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MYELINATION - keywords
myelination sequence: historical data Flechsig 1921: fetus 7 months old; postcentral gyrus myelinates first at cortical level, limited myelination in PLIC Altman and Bayer: 6 weeks after term birth Yakovlev and Lecours 1967 Buyanova and Arsalidou 2021 myeloarchitectonic cycles spinal cord myelination starts at 12-14 weeks PMA; last areas to myelinate are intracortical fibers in adults; cycles of myelination are long for supralimbic white matter corpus callosum myelinates from front to back; genu myelinated by 6 months after term; myelination of corpus callosum and fornix complete by age 20 years cerebral white matter: posterior to anterior gradient - first: median zone: median thalamus, hypothalamus, hippocampus, septal area - second: paramedian zone: paramedian thalamus, subthalamus, internal capsule, pallidum, striatum, amygdala, claustrum - third: supralimbic zone: bulk of white matter and opercula myelination sequence: Flechsig 1920 dark before gray before white - central sites (around central sulcus) before poles of brain lobes fronto-parieto-occipital areas before temporal and frontal sites central sensory before motor systems Flechsig P (1920) Anatomie des menschlichen Gehirns und R ckenmarks auf myelogenetischer Grundlage. Thieme, Leipzig Flechsig distinguished 45 myelogenetic areas, numbered according as a sequence of myelination during fetal and early postnatal life. Classified in three categories, primordial areas (1–16), which show signs of myelination before birth, intermediate areas (17–36), which become myelinated between birth and the second postnatal month and terminal areas (37–45), which myelinate after the second postnatal month. ü Prenatally myelinating fibres belong to the large sensory and motor projections. Postnatally maturing fibres between associative cortex areas; hence the intermediate and terminal areas were designated as association areas. Clusters of late-maturing areas form three association centres: a large posterior association centre (occupying much of the parietal, occipital and temporal lobes); an anterior association centre in front of the motor projection areas; a small insular association centre. term, one month old myelination sequence: review 2021 Buyanova and Arsalidou 2021. Review of myelination based on several MRI techniques and the histological postmortem findings. In the brainstem medial longitudinal fascicle and lateral lemniscus myelinate early and rapidly before birth; the fibers for general proprioceptive (muscle sense) and exteroceptive (tactile and pain) somatic experience (e.g. medial lemniscus, outer division of the inferior cerebellar peduncle and bracchium conjunctivum) myelinate later and at a slower rate. The middle cerebellar peduncles myelinate only after birth in a protracted cycle. The fibers in the reticular formation (and basal forebrain) continue to gain in density and tinctorial intensity of staining to at least the third decade. The geniculocalcarine (optic), postcentral (somesthetic) and precentral (propriokinesthetic) projections from the nuclei of the thalamus to their respective cortices myelinate rapidly during the first year after birth and precede myelination of the corticofugal systems. The specific thalamocortico-pyramidal arcs have a relatively short cycle of myelination completed during the first postnatal year. The non-specific thalamocorticopontine arcs, from the dorsolateral and posterior thalamus to the areas surrounding the primary cortical sensory-motor analysers and from there to the pons and cerebellum, exhibits a long cycle protracted into early childhood. In contrast the fibers in the paramedian zone of the forebrain (e.g. cingulum, striatum, pallidum, subthalamus and paramedian thalamus), exhibit a short cycle of myelination which appears to be completed at about the age of puberty. The short cycle of myelination of this zone appears to correlate with the rapid maturation of the reflex and behavioural patterns in the sphere of 'innate' or 