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 is 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 food rewards while enhancing the motivation for exercise, a desirable combination of behaviors.
Edra London, Jason C. Wester, Michelle S. Bloyd, Shelby Bettencourt, Chris J. McBain, Constantine A. Stratakis