Stress in the environment can lead to the development of a mood disorder. Yet, not everyone exposed to a stressful event develops a mood disorder. This suggests that mood disorders result from a unique confluence of genetic and environmental factors. While some factors have been identified that can increase susceptibility to mood disorders, the mechanisms underlying normal recovery after stress (resilience) or failure to recover (loss of resilience) remain unknown. This proposal will use rodent models of chronic restraint stress (CRS) and early life stress (ELS), which have been shown to alter mood-related behaviors and induce morphological and functional changes in the hippocampus to study recovery from stress as a model of susceptibility to mood disorders. The CA3 region of hippocampus is particularly sensitive to the effects of both CRS and ELS, therefore a novel transgenic reporter mouse in which EGFP has been fused to the L10a ribosomal subunit under control of a CA3-specific promoter (Gprin3) will be used to isolate in vivo translating RNA from CA3 neurons. Use of RNA-sequencing technology will allow for high-throughput analysis of gene expression changes implicated in neuroplasticity after CRS, recovery from CRS, and ELS in this highly dynamic subpopulation of neurons. These results will provide a map of altered gene function in normal resilience and impaired resilience, identifying genes that normally recover after CRS, but fail to recover when CRS is combined with ELS. Changes in expression will be correlated with the altered behavioral endpoints expected after ELS. Additionally, this proposal will use a genetic model of increased susceptibility to stress and mood disorders, the BDNF-Val66Met mouse, to study impaired resilience. This mutation in brain derived neurotrophic factor (BDNF) results in the substitution of a valine for a methionine in codon 66 (Val66Met). In clinical populations, carriers of the Met allele exhibit decreased hippocampal function and increased risk of mood disorders. Further, Met allele carriers exposed to ELS have reduced hippocampal volumes and altered BDNF levels as adults. The mouse model of this mutation exhibits anxiety and depression-like behaviors believed to recapitulate the human phenotype and is more vulnerable to CRS, but the effects of ELS on Val66Met mice have not been investigated. This study will use the Val66Met mice in combination with the CA3-reporter mice previously described to investigate the impact of a genetic predisposition to mood disorders on gene expression in CA3. Double transgenic mice will be subjected to ELS and CRS, combining genetic and environmental susceptibilities, to study their impact on gene expression in CA3 neurons as well as the still uncharacterized behavioral effects of ELS on BDNF-Val66Met mice. These experiments will identify genes that fail to recover after CRS, as a result of this highly prevalent genetic mutation, when compared with expression patterns from normal recovery. These gene expression profiles will provide new insight into BDNF's function in stress-induced neuroplasticity and identify new targets for the treatment of mood disorders.
Inability to recover normal cognition and affect after a stressful event can lead to the development of mood disorders, such as anxiety or depression. This research will provide novel insight into the molecular mechanisms of how the brain recovers from stress, and how genetic predisposition and early life stress can impair normal recovery, thereby modeling mood disorder susceptibility. The proposed experiments will provide a map of genes that change and recover, or do not recover, after stress in the vulnerable CA3 region of the hippocampus that will serve as an important resource for future researchers in the development of new treatments for mood disorders.
