*For those who wish to park at the NUHS Tower Block, kindly provide your name, institution, vehicle number and IU number to Rudy (rudy_saleh@ams.edu.sg) by Tuesday, 12 Mar 2019 before 10am. Kindly note that late submissions cannot be entertained as security would require enough lead time.
**Please note that the new NUHS gantry is already in effect. If you are coming to NUHS (Tower Block) via the Bridge Linkway from the Kent Ridge MRT, Medical Centre or NUH, you will have to register for a visitor pass on Level 3 of the Medical Centre first. Alternatively, if you come by the front door entrance of Tower Block (also a short walk from Kent Ridge MRT Exit B), you may bypass the gantries.
Synopsis
Synopsis
Stress is a well-established ‘trigger’ for multiple forms of chronic illness including mental disorders. Despite the compelling epidemiological evidence, most individuals exposed to chronic, severe stress during development or adulthood are largely unaffected with respect to serious health outcomes. These findings reflect the remarkable individual variation in susceptibility to stress. In the studies reported here, we attempted to integrate this knowledge into an analysis of the genetic architecture of stress susceptibility in humans. Our objective was not to seek ‘causal’ genetic variants but to define operative gene networks and better understand the biology underlying stress susceptibility. We used a publicly-available, genome-wide association study of addictions that included measures of environmental adversities known to increase the risk for psychopathology. We identified individual single-nucleotide polymorphisms (SNPs) that distinguished adversity-exposed individuals with (susceptible) or without (resilient) substance abuse in a training data set. The resulting SNPs were to develop a genomic profile score for stress susceptibility (GPSsus) that was subsequently validated in a test dataset. The resulting GPSsus also predicted adversity-related mental disorders in multiple independent samples of individuals exposed to early life adversity. The GPSsus genes are highly enriched for SNP’s associated with levels of DNA methylation, suggesting epigenetic mediation. Animal models identify transcriptional pathways and neural circuits associated with individual differences in susceptibility to adversity. We used one such model, chronic social defeat, and found a highly significant overlap between the genes that comprised our GPSsus and differentially expressed genes using RNAseq from the ventral hippocampus in resilient vs susceptible mice. Informatic analyses of both human and rodent data sets implicate both estrogen- and glucocorticoid-signaling pathways and implicate chromatin remodelling as a mediator. Direct manipulation of ESR1 expression resulted in significant alterations in stress susceptibility in the murine chronic social defeat model. In sum, our findings reveal a distinct genetic architecture that underlies individual differences in susceptibility to adversity in humans. The functional genomic analysis implies a role for brain region-specific, steroid-sensitive transcriptional signalling in defining individual differences in susceptibility to stress. These studies identify candidate biological mechanisms for differential susceptibility. Further bioinformatic analyses identified “neurogenesis” as an underlying biological process and an environmental manipulation (enrichment) in a rodent model that enhances neurogenesis increases resilience to chronic stress. Finally, studies with human cohort provide convergent evidence for the importance of neurogenesis for differential susceptibility to early life stress in relation to mental health outcomes. The results will be discussed in terms of implications for clinical interventions including those that might direct affect neurogenesis and dampen stress susceptibility.
Michael J. Meaney is primarily known for his research on stress, maternal care, and gene expression. His research team has "discovered the importance of maternal care in modifying the expression of genes that regulate behavioural and neuroendocrine responses to stress, as well as hippocampal synaptic development" in animal studies. The research has implications for domestic and public policy for maternal support and its role in human disease prevention and economic health.
Meaney is Director, Integrative Neuroscience Programme, Singapore Institute For Clinical Sciences, Associate Director of the Research Centre at the Douglas Mental Health University Institute, Director of the Program for the Study of Behaviour, Genes and Environment, and James McGill Professor, Departments of Psychiatry and Neurology and Neurosurgery, McGill University. He was named a "Most Highly Cited Scientist" in the area of neuroscience by the Institute for Scientific Information in 2007 and was also elected to the Royal Society of Canada (RSC) and named a Knight of the National Order of Quebec. For research on stress, he has received a Senior Scientist Career Award from the Canadian Institutes of Health Research (CIHR) in 1997. He also, along with fellow researcher from the Douglas Institute, Dr. Gustavo Turecki, was awarded the Scientist of the Year Award by Radio-Canada. In 2011, he was made a Member of the Order of Canada.
.jpg)
