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Myelin damage is known to increase in the normal aging brain and to correlate with age-related cognitive decline. While the causes of increased myelin damage are unknown, here we consider whether the brain’s innate capacity for remyelination diminishes with age and hence could contribute to myelin damage through slow accumulation of myelin defects. Maintenance and repair of myelin depends upon oligodendroglia precursor cells (OPCs), which must differentiate into a sufficient number of healthy mature oligodendroglia (oligos), the myelinating cell of the brain. The extracellular matrix molecule hyaluronic acid (HA) has been shown to inhibit maturation of OPCs into mature myelinating oligos. The present study examined aging changes in myelination using four markers: the damaged myelin basic protein (dMBP) antibody, a histochemical reaction to stain HA, and immunohistochemistry for OPCs and mature oligos. These markers were quantified using cell density (oligos and OPCs), percent area stained (HA and dMBP), and fluorescence intensity (HA and dMBP). Relationships between these markers, age, and behavioral measures of cognitive function were investigated using single and multiple regression analyses. Results showed that in the corpus callosum and cingulum bundle of the rhesus monkey, staining for dMBP as a marker of myelin damage strongly correlated with increases in HA. The increase in HA in the cingulum bundle correlated positively with age. OPC density increased with age in both the cingulum bundle and corpus callosum. Mature oligo density did not change significantly with age, but approached a significant increase in the cingulum and approached a significant decrease in the corpus callosum. The increase in OPC density correlated positively with both HA and dMBP in the cingulum bundle. These data are consistent with the hypothesis that HA accumulation contributes to myelin damage by inhibiting the differentiation of OPCs into mature oligodendrocytes, diminishing the brain’s innate capacity for remyelination with age.

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Chez les vertébrés, la vitesse de la conduction nerveuse dépend du processus de myélinisation. Dans le système nerveux périphérique, ce sont les cellules de Schwann (CS) qui en s’enroulant autour de l’axone, constituent les gaines de myéline, séparés par des nœuds de Ranvier. La succession de ces gaines augmente la vitesse de conduction nerveuse car les potentiels d’action sont forcés de « sauter » d’un nœud de Ranvier à un autre, ce qui accélère leur vitesse de propagation. La géométrie (l’épaisseur et la longueur) de la gaine de myéline est donc un paramètre essentiel de la conduction de l’influx. Une publication à laquelle j’ai participé, a mis en évidence la polarisation cellulaire de la cellule de Schwann myélinisante. Notre hypothèse est que ce processus est capital pour la formation d’une gaine de myéline fonctionnelle. Comme trois complexes protéiques, conservés au cours de l’évolution, établissent et maintiennent la polarisation cellulaire (ces complexes sont: aPKC/Par3/Par6, Pals1/Patj/Crb3 et Dlg1/Lgl/Scrib chez les mammifères), mon travail consiste à étudier le rôle fonctionnel des protéines de la polarité Dlg1 et Crb3 lors de la myélinisation. Comme l’altération de la géométrie de la myéline est la cause d’un grand nombre de pathologies du système nerveux périphérique mais aussi central. Mon travail sur la mise en lumière des mécanismes qui préside à ce phénomène permet d’envisager de nouvelles voies thérapeutiques. / In the mammalian nervous system, the nerve conduction velocity depends on the myelin sheath. Myelin is produced by Schwann cells in the peripheral nervous system. The myelin sheath, together with the highly specialized nodes of Ranvier that are regulary arrayed along the myelinated fibers, is responsible for efficient and rapid propagation of action potentials along the nerve. Optimal conduction is obtained by adjusting the geometry (length and thickness) of the myelin sheath When I arrived in the laboratory, the team just showed the polarization of the myelinating Schwann cell ( mSC). We hypothesized then that cell polarity proteins are key players for the formation of the myelin sheath. Three complexes, well conserved among species, organize polarized cellular processes. In mammals, these complexes are aPKC/Par3/Par6, Pals1/Patj/Crb3 et Dlg1/Lgl/Scrib. Using an approch allowing the in vivo transduction of mSC, I investigate the relevance of Dlg1 and Crb3 in myelin formation. Changes in the myelin geometry is linked to several human neuropathies in the central and peripheral nervous system. This work highlights mechanisms which control correct myelin formation and allow designing strategies for their treatment.

