The Role of Long Non-Coding RNA in Response to Stress

Epidemiological data consistently show that exposure to chronic stress precedes the onset of several psychiatric disorders. However, there are profound individual differences, with some people demonstrating resilience to the deleterious effects of chronic stress. The biological underpinnings of this individual difference remain poorly understood, hindering efforts to develop new and improved therapeutics. Emerging evidence suggests that long non-coding RNAs (lncRNAs), epigenetic regulators enriched in the human brain, contribute to individual differences in stress responses. LncRNAs comprise a large portion of the human genome and give rise to a comparable number of transcripts as protein-coding genes, yet our understanding of their contribution to human brain function is in its infancy. Several studies profiling the genomic and transcriptomic landscape of depression, a disorder associated with susceptibility to chronic stress, highlighted the regulation of lncRNAs. However, the role of lncRNAs in brain function, including those associated with chronic stress, remains uncharacterized, limiting mechanistic insight and translational potential. We hypothesize that lncRNAs play a key role in individual differences in responses to chronic stress. To test this hypothesis, we propose this study with the overarching objective to expand our knowledge of lncRNAs associated with the response to chronic stress. Bioinformatic integration of genetic, transcriptional, and epigenetic datasets offers a powerful strategy to pinpoint lncRNAs that mediate stress susceptibility and resilience. Specifically, we would harness published genetic analyses of depression to conduct extensive bioinformatic analyses to identify a subset of candidate lncRNA for future experimental analysis (Aim 1). As a proof of concept, we will experimentally explore LINC02977, identified through a multi-omics analysis (Aim 2). These aims will be addressed by: A. further bioinformatic analysis of genome-wide association studies (GWAS) results for depression, focusing on lncRNA and overlaying with data sets from transcriptional and epigenetic studies. B. Combination of genetic expression of LINC02977 in the medial prefrontal cortex of mice of both sexes, with a chronic stress model, followed by behavioral, molecular, and morphological analysis. In summary, this research program is poised to generate critical insights into the contribution of lncRNAs to the molecular basis of individual differences in response to chronic stress. Our application has potential implications for mental health as it may catalyze the development of therapeutic interventions for stress-induced mental health disorders. Project Number: 1R56MH139686-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Orna Issler | Institution: NEW YORK UNIVERSITY SCHOOL OF MEDICINE, NEW YORK, NY | Award Amount: $1,694,752 | Activity Code: R56 | Study Section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11536693