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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 5

RIIα-KO mice run more than twice the distance of their WT littermates during home cage running wheel access.

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RIIα-KO mice run more than twice the distance of their WT littermates du...
Heterozygosity for Prkar2a rescued the running phenotype. Voluntary running activity was graphed in bins of 30 minutes over a 2-week period for (A) female (n = 11–24/genotype) and (B) male (n = 8–12/genotype) RIIα-KO, RIIα+/–, and WT mice and (C) the total number of wheel turns during the 2-week period, analyzed by 1-way ANOVA with multiple comparisons (Bonferroni’s post hoc test). (D) Representative staining for c-Fos or c-Jun (red) (merged with DAPI) in WT and RIIα-KO mice either permitted to run as already acclimated for 2 weeks prior or blocked from running at the outset of the dark cycle (1800 hours). (E) The same images (4D) are shown with only c-Fos or c-Jun (red) and particle density of c-Fos and c-Jun was analyzed with ImageJ software (NIH); unpaired 2-way t tests, n = 5–17 sections from a total 3–5 mice per IEG/genotype (3 males, 7 females). Particle density is defined as the number of counted particles divided by the area ratio of the MHb, with the latter being the area of the MHb over the total image area. All data represent mean ± SEM; scale bars represent 100 μm; **P < 0.01, ***P < 0.001, ****P < 0.0001.

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