'instinctive' movements conventionally assigned to basal ganglia and the 'extrapyramidal' system. The commissural and association systems of the outermost or supralimbic zones of the hemispheres exhibit the longest cycles of myelination. The intracortical neuropil of the frontal, parietal and temporal association areas continue to show increase of the reticulum of fine myelinated fibres through years of maturity to senium. Myelination of the cortical end of the acoustic radiation in the temporal lobe is protracted beyond the first postnatal year, in sharp contrast to the optic radiation which myelinates rapidly soon after birth in one short spurt from retina to its end about the calcarine fissure. myelination sequence: histological data - first MBP in human thalamus ~18w PMA - no mature myelin in CNS before ~ 22w PMA - no myelin in forebrain before ~ 25w PMA (habenulo- - non-specific thalamic radiations myelinate entirely after - myelin in reticular formation starts after term and is - peridentate myelin from around 37w PMA interpeduncular tract first) very protracted term - internal capsule at mesencephalon: central before medial and lateral sides Pathway begin* completed* Spinal motor roots 16 weeks 42 weeks Spinal sensory roots 20 weeks 5 months Cranial motor nerves III,IV,V,VI 20 weeks 28 weeks Ventral commissure, spinal cord 24 weeks 4 months Dorsal columns, spinal cord 28 weeks 36 weeks Medial longitudinal fasciculus 24 weeks 28 weeks Habenulopeduncular tract 28 weeks 34 weeks Acoustic nerve 24 weeks 36 weeks Trapezoid body & lateral lemniscus (octavus system) 24 weeks 36 weeks Acoustic radiations (thalamocortical) 40 weeks 3 years Inferior cerebellar peduncle (inner part)(outer: later, protracted) 26 weeks 36 weeks Subthalamus (biphasic course, starts early, potracted after term) 26 weeks > 1 year Middle cerebellar peduncle 42 weeks 4 years Superior cerebellar peduncle arriving at VL thalamus ~36w PMA 28 weeks 8 months Medial lemniscus arriving at VL thalamus ~32w PMA 24 weeks 12 months 36 weeks 6 months 37 weeks 6 months Ansa lenticularis 28 weeks 8 months Pallidum (internum myelinates earlier than externum) 25 weeks 1-2 years Fornix (limbic system myelinates after term)(cingulum before fornix) 2 months 2 years Caudate and putamen 35 weeks 4 years Mammillothalamic tract 38 weeks 6 years Thalamocortical specific radiations (acoustic:somesthetic before visual) 38 weeks 7 years Corticospinal tract, rolandic cortex (pyramidal tract extends up from pons) 35 weeks 2 years Corpus callosum (from splenium to genu) 2 months 14 years Internal capsule (PLIC before ALIC) 25 weeks first year Cortico-pontine tracts after 40w > 1 year Subcortical fibers (first pericentral, calcarine and Heschl gyri) 35 weeks years Intracortical association fibers (frontotemporal & frontoparietal)) 3 months 32 years Optic nerve and tract, superior colliculi Optic radiations late onset of optic myelination, but short postnatal cycle * myelination as observed with LM methods (e.g. luxol fast blue or Loyez); adding MBP (myelin basic protein) for staining advances detection of myelin by a few weeks (correction of Yakovlev and Lecours data) Hasegawa et al. 1992, Yakovlev and Lecours 1967 myelination sequence: MRI data radial diffusivity and fractional anisotropy correlate with amount and quality of myelin myelin: high lipid content, only 70 % H2O, tight multi-lamellar structure T1 relaxation (increased signal, more white) is more sensitive to myelin T2 relaxation (decreased signal, more dark) correlates best with compact myelin quantity GA w myelinating structure 16 spinal motor roots 20 spinal sensory roots multimodal MRI necessary McArdle MR motor nerves for eye muscles (III, IV, VI) 22 medial longitudinal fascicle (pons before medulla) lateral lemniscus stato-acoustic tectum and tegmentum (trapezoid body) inferior collicle cuneate fascicle 23 inferior cereballar peduncle (restiform body) inner part 24 medial lemniscus 26 spinocerebellar and spinothalamic tracts subthalamus nerves VII and VIII 28 ventrolateral thalamus (related