Hypoglycemia Induces Transient Neurogenesis and Subsequent Progenitor Cell Loss in the Rat Hippocampus

Abstract

Neurogenesis after brain injury not only leads to the replacement of damaged cells but might also contribute to functional recovery, suggesting the possibility of endogenous neural repair. We investigated the extent of hippocampal neural regeneration in a rat model of hypoglycemia. Two weeks after 30 min of insulin-induced isoelectric electroencephalogram, extensive neuronal loss was observed in the hippocampus, including area CA1 and dentate gyrus (DG). A transient increase in progenitor cell proliferation in the DG subgranular zone (SGZ) was detected, leading to an increase of immature neuroblasts 1-2 weeks after hypoglycemic insult. Most of the surviving newborn cells assumed a neuronal phenotype within 1 month in DG, a few cells near the site of granule-cell death becoming astroglia or microglia. No neuronal regeneration was observed in the CA1 after hypoglycemia, although dividing cells appeared to be astroglia or microglia in CA1 and dentate hilus. At 4 weeks after hypoglycemia, proliferative activity in the SGZ diminished below baseline in experimental versus control rats, with a subsequent reduction of neuroblasts. Morphological findings (doublecortin staining) suggest permanent progenitor cell loss in some areas of SGZ. Reduced neurogenesis in DG and lack of neuronal regeneration in CA1 may impede cognitive recovery after severe hypoglycemia injury.

Decreased Brain Zinc Availability Reduces Hippocampal Neurogenesis in Mice and Rats

“…Therefore, we tested our hypothesis that zinc chelation by CQ would reduce neurogenesis in the hippocampus of normal rats and in rats with a hypoglycemic insult. The results of our previous study showed a transient increase of progenitor cells after hypoglycemia until 2 weeks after insult (Suh et al, 2005). The reason for an increase in neurogenesis activity at early time points after hypoglycemia is uncertain.…”

“…The results of our previous study showed that neurogenesis after hypoglycemia was significantly depressed at 4 weeks after insult (Suh et al, 2005). To investigate the relationship between the amount of vesicular zinc and the state of hippocampal neurogenesis, brain sections were processed for TSQ (Frederickson et al, 1987) and AMG zinc staining (Danscher and Rytter Norgaard, 1985).…”

“…Their brains were removed, postfixed, and then cryoprotected by 20% sucrose. Free-floating coronal sections of 40-mm thickness were immunostained as described (Suh et al, 2005) using the following reagents: mouse anti-BrdU (Roche, Indianapolis, IN, USA); rat anti-BrdU (Accurate Chemicals, Westbury, NY, USA); rabbit anti-Ki67 (recognizing nuclear antigen expressed during all proliferative stages of the cell cycle, except G0 (Kee et al, 2002); Novocastra, Newcastle UK); goat anti-doublecortin (DCX) (recognizing immature neurons) (Nacher et al, 2001); Santa Cruz Biotechnology, Santa Cruz, CA, USA); and ABC solution (Vector laboratories, Burlingame, CA, USA).…”

“…The results of our previous study showed that hypoglycemic brain insult transiently increases the number of proliferating progenitor cells and immature neurons in the DG of rats (Suh et al, 2005), followed by a sustained decrease in progenitor cell proliferation and immature neurons weeks later. The mechanism underlying the rise and decline in the hippocampal progenitor cell proliferation is unclear.…”

Adult Neurogenesis and the Ischemic Forebrain

“…For example, damage induced by mechanical lesions, prolonged seizures, hypoglycemia, fluid percussion injury or stroke increases dentate gyrus cell proliferation by approximately 5-to 12-fold. As in the intact brain, many newly generated cells die, but the vast majority of those that survive differentiate into neurons, and typically less than 20% of adult-born cells become glia or remain undifferentiated (Gould and Tanapat, 1997;Parent et al, 1997;Liu et al, 1998;Jin et al, 2001;Rice et al, 2003;Suh et al, 2005).…”