Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that approximately 7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.

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Female rats drink more 3% NaCl solution than do males, both when they need sodium (need-induced sodium intake or sodium appetite) and when they do not (need-free sodium intake). The sexual dimorphism of sodium intake is a secondary sexual characteristic because after castration at 1 day of age male rats drank 3% NaCl in adulthood in a manner similar to that of females in both the need-free and need-induced state, and females given long-term, neonatal testosterone drank low, malelike volumes of 3% NaCl on a daily need-free basis, but their response to sodium depletion was unchanged. This sexual dimorphism of sodium intake seems to be governed by testosterone that has been converted in the brain to estrogen because treatment of Day 1 castrated females with a nonaromatizable androgen, dihydrotestosterone, did not change either their need-free or their need-induced 3% NaCl intake. Castration in adulthood of male and female rats did not change their sodium consumption. However, when castrated adults received testosterone, need-free intakes of NaCl were suppressed in both sexes, but the suppression of 3% NaCl intake occurred only while the steroid was present. Exogenous testosterone also lowered the need-induced sodium intake of adult castrated females. Thus, in castrated adults, need-free intake was actively suppressed by exogenous testosterone in both sexes, whereas need-induced intake of NaCl was suppressed only in females. These data indicate that sodium intake in the rat is a sexually dimorphic behavior that is organized neonatally and can be actively suppressed in adulthood by testosterone.

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