to lateral lemniscus) M2 pallidum (efferent fibers) gracile fascicle nerves V, IX, X, XII superior cerebellar peduncle (fibers to thalamus at 36 w) 30 optic chiasm and tract 32 rubrospinal and tectospinal tract 34 posterior commissure M1 M3 pt posterior limb internal capsule M4 comp 36 optic nerve and radiation M5 38 pre- and postcentral gyri (post slightly earlier) acoustic radiation 40 middle cerebellar peduncle > 44 corona radiata M6 anterior limb internal capsule M7 myelin at PMA, LFB onset mature myelin comment PLIC 38 w 44 w optic radiation 43 52 optic radiation proximal before distal before calcarine cortex acoustic radiation 41 67 proximal auditory radiation before Heschl gyri corpus callosum 44 60-65 splenium weeks before genu, posterior to anterior gradient precentral gyrus subcortical white matter 41 70 posterior frontal subcortical white matter 47 80 occipital pole 47 87 posterior parietal subcortical white matter 53 99 Brody et al. 1987, Kinney et al. 1988 the oligodendrocyte lineage block by ischaemia, inflammation, excitotoxic cascade ——> mature OL, O1 + and MBP + immature OL, O1 + and MBP + I I I weeks before mature I stage I I I I I I predominate 20-30wI PMA I I I I I I I I I I I I I I I I I I I I I I I I I 18w PMA 30w PMA 40w PMA ——> premyelinating late OPC (pre-OL), PDGFR-, O4 + and O1 - near term and after PDGFR@ + early OPC Olig 1 + I I I I 9w PMA OL precursors derive from neural stem cells in the SVZ that become oligodendrocyte progenitors (influenced by Olig 1, Olig 2, Nkx2.2, Sox 10) MYELINATION mainly after term PREMYELINATION human 20-30+w PMA between late oligodendrocyte precursor and OL stages - premyelination starts with O1 positivity in subplate - - slow myelin turn-over in humans activity dependent (re)myelination homeostatic balance by stable pool of mature OL (O1+ and MBP+) stimulation (PDGF@ from astrocytes) disinhibtion OL precursors migrate along vessels OL precursors promote angiogenesis because they need vessels for migration and for myelin deposition CNP, MAG, GALC, sulfatide O4+, O1 and MBP- mature myelin contains MAG, MOG, MBP, PLP sources of oligodendrocyte precursors (OPC) MAG, MOG, MBP, PLP OL precursors (OPC) secrete semaphorin 6a/6b that binds to plexin receptors on interneurons, which drives these interneurons into a migration path away from blood vessels OL-vascular interaction: migration along vessels and jumping from one vessel to another - - neural stem cells (NSCs) differentiate into (OPCs) under the influence of OL-specific transcription factors Olig1/2, Nkx2.2, and Sox10 OPCs migrate toward an appropriate site via blood vessels, at the same time promoting angiogenesis in a HIF1adependent manner, in areas requiring more oxygen slow turn-over in humans activity dependent - - at their final destination, OPCs proliferate to expand the pool of OPCs, under the regulation of transcription factors such as Id2, Id4, Tcf4, and Hes5 when proliferation is inhibited, OLs differentiate into premyelinating OLs (pre-OLs), and finally into mature OLs that enwrap neuronal axons with myelin sheaths, under the influence of, for example, Myrf ventral wave MGE and anterior entopeduncular area (SHH dep.) —-> OL for hypothalamus, optic nerve … mouse E12.5 medial wave LGE and CGE ——> OL for entire forebrain dorsal wave cortical SVZ (SHH indep.) OL for cortex throughout preterm period human OPC cells in dorsal areas from 19w PMA human 10w PMA PDGFR@+ cells present in forebrain this OL population disappears after birth mouse P0 human liflelong Jakovcevski et al. 2009 Lepiemme et al. 2002 van Tilborg et al. 2018 mouse E15.5 OPC come from the subventricular zone (Ortega et al. 2018) - subpallial germinal matrix GM is considered the ‘factory’ - the subplate has spontaneous electrical activity, the SVZ - - RGCells transform into astrocytes (GFAP and vimentin for production of most brain cells neurons and most macroglia originate in the ventricular zone (VZ) but later on also in a secondary germinal area, the subventricular zone (SVZ) - SVZ appears at 8 weeks of gestation and persists