5th International Conference on Epigenetics and Bioengineering (EpiBio)
The Expression of Key Hub Genes within the Nucleus Accumbens Mediates Resilience to Chronic Stress.
Authors
Nestler, E., Icahn School of Medicine at Mount Sinai
Parise, E., Icahn School of Medicine at Mount Sinai
Godino, A., Icahn School of Medicine at Mount Sinai
Browne, C., Icahn School of Medicine at Mount Sinai
Major depressive disorder (MDD) is the leading leading contributor to
suicide according to the World Health Organization. Half of all patients
diagnosed with MDD are at least partly resistant to antidepressant treatment. Notably, both genetic
and environmental factors, including exposure to chronic social stress, play a role in the
development of MDD and related syndromes. The chronic social defeat stress (CSDS) paradigm
in mice has proven to be a highly useful animal model for studying depression-related behavioral
abnormalities. Importantly, this paradigm allows for the identification of animals that succumb to
the effects of the stress, termed susceptible, from those that do not, termed resilient. To better
understand the potential genes underlying the resilient phenotype, we performed RNA-sequencing
on mice exposed to CSDS and compared gene expression changes within the nucleus accumbens
(NAc) between resilient and susceptible mice. Using weighted gene co-expression network
analysis (WGCNA), we identified gene expression patterns that are associated with
resilience. Then using an undirected key driver analysis that allows for
the reconstruction of accurate cellular networks (ARACNE) based on gene-gene correlations. We
identified three genes (Gprin1, Bcr, and Stx1a) that were predicted to be key drivers
(regulate other genes within a highly significant), resilient-specific module. We are now
suicide according to the World Health Organization. Half of all patients
diagnosed with MDD are at least partly resistant to antidepressant treatment. Notably, both genetic
and environmental factors, including exposure to chronic social stress, play a role in the
development of MDD and related syndromes. The chronic social defeat stress (CSDS) paradigm
in mice has proven to be a highly useful animal model for studying depression-related behavioral
abnormalities. Importantly, this paradigm allows for the identification of animals that succumb to
the effects of the stress, termed susceptible, from those that do not, termed resilient. To better
understand the potential genes underlying the resilient phenotype, we performed RNA-sequencing
on mice exposed to CSDS and compared gene expression changes within the nucleus accumbens
(NAc) between resilient and susceptible mice. Using weighted gene co-expression network
analysis (WGCNA), we identified gene expression patterns that are associated with
resilience. Then using an undirected key driver analysis that allows for
the reconstruction of accurate cellular networks (ARACNE) based on gene-gene correlations. We
identified three genes (Gprin1, Bcr, and Stx1a) that were predicted to be key drivers
(regulate other genes within a highly significant), resilient-specific module. We are now
investigating how changes in the expression of these genes could lead to changes in depressive-
like behavior. To test this, multiple cohorts of mice were exposed to CSDS or another stress
paradigm, chronic variable stress, and mRNA expression levels of these target genes were
assessed. We also tested the functional consequences of virally manipulating these genes following
prior to CSDS. These studies suggests that overexpression of these genes in
NAc neurons produces a pro-resilient effect. Together, these studies are providing
novel insight into the molecular basis of stress resilience.