Recurrent insulin-induced hypoglycemia (RIIH) results in glucose counterregulatory dysfunction in men and male rodents. Intensified hypoglycemia in the latter coincides with diminished neuronal Fos expression in central metabolic regulatory structures, evidence that supports habituation of CNS-mediated compensatory motor outflow during re-exposure to this metabolic stress. In light of the evidence for counterregulatory resistance to precedent hypoglycemia in women, we utilized estradiol-treated ovariectomized (OVX) female rats to examine the hypothesis that this hormone regulates neural adaptability to recurring hypoglycemia. Groups of OVX rats were implanted with subcutaneous silastic capsules containing estradiol benzoate (E) or oil alone, and injected subcutaneously with one or four doses of the intermediate-acting insulin, Humulin NPH, one dose daily, or with diluent alone. Blood glucose levels were not altered by RIIH in E-implanted OVX animals, but were significantly decreased after four versus one insulin injection in the OVX+oil group. Mean numbers of Fos-immunoreactive (ir) neurons in the paraventricular nucleus hypothalamus (PVH), dorsomedial nucleus hypothalamus (DMH), and lateral hypothalamic area (LHA) were higher in both E- versus oil-implanted OVX rats injected with diluent only. Acute hypoglycemia significantly increased mean counts of Fos-ir-positive neurons in the PVH, DMH, and LHA, as well as the nucleus of the solitary tract (NTS) and area postrema (AP) in E- and oil-treated animals to an equivalent extent. OVX+E rats exhibited comparable numbers of Fos-positive neurons in the PVH, DMH, and LHA after one versus four insulin injections, whereas the numbers of labeled neurons in NTS and AP were increased or decreased, respectively, by RIIH. Oil-implanted OVX rats showed significantly diminished numbers of Fos-ir-positive neurons in each neural structure after repeated hypoglycemia. The present data demonstrate that estradiol sustains or enhances neuronal reactivity to recurring hypoglycemia in central metabolic structures, whereas hypoglycemic patterns of Fos expression in each site become habituated during RIIH in the absence of this steroid. The brain sites characterized here by estrogen-dependent maintenance of neuronal genomic reactivity to this substrate fuel imbalance may contain direct and/or indirect cellular targets for hormonal actions that prevent adaptation of CNS-controlled motor responses to this metabolic stress.

Objectives. To study possible nerve regeneration of a damaged auditory nerve by the use of stem cell transplantation. Methods. We transplanted HNPCs to the rat AN trunk by the internal auditory meatus (IAM). Furthermore, we studied if addition of BDNF affects survival and phenotypic differentiation of the grafted HNPCs. A bioactive nanofiber gel (PA gel), in selected groups mixed with BDNF, was applied close to the implanted cells. Before transplantation, all rats had been deafened by a round window niche application of β-bungarotoxin. This neurotoxin causes a selective toxic destruction of the AN while keeping the hair cells intact. Results. Overall, HNPCs survived well for up to six weeks in all groups. However, transplants receiving the BDNF-containing PA gel demonstrated significantly higher numbers of HNPCs and neuronal differentiation. At six weeks, a majority of the HNPCs had migrated into the brain stem and differentiated. Differentiated human cells as well as neurites were observed in the vicinity of the cochlear nucleus. Conclusion. Our results indicate that human neural precursor cells (HNPC) integration with host tissue benefits from additional brain derived neurotrophic factor (BDNF) treatment and that these cells appear to be good candidates for further regenerative studies on the auditory nerve (AN).

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