Brain Expression, Physiological Regulation and Role in Motivation and Associative Learning of Peroxisome Proliferator-activated Receptor γ

Abstract

Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study aimed to (i) map PPARγ expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARγ by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARγ-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARγ by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARγ on learning behavior and motivation. Immunoreactive PPARγ was detectable in specific sub-nuclei/subfields of the FC, HP, nucleus accumbens, amygdala, hypothalamus, thalamus, and granular layers of the cerebellum. PPARγ protein levels were upregulated during aging and in high fat diet-induced obesity. PPARγ mRNA expression was upregulated in the amygdala of females (but not males) that were made obese. Neural precursor cells, mature neurons, and astrocytes in primary FC and HP cultures were shown to express PPARγ. Pioglitazone dose-dependently upregulated PPARγ target genes in manner that was specific to the origin (FC or HP) of the cultures. Lastly, administration of Pio impaired motivation and associative learning. Collectively, we provide evidence for the presence of regulatable PPARγ in the brain and demonstrate their participation the regulation of key behaviors.