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キーワード:
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要旨:
Hypothalamic (HY) and extra-HY corticotropin releasing factor (CRF) mediate neuroendocrine and behavioral aspects of the stress response. Stress in adults transiently alters CRF mRNA levels in the HY paraventricular nucleus (PVN). In response to neonatal maternal separation, both HY and extra-HY CRF mRNA is permanently elevated. It has been hypothesized that this permanent increase in central CRF mRNA beginning in the first neonatal week may account for the biobehavioral phenotype of these animals, including pituitary-adrenal stress hyper-responsiveness and anxiety-like behavior. In order to test this hypothesis, we developed a lentiviral vector carrying both a gene for CRF over-production and for green fluorescent protein (GFP). Initial experiments demonstrated that unilateral or bilateral PVN injection of this construct (500 nL/side) into adrenalectomized, basal corticosterone pellet-replaced adult male rats leads to an increase of CRF mRNA in the injected PVN, increased median eminence CRF content and elevated circulating ACTH levels. Subsequent experiments demonstrate that stereotaxic injection of this construct (400 nL) into the region of the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) on postnatal day (PND) 3 yields both GFP expression and CRF over-expression by PND10. These experiments demonstrate the feasibility of this approach. Future experiments will focus on examining the temporal and spatial effects of CRF over-production in the developing brain on the biobehavioral phenotype as well as on CNS adaptations of stress-responsive brain circuits.
