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Research Projects

Sexual Differentiation
Kennedy Disease/Spinal and Bulbar Muscular Atrophy

Sexual Differentiation of Neuromuscular Systems
The spinal cord provides an excellent means of studying sexual differentiation for several reasons : 1) robust and easily observed sex differences exist in the spinal cord, 2) there is a much more compelling link between structure and function in the spinal cord than in identified sex differences in the brain and 3) we understand much more about the mechanisms that create these differences in the spinal cord . The best studied sex difference in the spinal cord, and that in which we are most interested, is in spinal nucleus of the bulbocavernosus (SNB) motoneurons which mediate genital reflexes in males. Like all sexual dimorphisms, we believe that hormonal and experiential factors contribute to their development. We have been engaged in research on both of these fronts.

Hormonal regulation
The current model of the mechanisms of SNB dimorphism has been largely unchanged since the mid 1990s. It holds that SNB motoneurons and the muscles that they innervate develop embryonically in a manner that is independent of sex, and that muscles and motoneurons die off to a lesser extent in males around the time of birth due to male production of testosterone. The site of action of testosterone is believed to be exclusively on androgen receptors in target muscle fibers, and this leads to the rescue of both the muscles and their innervating motoneurons (Morris et al. 2005). We are studying the cellular basis of SNB differentiation; that is, we are interested in identifying the cell type(s) on which testosterone acts to prevent this system from dying in males. To date we have only indirect evidence on this topic, much of which is focused on spatial resolution which can only identify the tissue of interest (e.g. a muscle or a region of the spinal cord). My contribution to this has been to study genetically engineered animals (and in some cases to engineer such animals) to study individual cell types within complex tissues. In this way, we can determine the role of motoneurons within the spinal cord, or muscle fibers within muscle.

Experiential factors
Along with hormonal factors, experiential factors, and especially social interactions, are thought to influence sexual differentiation in mammals. Previous research has identified sex biased maternal care as one such factor. According to this model, pheromones produced by male pups encourage rat dams to lick male pups to a greater extent than female pups and this additional sensory stimulation is thought to contribute to male-typical copulatory behaviour and its neural substrates (see Moore 1992 for review). The experimental paradigm governing these studies has been to make dams anosmic, thereby eliminating sex-biased licking throughout rearing. Several studies have found that pups reared by anosmic dams have SNB motoneurons, whose structure is less masculine than pups of control dams (Juraska and Moore, Lenz and Sengelaub). We have extended this research by using two additional experimental paradigms: artificial rearing and neonatal anesthesia. We find that simulated licking can somewhat normalize SNB morphology in artificially reared pups (Lenz et al. 2007) and that copulatory deficits can be observed following acute, neonatal perineal anesthesia of male pups.

Kennedy Disease/Spinal and Bulbar Muscular Atrophy

One application of knowledge concerning the cellular and molecular bases of sexual differentiation is in understanding the etiology and developing new therapeutic strategies for disorders relating to this process. Notably, there are several neuromuscular disorders that are more common in males than females, including Muscular Dystrophy, Amyotrophic Lateral Sclerosis and Kennedy Disease/Spinal and Bulbar Muscular Atrophy (KD/SBMA). We have recently observed that overexpression of a normal androgen receptor in muscle fibers results in male motoneuron loss and muscular atrophy in a manner consistent with KD/SBMA. Although KD/SBMA is caused by androgen receptor mutations, this result is surprising for several reasons. Firstly, the KD/SBMA mutation is a glutamine expansion, which is not found in our model and secondly, KD/SBMA is thought to be caused by effects within motoneurons rather than muscles. We are therefore characterizing these mice to determine the extent to which they conform to the KD/SBMA phenotype and investigating different therapeutic strategies to alleviate the neuromuscular atrophy. In addition, we are developing more explicit models of KD/SBMA, by generating mice which express a polyglutamine expanded androgen receptor selectively expressing in either muscle or motoneurons to obtain a more definitive answer to this question.

Information regarding our other research projects will be added shortly.