| To better understand how spontaneous motoneuron activity and intramuscular nerve branching influence motoneuron survival and spinal cord circuit formation, I chronically treated chicken embryos in ovo with either dTC, nicotine, or muscimol during the naturally occurring cell death period (or earlier), assessing effects on bursting activity, branching and survival. The results indicate that the bursting activity of the motoneuron is critical for increased survival, but that this must be coupled to an inactive target muscle. While dTC-induced activity blockade promoted motoneuron survival and increased intramuscular nerve branching, muscimol did not. These studies also demonstrated that motoneurons continued to burst in the presence of dTC, whereas muscimol blocked all bursting activity, suggesting a critical role of bursting activity possibly in affecting the uptake or expression of trophic molecules. A variety of drug treatments, alone or in combination demonstrated that both motoneuron bursting and intramuscular nerve branching can affect motoneuron survival, confirming the hypothesis that increases in branching support increases in survival perhaps through increased trophic uptake/access.; Preliminary studies were undertaken to elucidate cellular/molecular mechanisms possibly underlying the different effects of muscimol vs. d TC-induced activity-blockade on motoneuron survival and branching. Different expression patterns of the adhesion molecules NCAM-PSA and N-cadherin on intramuscular nerves and myotubes may contribute to the observed alterations in both myogenesis and branching. These studies show that the expression of these molecules in both nerve and muscle is sensitive to activity. Preliminary results also indicate the presence of neurotrophins at both the NMJ and in the spinal cord and also suggest a role of BDNF in modulating bursting activity in the spinal cord.; Characterization of the neurotransmitter systems driving spontaneous bursting during the cell death period showed a switch from cholinergic to glutamatergic inputs that occurred early in the cell death period. Given the importance of the cholinergic inputs in early spontaneous bursting activity, the effect of chronic nicotine treatment was also examined. Nicotine-induced neuromuscular blockade blocked spontaneous bursting but had little effect on motoneuron survival or branching. However, early chronic nicotine treatment resulted in an abnormal motoneuron burst structure, which may indicate alterations in the spinal cord circuitry. |
