| First Author | Domi E | Year | 2016 |
| Journal | J Neurosci | Volume | 36 |
| Issue | 50 | Pages | 12611-12623 |
| PubMed ID | 27810934 | Mgi Jnum | J:237514 |
| Mgi Id | MGI:5812841 | Doi | 10.1523/JNEUROSCI.4127-15.2016 |
| Citation | Domi E, et al. (2016) Genetic Deletion of Neuronal PPARgamma Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARgamma Function. J Neurosci 36(50):12611-12623 |
| abstractText | PPARgamma is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARgamma is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPARgamma is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPARgamma in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARgamma by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARgamma (PPARgammaNestinCre), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARgamma antagonist, elicited a marked anxiogenic response in PPARgamma wild-type (WT), but not in PPARgammaNestinCre knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPARgammaNestinCre KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPARgamma colocalizes with GABAergic cells. These findings demonstrate that neuronal PPARgamma is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPARgamma. SIGNIFICANCE STATEMENT: Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) is a classical target for antidiabetic therapies with thiazolidinedione compounds. PPARgamma agonists such as rosiglitazone and pioglitazone are in clinical use for the treatment of insulin resistance. PPARgamma has recently attracted attention for its involvement in the regulation of CNS immune response and functions. Here, we demonstrate that neuronal PPARgamma activation prevented the negative emotional effects of stress and exerted anxiolytic actions without influencing hypothalamic-pituitary-adrenal axis function. Conversely, pharmacological blockade or genetic deletion of PPARgamma enhanced anxiogenic responses and increased vulnerability to stress. These effects appear to be controlled by PPARgamma neuronal-mediated mechanisms in the amygdala. |
