Stress-Induced Neurodegeneration: Mechanisms and Interventions.
Abstract
Soldiers face a broad range of occupational/environmental threats which are hazardous to central nervous system (CNS) function. One of these, exposure to prolonged, extreme stress, has been recently associated with neuronal loss. Vietnam veterans with PTSD have decreased hippocampal volume on MRI, as well as decreased scores on standardized tests of memory. Short term (recent) memory function has been localized to the hippocampus. Humans exposed to extreme stress for sustained periods have suffered deterioration of memory and inability to concentrate, as well as CNS atrophy. chronic stress in several species, including mouse, rat, tree shrew and monkey, have been reported to develop alterations in hippocampal morphology, including apical dendritic atrophy, depletion of vesicles in mossy fiber terminals, as well as actual loss of neurons. A number of stress-induced molecular pathophysiological mechanisms leading to neuronal loss/dysfunction have been described, including: (1) excessive release of excitatory amino acids (in particular, glutamate), leading to massive influx of extracellular calcium into neurons; (2) excessive release of adrenal glucocorticoids, which exacerbates the effect of excitatory amino acids. We have successfully characterized acute social defeat in the mouse as a model for eliciting high plasma levels of adrenal glucocorticoids, inducing high levels of stress and persistent avoidance behavior, as well as increased brain regional levels of mRNA for corticotrophin-releasing hormone and decreased hippocampal levels of mRNA for brain-derived neurotropic factor BDNF. We will characterize the hippocampal neuronal changes induced in this paradigm, and then after chronic stress attempt to block them with a range of pharmaceutical interventions, including neurosteroids, antagonists to CRH and antagonists to excitatory amino acids.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2000
- Accession Number
- ADA377128
Entities
People
- James L. Meyerhoff
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine