Research Projects

Major depressive disorder (MDD) is a debilitating psychiatric disorder that takes a huge toll on individuals, families and societies throughout the globe. There are medications to treat MDD, but are not very efficacious in nearly one third to half of the affected individuals. Unfortunately, there is a dearth of new, more effective therapeutics in the last 5-6 decades, and the main reason being incomplete understanding of the molecular aetiology. Epigenetic mechanisms play a crucial role in the etiopathology of depression, and this has been shown in terms of major epigenetic changes in the brain in animal models of depression as well as post mortem human brains. To further reveal the underlying molecular mechanisms, we have investigated the epigenetic and transcriptional regulatory mechanisms dysregulated in neural circuitries that control emotions, mood, reward and/or motivation in a mouse model of depression . Chronic stressful episodes have been shown to perturb the nervous system in rodent models of depression, anxiety and related affective disorders of emotions. Our earlier findings and also that from other groups have shown increase in the transcriptionally repressive epigenetic mark H3K9me2 in reward circuitry in chronic social defeat stress (CSDS) mouse model of depression. Interestingly, our intervention of antidepressant imipramine administration for a month resulted in recovery from depression and was associated with attenuation in repressive methylation on many of the gene promoters (Wilkinson et al 2009). Our recent effort has led us to uncover the role of Jmjd2 or Kdm4 family histone lysine demethylases (KDMs), which act on H3K9me2, to get better mechanistic insights into the depression associated neural, neuroglia, neurogenic and neuroplastic changes (Pathak et al 2017; Maitra et al. 2020). Additionally, we have interesting preliminary results about the dysregulation of Phf8, Phf2, Jhdm/KIAA1718 and the putative member,49….Rik, of the KDM7 family in critical region of mouse brain reward circuitry in susceptible mice. We also observed their altered expression levels in the hippocampal dentate gyrus (DG) and further in neural stem/progenitor cell proliferation vs differentiation in culture. This has driven us to propose this study, to uncover their important role in depression via affecting/dysregulating genes important for neuroglial functions. Using tools of cell biology, biochemistry and molecular biology including NGS based high throughput transcriptomics and epigenomics tools such as RNA-Seq, ChIP-Seq, the outcome of the proposed study is likely to give us better insight into the function of this less studied KDM7 family in brain and behaviour and psychoneuropathology. This approach might yield not only in molecular markers’ discovery, but also in developing better and more efficacious therapeutics since some chemical modulators of the KDM7 family are already being tested in cancer research and therapy.