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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH041256-27
Application #
8628174
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
1991-04-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
27
Fiscal Year
2014
Total Cost
$527,098
Indirect Cost
$216,126
Name
Rockefeller University
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Lau, T; Bigio, B; Zelli, D et al. (2016) Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant. Mol Psychiatry :
Gray, J Megan; Wilson, Christopher D; Lee, Tiffany T Y et al. (2016) Sustained glucocorticoid exposure recruits cortico-limbic CRH signaling to modulate endocannabinoid function. Psychoneuroendocrinology 66:151-8
Gray, J D; Rubin, T G; Kogan, J F et al. (2016) Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol Psychiatry :
McEwen, Bruce S; Nasca, Carla; Gray, Jason D (2016) Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex. Neuropsychopharmacology 41:3-23
Hunter, Richard G; Seligsohn, Ma'ayan; Rubin, Todd G et al. (2016) Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor. Proc Natl Acad Sci U S A 113:9099-104
Picard, Martin; McManus, Meagan J; Gray, Jason D et al. (2015) Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. Proc Natl Acad Sci U S A 112:E6614-23
Nasca, C; Bigio, B; Zelli, D et al. (2015) Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol Psychiatry 20:755-63
Nasca, Carla; Zelli, Danielle; Bigio, Benedetta et al. (2015) Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proc Natl Acad Sci U S A 112:14960-5
McEwen, Bruce S; Gray, Jason D; Nasca, Carla (2015) 60 YEARS OF NEUROENDOCRINOLOGY: Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation. J Endocrinol 226:T67-83
McEwen, Bruce S; Bowles, Nicole P; Gray, Jason D et al. (2015) Mechanisms of stress in the brain. Nat Neurosci 18:1353-63

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