A major goal of our research is to understand the mechanisms underlying depression including post-stroke depression and the therapeutic actions of antidepressants. To address factors that impact chronic depression we examine the mechanisms of functional promoter polymorphisms and chronic stress induced epigenetic modification actions on gene expression, behavior, and antidepressant response in humans and mouse models of mental illness. Our fundamental research has identified multiple molecular mechanisms that regulate key genes in mental illness including serotonin-5-HT1A; dopamine-DRD2; and 5-HT synthesizing TPH2 genes. We have identified novel DNA elements that regulate these genes, cloned the novel transcription factors targeting them, and identified new functional gene polymorphisms associated with mental illness (Albert, 2019). We have elucidated their roles in vitro, in mouse models and in humans.

For the 5-HT1A receptor, we identified rs6295 as a functional polymorphism associated with depression and suicide that leads to dys-regulation of receptor expression (Lemonde et al., 2003). We have shown changes in mental illness of RNA and protein expression of the 5-HT1A receptor and its key transcriptional regulators that we have identified, including Freud-1, Freud-2 and Deaf1. In mouse models we have shown that alterations in these transcription factors result in altered 5-HT1A expression, and antidepressant-resistant anxiety and depression phenotypes. Our current research addresses which treatments are effective in these mice (Vahid-Ansari et al. 2024). In addition, we have recently examined the DNA methylation patterns of the 5-HT1A promoter sites, and upstream sites recognized by these transcription factors (Albert et al., 2019).  These studies demonstrate the potential to target multiple mechanisms to for treatment of mental illness.

We have also established a new mouse model of post-stroke depression that responds to antidepressants (Vahid-Ansari and Albert, 2018), which promote 5-HT re-innervation of the stroke site (Zahrai, 2020). We are currently addressing the role of this re-innervation in antidepressant actions using ontogenetic and gene knockout approaches.  We are also examining the role of 5-HT innervation changes in other mouse models of depression including genetic, stress-induced, and depression associated with Parkinson’s and Alzheimer’s disease.