Mammalian motor units (MU) retain a remarkable degree of plasticity throughout postnatal life. One expression of this plasticity is seen when a portion of the MU population is lost due to injury, disease or aging. Under these circumstances the remaining intact motoneurons sprout new connections to increase their innervation ratio and thereby maintain, at least for a time, overall force production. This phenomenon has been studied extensively but important questions remain. For example, it is proposed that MU expansion reaches a """"""""threshold"""""""" beyond which the increased innervation ratio can no longer be sustained, but a precise description of such a threshold and the factors that determine it remain to be clarified. We propose a unique approach that will combine the genetic power of the mouse with sensitive functional and structural assays. Specifically, we will examine the response to functional partial """"""""denervation"""""""" of intact motor units, within a specified motor pool, in the presence of """"""""silent"""""""" intact motor units in which cholinergic neurotransmission has been totally and verifiably eliminated. The study of a specific motor pool in which all motor units are intact, but where synaptically """"""""silent"""""""" and normal functioning units are interspersed, is a more accurate model of events observed in aging and disease. We will use a conditional allele of the gene for choline acetlytransferase (ChAT) to eliminate the production of acetylcholine and thereby neurotransmission. By varying the dose of tamoxifen used to induce the knockout, a dose-dependent number of motoneurons are """"""""silenced"""""""", effectively allowing us to reproducibly vary the extent of the """"""""genetic partial denervation"""""""". The work proposed here will establish the effectiveness and reliability of the tamoxifen- induced response as well as the fidelity of the associated reporter construct. Comprehensive physiological and immunohistochemical analysis will provide detailed functional characterization. Relevance to public health: This work will improve our understanding of how muscles maintain their ability for normal force production throughout the life of the organism. The results will provide basic insights into the normal aging process, as well as motoneuron diseases such as amyotrophic lateral sclerosis and post polio syndrome and enable future studies that could lead to novel therapeutic interventions. ? ?
| Wooley, Christine M; Xing, Shuqin; Burgess, Robert W et al. (2009) Age, experience and genetic background influence treadmill walking in mice. Physiol Behav 96:350-61 |
