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Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation
Edra London, … , Chris J. McBain, Constantine A. Stratakis
Edra London, … , Chris J. McBain, Constantine A. Stratakis
Published November 3, 2020
Citation Information: JCI Insight. 2020;5(23):e141670. https://doi.org/10.1172/jci.insight.141670.
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Research Article Metabolism Neuroscience

Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation

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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.

Authors

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

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Figure 1

In brain, Prkar2a expression is nearly exclusive to Hb.

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In brain, Prkar2a expression is nearly exclusive to Hb.
(A) In situ hybr...
(A) In situ hybridization (ISH) for Prkar2a (left) and immunofluorescence (IF) for PKA RIIα protein (right, original magnification 20×) with higher magnification (60×) detail show that expression in WT (C57BL/6) mouse brain is primarily in the MHb, and (B) 3D ISH for Prkar2a shows robust and specific habenular localization of Prkar2a (3D image: Allen Brain Institute). Representative ISH images (20×, and the higher magnification details, 60×) show colocalization of Prkar2a with (C) Slc17a7 and Chat, (D) Tac1 and Chat and (E) Tac2, and (F) Tac1r in dMHb and vMHb. (G) In MHb, Chat, Tac1, Tac2, and Tacr1 were expressed in approximately 15%, 46%, 65%, and 40% of Prkar2a-expressing cells; n = 6–11 sections from 3 different mice (1 male, 2 female) for each target; 2-tailed unpaired t tests; *P < 0.05. All data represent the mean ± SEM.

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