The response to stressors involves essential, integrative brain-behavior reactions that are engaged in order to ensure survival and are initially protective and adaptive for many processes such as avoidance of, and vigilance towards, threat, as well as memory, immune function and metabolism. Stress can also have deleterious effects, including mood alterations and anxiety that, if they persist after the stressor is terminated, can become an anxiety or depressive disorder. One salient response of the brain to stress can be seen in the form of structural plasticity that has been most extensively studied in the hippocampal formation and is now found in prefrontal cortex (PFC) and amygdala. In young animals, this plasticity is largely reversible after chronic stress but the reversal is lost in older animals. Thus we propose that chronic stress causes a type of "accelerated aging", i.e., a loss of resilience. If these behavioral and structural changes do not spontaneously recover, inappropriate neurobehavioral functions, such as anxiety or depression, can persist and become maladaptive. Stress effects on structural plasticity and other functions involve interactions among endocannabinoids, excitatory amino acids and glucocorticoids and neuroprotective agents, such as the chaperone, BAG1. The central hypothesis of this proposal is that, along with resilience conferred by adaptive behaviors, resilience in the form of structural plasticity in the hippocampus and prefrontal cortex is a feature of the healthy brain's response to stress. In contrast, loss of resilience is a feature of mood and anxiety disorders and may be a consequence of repeated stress that is mediated by repeated elevation of glucocorticoids (GC's) and excitatory amino acids (EAA) that, together, activate genes related to oxidative stress and possibly inflammation and also alter neurotransmission and cytoskeleton. We plan to identify genes and gene products related to stress and GC effects by perturbing the endocannabinoid (eCB) and BAG1 chaperone systems that modulate glucocorticoid and EAA actions in hippocampus and also in the stress-sensitive mPFC. We postulate that reduced eCB and BAG1 signaling will increase the vulnerability of CA3 and mPFC neurons and confer a loss of resilience. We also plan to look in depth at stress-vulnerable CA3 neurons using a BAC transgenic mouse. There are three Specific Aims:
Aim 1. How do chronic stress and exposure to chronic glucocorticoid alter behavior and PFC and CA3 morphology and affect the pattern of gene expression in vulnerable CA3 neurons? Aim 2. What is the role of endocannabinoid CB1 receptors in moderating negative effects of chronic stress and in hippocampus and prefrontal cortex? Aim 3. What is the moderating role of the neuroprotective factor and glucocorticoid receptor (GR) chaperone, BAG1, in effects of chronic stress on behavior, morphology and gene expression in hippocampus and prefrontal cortex? Our work has had major impact on the field of biological psychiatry by directing attention to structural changes in the brain as a result of stress.

Public Health Relevance

Depression and anxiety disorders caused by stress are a major health problem and major contributor to lost productivity and increasing health care costs, and they involve changes in brain circuitry. Elucidation of mechanisms of resilience of the brain to such stress can lead to better prevention and treatment.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rockefeller University
Other Domestic Higher Education
New York
United States
Zip Code
McEwen, B S (2014) Sex, stress and the brain: interactive actions of hormones on the developing and adult brain. Climacteric 17 Suppl 2:18-25
Picard, Martin; McEwen, Bruce S (2014) Mitochondria impact brain function and cognition. Proc Natl Acad Sci U S A 111:7-8
Rubin, Todd G; Gray, Jason D; McEwen, Bruce S (2014) Experience and the ever-changing brain: what the transcriptome can reveal. Bioessays 36:1072-81
Gray, J D; Rubin, T G; Hunter, R G et al. (2014) Hippocampal gene expression changes underlying stress sensitization and recovery. Mol Psychiatry 19:1171-8
Lee, Tiffany T-Y; Filipski, Sarah B; Hill, Matthew N et al. (2014) Morphological and behavioral evidence for impaired prefrontal cortical function in female CB1 receptor deficient mice. Behav Brain Res 271:106-10
Kinoshita, Yayoi; Hunter, Richard G; Gray, Jason D et al. (2014) Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress. Proc Natl Acad Sci U S A 111:16130-5
Burghardt, Nesha S; Sigurdsson, Torfi; Gorman, Jack M et al. (2013) Chronic antidepressant treatment impairs the acquisition of fear extinction. Biol Psychiatry 73:1078-86
Gray, J D; McEwen, B S (2013) Lithium's role in neural plasticity and its implications for mood disorders. Acta Psychiatr Scand 128:347-61
Hunter, Richard G; McEwen, Bruce S (2013) Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation. Epigenomics 5:177-94
Datson, Nicole A; van den Oever, Jessica M E; Korobko, Oksana B et al. (2013) Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. Endocrinology 154:3261-72

Showing the most recent 10 out of 201 publications