Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation.

Edra London,Shelby Bettencourt,Michelle Bloyd,Constantine A Stratakis,Jason C Wester,Chris J Mcbain

doi:10.1172/jci.insight.141670

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, addiction, rewards processing, and motivation. Of its 2 major subdivisions, the medial Hb (MHb) and lateral Hb (LHb), MHb circuitry and function are poorly understood relative to those of the LHb. 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. We previously showed that RIIα-knockout (RIIα-KO) mice resist diet-induced obesity. In the present study, we report that RIIα-KO 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. Reexpression 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.

Highlights

In the face of the global obesity epidemic, it remains unclear what makes some individuals more susceptible to obesity than others
We show here that Prkar2a, which codes for the cAMP-dependent protein kinase (PKA) regulatory subunit IIα (RIIα), is highly expressed in the medial Hb (MHb) in a region that overlaps the dMHb and ventral MHb subnuclei (vMHb) subnuclei and is present in both acetylcholine- and substance P–expressing cells
These mapping studies showed that Prkar2a expression patterns throughout the dMHb and vMHb varied from anterior to posterior points in the MHb

Summary

Introduction

In the face of the global obesity epidemic, it remains unclear what makes some individuals more susceptible to obesity than others. As a major player in the regulation of the midbrain monoaminergic system [2], the habenula (Hb) is a central structure that integrates rewards with cognition and emotion [3]. While these Hb functions have been investigated in the context of substance abuse, a role for the Hb in obesity and susceptibility to the energy imbalance that drives preventable metabolic dysregulation is less clear. While lateral Hb (LHb) connectivity and function have been more extensively studied [10, 11], it is increasingly evident that there may be complementary or synergistic roles for the MHb and LHb in regulating stress response, nociception, rewards, locomotor activity, and food intake. Crosstalk between the MHb and LHb is unidirectional from the MHb to LHb [13], and while the interpeduncular nucleus (IPN) is a primary output target of both the LHb and MHb, each innervates distinct IPN structures [14, 15]

Methods

Results

Conclusion