VULNERABILITY FACTORS IN STRESS-RELATED DISORDERS: ROLE OF 5α-REDUCTASE IN THE NEUROBIOLOGY OF DEPRESSIVE AND ANTISOCIAL BEHAVIORS

The inhibitor of 5α-reductase enzymes (5αRs), finasteride (FIN), has potent depressogenic effects and can decrease impulsive-like behaviors in rodents. In light of this evidence, changes in genes transcription of 5αR enzyme 1 (SRD5A1) and 5αR enzyme 2 (SRD5A2) could be indicative of whether these genes are implicated in depressive- and aggressive-like behaviors. Transcriptomics analyses performed in human brain samples of Major Depressive Disorder (MDD) patients or rodent models of depression did not demonstrate changes in SRD5A1 and SRD5A2. Transcriptomics data from brain samples of subjects with an Antisocial Behavior (ASB) diagnosis are not presently available. Here, I performed the first transcriptomic study in brain samples of ASB subjects. However, these analyses did not show differences between the experimental groups in terms of SRD5A1 and SRD5A2 mRNA levels. One plausible explanation could be the restricted cell-specific pattern of 5αRs in the brain. Therefore, I collected human brain samples from NIH NeuroBioBank and performed western blot analyses in both experimental groups (MDD and ASB subjects) and their respective control groups. Protein analyses revealed reductions in 5αR2 levels in MDD samples, suggesting that 5αR2 levels could be correlated to MDD development or expression, although no differences were detected in RNA levels. One of the most relevant conditions related to the onset of MDD disorders is a stressful environment across the entire lifespan. To further investigate whether stress is directly linked to a reduction in the levels of 5αRs, I evaluated the expression of these enzymes in three commonly used models of depression in rats, the Chronic Mild Stress, Social Isolation and Social Defeat models. Interestingly, the expression of 5αR2 was reduced in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of rats exposed to long term stress, that is, in the same areas where a decrease in 5αR2 levels was detected in MDD subjects. However, a correlation between stress and altered expression levels of 5αR2 is not sufficient to prove that this enzyme is involved in the onset of the disorder. Therefore, I knocked down the expression of SRD5A2 in the PFC or NAc of rats and then I evaluated the depressive-like behaviors to assess the induction of a depression-like condition. Indeed, the knock down of SRD5A2 in the PFC and NAc was accompanied by the development of distinct behavioral modifications akin to depressive symptoms. I also performed knock-down experiments of SRD5A1 in the PFC and NAc to determine whether 5αR1 is also involved in the development of depressive phenotypes or if depressive symptoms are mainly related to reduced expression of 5αR2. Interestingly, rats with reduced expression of 5αR1 did not display depressive-like behaviors. To summarize, I studied: 1- 5αR1 and 5αR2 expression, in terms of RNA levels by transcriptomic analysis and protein expression levels by immunoblotting, in the orbitofrontal cortex (OFC) of human samples of ASB subjects; 2- 5αR1 and 5αR2 protein expression levels in human samples of MDD in the OFC, anterior cingulate cortex (ACC), NAc, hippocampus (HIPPO) and amygdala (AMY) by immunoblotting; 3- 5αR1 and 5αR2 protein expression levels in the PFC, NAc, HIPPO, and AMY of rats in three different animal models of MDD: the social defeat, social isolation, and chronic mild stress models, accompanied by the assessment of depressive-like behaviors (novelty-induced hypophagia test, sucrose preference test and forced swim test); 4- behavioral consequences of the knock-down of 5αR1 or 5αR2 in the PFC and NAc of rats, assessing depressive-like behaviors with novelty-induced hypophagia test, sucrose preference test, and forced swim test.