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Abstract

other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor y (PPARy), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARy in the CNS, many reports suggest direct PPARy-mediated actions in the brain. This study aimed to (i) map PPARy expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARy by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARy-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARy by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARy on learning behavior and motivation. Immunoreactive PPARy was detectable in specific sub-nuclei/subfields of the FC, HP, nucleus accumbens, amygdala, hypothalamus, thalamus, and granular layers of the cerebellum. PPARy protein levels were upregulated during aging and in high fat diet-induced obesity. PPARy 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 PPARy. Pioglitazone dose-dependently upregulated PPARy 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 PPARy in the brain and demonstrate their participation the regulation of key behaviors. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).