The mammalian neocortex contains diverse neuronal and glial cell types. Among them lies an important subclass, the subcerebral projection neurons (SCPN) that project to distant targets like the spinal cord. Aiming at identifying molecular controls over the postnatal development of SCPN, I focus my investigations on the role of Ppargc1á because its function remains relatively unknown in the brain while it is important for metabolism and survival in other tissue systems.

In the central nervous system (CNS), oligodendrocytes (OLs) generate myelin to facilitate the rapid propagation of neuronal impulses. In multiple sclerosis (MS), chronic demyelination leads to irreversible neurodegeneration that eventually impairs physical and cognitive function. Much effort is directed at elucidating the mechanisms underlying OL development in hope to unveil therapeutic targets for promoting remyelination in MS. Many aspects of OL biology are regulated by the integrins, a large family of transmembrane extracellular matrix (ECM) receptors. ECM components such as laminin and fibronectin bind to OL integrin receptors and initiate downstream signaling cascades involved in survival, proliferation, differentiation/myelination and migration. Integrin-linked kinase (ILK), an adaptor protein that binds to integrin cytosolic tails, works to stabilize the ECM-integrin connection by indirectly targeting the actin cytoskeleton to ECM adhesion sites. We hypothesized that ILK played an important role in OL migration, differentiation and capacity to myelinate neuronal projections. To address this hypothesis, we developed three cell culture techniques to assess these cellular phenomena in vitro. Conditional knockout of Ilk compromised both the morphological and molecular differentiation of primary mouse OLs in vitro, and reduced their capacity to produce myelin-like membrane. ILK was required for proper OL ensheathment of neuronal extensions when co-cultured with primary neurons. Conditional ablation of Ilk in vivo produced a transient amyelination defect that was endogenously compensated for at later time points. Loss of ILK in primary OLs was associated with upregulated RhoA signaling, and pharmacological inhibition of the RhoA axis restored the morphology of a distinct subset of NG2+ OPCs. ILK depletion in OL precursor cells (OPCs) resulted in a substrate-dependent defect in migration velocity and migration initiation. Inhibition of the RhoA signaling pathway enhanced the migratory velocity of wild-type OPCs, an effect that was dependent on ILK expression. In sum, we established three primary mouse OL cell culture techniques, with which we defined roles for ILK in OL biology. Our work highlights the importance of integrin signaling in OLs and provides new experimental methods useful in MS research.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) whereby abnormal autoimmune responses cause damage to myelin, the lipid-rich layer that surrounds and insulates axons. This results in interruptions in communication within the CNS and between the CNS and peripheral nervous system (PNS). This dysfunction contributes to a variety of symptoms that negatively impact the lives of individuals with MS. Sleep disturbances and memory difficulties are two common challenges faced by MS patients, but are not comprehensively understood within the MS literature. Additionally, despite general consensus with regard to the important role that sleep plays in memory function, studies investigating the links between sleep disturbance and memory in MS are sparse. As such, the purpose of this dissertation was to determine whether sleep disturbance helps to explain differential memory functioning in individuals with MS, both cross-sectionally and over time. A sample of 165 early MS patients participated in cognitive measures, gait assessments, sensorimotor assessments, and self-report questionnaires once at baseline, and again 3 years after their initial assessment. Magnetic Resonance Imaging (MRI) data were collected at baseline. The primary predictor variable for the present study was sleep disturbance, as measured by two validated self-report measures of sleep functioning, the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI). This study’s primary outcome was memory function, which was assessed by the CANTAB Paired Associate Learning (CANTAB PAL), Brief Visuospatial Memory Test, Revised (BVMT-R), Selective Reminding Test (SRT), and Verbal Paired Associate Learning (VPAL). Additional predictors included mood, disease burden, estimated premorbid intelligence, and demographic variables (age, sex, BMI). As hypothesized, results revealed that changes in sleep significantly predicted changes in memory over time. Patients with stable sleep and worsened sleep demonstrated an average decline in memory z-score from baseline to follow up, whereas patients whose sleep improved demonstrated an average improvement in memory z-score. Cross-sectionally, the presence of sleep disturbance significantly predicted worse memory performance when the ISI was used a measure of sleep disturbance, but not when the PSQI was used as a measure of sleep disturbance. Taken together, results highlight the importance of acknowledging sleep disturbance as an important predictor of memory function in individuals with early MS, paving the way for highly needed efforts toward prevention and intervention. However, findings should be extended to both objective and subjective sleep measures beyond the ISI.

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