PubMed · 4182324
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G Lidén, A Kankkunen. 1969. Visual reinforcement audiometry.. https://doi.org/10.1001/archotol.1969.00770020867013
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In order to detect the dysfunction of central and peripheral nervous systems among rats with varied duration of hypothyroidism and to elucidate the pattern of recovery after thyroxine replacement, a series of BAEP and PNCS (Peripheral Nerve Conduction Study) were conducted and compared with age-matched controls. BAEP and PNCS were performed in three groups of hypothyroid animals 1, 3 and 5 months after thyroidectomy, respectively. Following initial electrophysiological assessment, thyroxine replacement was administered to each group of hypothyroid rats, and BAEP and PNCS were performed at two month intervals, up to two successive normal studies, or six months after the initiation of therapy, whichever came first. For BAEP, prolonged I-V interpeak latency was the most consistent abnormal finding in all groups of hypothyroid rats, and longer hypothyroid states correlated well with more severe central conduction disorder. Nevertheless, these abnormalities usually returned to normal after thyroxine replacement if the duration of hypothyroidism was less than 5 months. Regarding PNCS, all groups of thyroidectomized rats showed normal conduction before and after thyroxine therapy. The present study indicates that, in rats: (1) the peripheral nervous system seems to be more resistant to hypothyroidism than the central nervous system, or (2) the pathogenesis of central and peripheral nerve dysfunction in hypothyroid rats may occur through different mechanisms.
Glial cell line-derived neurotrophic factor (GDNF), the most potent trophic factor yet described for both dopaminergic neurons of the substantia nigra and spinal motorneurons, has recently been shown to signal through a multireceptor complex composed of a novel glycosylphosphatidylinositol-anchored GDNF receptor-alpha (GDNFR-alpha) and the receptor tyrosine kinase product of the c-ret proto-oncogene (RET). Despite its importance, the individual expression patterns and the relationships between domains of expression of the different components of this trophic system are not understood. We show here by in situ hybridization that GDNF mRNA is expressed in the normal adult rat brain in several targets of substantia nigra neurons, including striatum, nucleus accumbens, thalamic nuclei, olfactory tubercle, hippocampus, cerebellum, and cingulate cortex as well as in the internal granular cell layer of the olfactory bulb. Within the basal ganglia we observe a pronounced segregation of regions expressing GDNF from those expressing GDNF receptors, suggesting that within these structures GDNF is functioning in its anticipated role as a target-derived trophic factor. In addition, the expression of GDNF and both GDNF receptors within the cerebellum, hippocampus, and olfactory bulb may indicate a paracrine mode of action. Importantly, we also see expression of RET mRNA in cellular populations within the cerebellum and the glomerular layer of the olfactory bulb, as well as in the subthalamic nucleus, which lack GDNFR-alpha expression, indicating that RET functions either independently of GDNFR-alpha or with GDNFR-alpha presented in trans. Conversely, GDNFR-alpha is widely expressed in many regions in which RET expression is absent, suggesting that GDNFR-alpha may associate with additional signaling receptors. Finally, RET and GDNFR-alpha show distinct patterns of regulated expression in the brain after kainic acid stimulation and in the sciatic nerve after nerve transection. Taken together these findings indicate that GDNF, RET, and GDNFR-alpha utilize multiple mechanisms to comprise physiologically relevant trophic circuits for different neuronal populations.
The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-alpha mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab, with minimal astrogliosis. We determined whether endogenous interferon (IFN)-gamma could be responsible for the observed increases in IL-1 and TNF-alpha, because IFN-gamma is a potent microglia/macrophage activator, and because its exogenous administration to rodents enhanced astrogliosis after adult or neonatal insults. A lack of requirement for endogenous IFN-gamma was demonstrated by three lines of evidence. First, no increase in IFN-gamma transcripts could be found at injury. Second, the administration of a neutralizing antibody to IFN-gamma did not attenuate astrogliosis. Third, in IFN-gamma knockout adult mice, astrogliosis and increases in levels of IL-1alpha and TNF-alpha were induced rapidly by injury. The marked elevation of inflammatory cytokines is discussed in the context of astrogliosis and general CNS recovery.