brain and plays a role in the modulation of brain areas associated with food-related behaviors.…”