Stress initiates a cascade of biochemical events in the brain and peripheral systems that enable the organism to cope with novel and challenging situations. However, the cumulative effects of chronic stress states negatively affects most physiologic systems because the target cells are exposed to the stress mediators over a long period of time. Human findings, pointing to a linkage between chronic stress and anxiety disorders, depression and cognitive impairments, have been extensively supported by behavioral observations in rodents. The physiological and behavioral consequences of chronic or prolonged stress depend on genetic and environmental mediators of the individual's vulnerability. The molecular mechanisms of vulnerability or resilience are not known despite the large number of studies investigating stress. This proposal aims to determine the molecular markers of sensitivity and resilience to chronic stress as a first step towards the identification of stress mediators.
The aims of this proposal are:
Specific Aim 1) Determine the behavioral consequences of chronic restraint stress, during and after the cessation of a chronic restrain stress (CRS) paradigm in four different inbred strains of rats. These inbred strains, the Wistar Kyoto (WKY), Fisher 344 (F344), Brown Norway (BN) and Lewis (LEW), are chosen to represent distinctive susceptibility and/or resilience to chronic stress. The elevated plus-maze (EPM) test will be employed to assess the effect of chronic stress on anxiety-related behavioral responses.
Specific Aim 2) Using a hypothesis-generating, unbiased approach, the Affimetrix DMA microarray analysis, we will examine the gene expression profile changes in two brain areas, the amygdale and the hippocampus, and blood of male animals from the four inbred strains in response to CRS. Microarray analysis will be carried out on tissues obtained from animals exposed to: i) No stress, which will serve to determine the baseline gene expression ii.) 14 days of the CRS paradigm, which will inform us on the molecular markers of stress responsivity, and iii.) 10 days after the cessation of CRS to determine markers of post-stress responsivity. By employing microarray analyses of RNA isolated form two brain regions highly relevant to anxiety and stress and from blood, we will determine the common profiles of gene expression in these tissues during and after chronic stressor exposure.
Specific Aim 3. Confirm the most promising candidate marker genes by quantitative real-time RT-PCR. This exploratory study will identify genes that are altered solely or concomitantly in specific brain regions or blood in response to chronic stress. These scenarios would allow us to identify candidate markers of chronic stress from the blood representing an accessible source of genetic material in humans. ? ? ?
| Redei, E E; Andrus, B M; Kwasny, M J et al. (2014) Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy. Transl Psychiatry 4:e442 |
| Andrus, B M; Blizinsky, K; Vedell, P T et al. (2012) Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol Psychiatry 17:49-61 |
| Pajer, K; Andrus, B M; Gardner, W et al. (2012) Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression. Transl Psychiatry 2:e101 |
