Corticotropin Releasing Hormone Antagonist Does Not Prevent Adrenalectomy-Induced Apoptosis in the Dentate Gyrus of the Rat Hippocampus

Abstract

Adrenalectomy in the mature rat leads to death of granule cells in the dentate gyrus of the hippocampal formation. The mechanisms underlying this cell death have not been fully clarified: It has been considered that the granule cells require adrenal steroids for their survival, since corticosterone replacement prevents their death. However, adrenalectomy-induced loss of negative feedback also increases levels of corticotropin releasing hormone (CRH) in several limbic brain regions. CRH is known to induce neuronal death in hippocampal regions rich in CRH receptors. This study tested the hypothesis that adrenalectomy-induced granule cell death is mediated via the enhanced activation of CRH receptors. The extent of granule cell degeneration was compared among 4 groups of young adult male rats: Sham-adrenalectomy controls, adrenalectomized rats, adrenalectomized rats infused with a CRH antagonist from the onset of steroid deprivation to the time of sacrifice, and adrenalectomized rats infused with vehicle only. (9-41)-alpha-helical CRH was administered using an osmotic pump into the cerebral ventricles. Adrenalectomy led to robust granule cell degeneration, which was maximal in the suprapyramidal blade of the dentate gyrus. Infusion of the CRH antagonist in doses shown to block CRH actions on limbic neurons did not decrease the number of degenerating granule cells compared with the untreated or vehicle-infused adrenalectomized groups. Therefore, blocking the actions of CRH does not prevent adrenalectomy-induced granule cell death, consistent with a direct effect of corticoids on the survival of these neurons.

Hippocampal neurogenesis is not enhanced by lifelong reduction of glucocorticoid levels

“…4D,F). This effect, likely attributable to loss of MR activation (Reul and de Kloet, 1985;Hornsby et al, 1996;Gerth et al, 1998), was similar in magnitude to the apoptosis evoked by a 6 day adrenalectomy in previously intact 3-month-old rats (Fig. 4C,E).…”

“…Indeed, we found a transient but robust enhancement of MR mRNA expression that lasted throughout the developmental period, when MR expression is dynamically regulated (Vazquez et al, 1998). Thus, by upregulating MR expression, granule cells may attempt to compensate for abnormally low CORT levels and maintain MR signaling at a level necessary for both control of neurogenesis and protection against apoptosis Hornsby et al, 1996;Gerth et al, 1998;Montaron et al, 2003). Indeed, our data, together with previous studies, suggest that this adaptive mechanism might be successful: chronically ADX/clamped rats, when tested as adults, performed without impairment in hippocampus mediated learning and memory tasks, even at age 12 months (Brunson et al, 2001b).…”

“…First, granule cells were considered to be undergoing apoptosis based on morphological characteristics, including pyknotic, shrunken nuclei and an eosinophilic cytoplasm (Gerth et al, 1998). Thus, cells exhibiting dense chromatin forming crescent or ring-like structures or discrete clumps were counted in the cresyl violet-stained sections (see above).…”

Androgens Are Neuroprotective in the Dentate Gyrus of Adrenalectomized Female Rats

“…Cells that had a smaller volume, had multiple, densely-stained clumps of chromatin, a condensed shrivelled nucleus, and blebbing of the membrane were considered apoptotic (see Gerth et al, 1998). Cells with pyknotic, single nuclear clumps were excluded.…”

“…Apoptotic cells were counted within a l00x visual field in which the arch of the suprapyramidal blade was centered (see Figure 2). The supramarginal blade was chosen as a site for analysis due to the high numbers of apoptotic cells found there compared to the infrapyramidal blade (Gerth et al, 1998;Sloviter et al, 1993). When apoptotic neurons were observed they were marked on a grid to prevent multiple counts of the same cell.…”