Myelin Acquisition and Maintenance in Adult Spinal Cord and Brain: Dependence on Activity and TSC Signaling

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

How the process of myelination is regulated during development of the central nervous system (CNS) has been the focus of numerous studies, but less is known about what regulates myelin in the adult CNS. It is now appreciated that myelination is a highly dynamic process throughout life. Myelin plasticity and adaptive myelination are relatively recent concepts describing myelin remodeling in the adult brain in response to stimuli such as learning paradigms or electrical activity. However, there is little knowledge of myelin alterations in the adult spinal cord or of the mechanisms for how myelin is maintained over time in adult brain and spinal cord. Such information is important for determining how changes in levels of myelin contribute to normal adult function and to susceptibility or recovery from demyelinating events. We have recently discovered a novel process of myelin acquisition in the adult mouse spinal cord whereby existing myelin becomes thicker in the normal adult white matter tracks between 2 months of age to 1.5 years of life. In contrast, myelin acquisition does not occur in the corpus callosum of the brain. We also show that loss of the tuberous sclerosis complex 1 (Tsc1) gene in adult oligodendrocytes prevents myelin acquisition in the spinal cord white matter without altering oligodendrocyte differentiation or survival and is necessary for myelin maintenance in the corpus callosum. These findings form the basis of our hypotheses that 1) myelin acquisition in the adult spinal cord is regulated by neuronal activity and occurs in both ascending and descending WM tracts, and 2) adult myelin acquisition in the spinal cord and maintenance in the corpus callosum are regulated by TSC signaling. These findings raise important questions that will be addressed in the aims of the proposal. Aim 1: Determine activity dependence of myelin acquisition in spinal cord WM tracts. This aim will address how myelin acquisition in spinal cord is modulated by neuronal activity and differs according to ascending/ sensory or descending/ motor spinal tracts. Aim 2: Determine the mechanistic basis for how TSC signaling regulates myelin acquisition and maintenance in the CNS. The goal of this aim is to define activation and function of known downstream targets of TSC to determine how TSC signaling contributes to myelin acquisition in the spinal cord and to myelin maintenance in the corpus callosum.