Noradrenergic regulation of reactive astrocyte formation in central nervous system injury

A challenging problem in neuroscience is the frequent failure of the adult mammalian central nervous system (CNS) to reestablish normal function after injury. Several strategies have been used to improve regeneration. These include transplantation of fetal tissue into the injured adult CNS to provide trophic support for regenerating axons and neurons, administration of growth and trophic factors, and implantation of various materials to serve as a substrate for axon growth through the site of injury. Another strategy that has been less thoroughly investigated is the reduction of the astrocyte reaction that results from CNS injury. Injury to the adult CNS initiates several cellular events. Vascular endothelia undergo mitogenesis and microglia proliferate and shift from a ramified resting morphology to an ameboid reactive state. Astrocytes hypertrophy and/or proliferate and express increased amounts of the glial fibrillary acidic protein (GFAP) and beta-adrenergic receptors ({dollar}beta{dollar}-AR). Reactive astrocytes have the potential to form a barrier to regenerating axons and to express inhibitory cell surface or extracellular matrix molecules which further impede axon growth.; The finding that blockade of {dollar}beta{dollar}-AR reduces the astrocytic reaction to neuronal degeneration led me to investigate the link between the noradrenergic system and astrocyte reactivity. To test the hypothesis that the density of noradrenergic innervation is one factor in the regulation of astrocyte reactivity, I measured changes in GFAP after neuronal degeneration in CNS areas with hyperinnervated or depleted noradrenergic innervation.; Neonatal 6-hydroxydopamine (6-OHDA) treatment was used to induce permanent sprouting of noradrenergic terminals in the trigeminal motor nucleus (MoV). N-(2-chlorethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) was used to eliminate noradrenergic terminals from the spinal cord dorsal horn. Neuronal injury in MoV and spinal cord was induced by injection of the toxic lectin from Ricinus communis (ricin lectin) into the masseter or sciatic nerves, respectively. GFAP optical density (O.D). was increased approximately 36% in the hyperinnervated MoV, and reduced approximately 65% in the NE depleted spinal cord dorsal horn. My experiments indicate that the degree of noradrenergic innervation is a factor in the intensity of astrocyte reactivity.