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

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 2

RIIα-KO mice had reduced habenular PKA enzymatic activity, decreased IPN acetylcholine and glutamate levels, and altered localization of PKA catalytic subunit to dendrites compared with WT mice.

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RIIα-KO mice had reduced habenular PKA enzymatic activity, decreased IPN...
(A) Basal and total (cAMP-stimulated) PKA enzymatic activities in Hb, striatum (Str), and prefrontal cortex (PFC); n = 5–8/group (female data shown). (B) Acetylcholine concentrations in Hb and IPN were lower in RIIα-KO mice compared with WT littermates; n = 6–7/sex/group (male data shown). (C) Glutamate concentrations did not differ in Hb but were lower in IPN of KO compared with WT mice; n = 7–9/group (female Hb and male IPN data shown). (D) Habenular Prkar1a and Prkaca mRNA levels did not differ between WT and RIIα-KO mice; n = 7/group (male data shown). (E) Representative Western blots of Hb lysates for PKA subunits RIα and Cα (first membrane with Gapdh as housekeeper, females) and combined Cαβγ (second membrane with Histone 3 as housekeeper, males); n = 4/genotype. Representative immunofluorescent images of WT (left) and RIIα-KO (right) brain sections (MHb) showed differences in the subcellular localization of (F) PKA catalytic subunits (αβγ, green) in lower dMHb in WT, and mutant mice that had impaired dendritic localization (shown by staining for MAP2, red), and (G) PKA RIIα (green) that is localized both to the cell body and dendrites (MAP2, red) in WT mice (female data shown). *P < 0.05; **P < 0.01, ***P < 0.001, unpaired 2-tailed t tests. All data represent the mean ± SEM.