until does not positive cells) from early fetal life on until term - neuroblasts derived from the subpallial eminences migrate to reach the cortex along a scaffold of radial glial fibers; precursor cells first migrate laterally (radially) and then change direction in the subventricular zone, engaging in tangential migration birth and in a rudimentary form later (the subependymal zone), in subpallium but also in cortical areas - pyramidal (projection) neurons for the deep cortical plate are generated in the VZ but glutamatergic neurons for the upper cortical plate, some interneurons, some oligodendrocytes (mainly after birth) and astrocytes are generated in the SVZ - as GM is a major source for oligodendrocytes, their number can be reduced and differentiation can be impaired due to GMH; this may therefore contribute to white matter injury (Ulfig 2002). - the SVZ is subdivided into the smaller inner (iSVZ) and expanded outer SVZ (oSVZ) lateral section medial section cortical matrix ganglionic eminence matrix migratory pathways of oligodendrocyte progenitors (OPCs) in the human forebrain at mid-gestation - Vimentin+ radial glial cells co-label with the oligodendrocyte marker OLIG2, suggesting oligodendroglia is gnerated in the cortical VZ at mid-gestation - from the cortical proliferative zone multipotent cells migrate toward white matter (IZ) or first to the SVZ and then to the IZ - late, non-migratory O4+ OPCs are dispersed throughout the VZ/SVZ and accumulate in the subplate PDGFRα+ cells migrate in the fetal human cortex and are also observed in the amygdala A, amygdala; BG, basal ganglia; CC, corpus callosum; Cx, cortex; CP, cortical plate NG2 glia as progenitors for oligodendrocytes Progeny of NG2-glia at different developmental stages and in disease while during development NG2-glia generate more NG2-glia, oligodendrocytes and astrocytes, in the adult CNS their progeny remains purely oligodendrogenic. However, under some pathological conditions of the adult brain, NG2-glia can also generate astrocytes and myelinating Schwann cells. Evidence in favor of generation of neurons from NG2-glia still remains highly contentious. (Dimou and Gallo 2015) oligodendrocyte precursors for life in adults precursors for OL mainly come from dorsoventral SVZ VZ SVZ pre neuroblast C ependyma A B B vessel apical cilium pre OPC C C matrix fractones - cells with astroglial properties (type B cells) function as stem cells - type B cells slowly divide and give rise to rapidly dividing intermediate progenitor cells (IPCs) or transient amplifying progenitors (type C cells) - type C divide further to generate neuroblasts (type A cells) or OPC Maki et al. 2013 migration and differentiation of oligodendrocytes adaptive myelination throughout life - some OLs are specific for glutamatergic neurons, others for GABAergic or mixed neurons sensory experience: auditory, visual, sensory social experience in critical periods (deprivation)(neuregulin, endothelin) motor learning memory and cognition (BDNF on TrkB receptors on OL) at least 7 OL phenotypes trophic factors ————————— BDNF neurotrophin 3 PDGF CNTF activity regulated myelination final postioning and differentiation CXCL1 tenascin-C neurotransmitters and channels regulation of intracellular Ca++ via glutamate on AMPA/integrin receptors and via voltage gated channels astrocytes produce semaphorins that repel OL from vessels and place astrocyte endfeet at the space free of OL; IL6 from astrocytes induces CXCL1 expression in OL neuromodulation via adenosine growth factors PDGF (ubiquitous stimulus of motility) HGF, FGF8 OL motility extracellular matrix components laminin fibronection vitronectin molecular cues netrin-1 chemorepellent TGFß repellent different functions for different semaphorins (on neuropilins and plexins as receptors) inhibition by tenascin and collagen reelin repellent CNTF attractant cell polarity proteoglycan NG2 engagement to vessel scaffold angiopoietin-1 expressed by progenitor cell and TGFß from endothelium in return to commit OL precursor (coupling by HIF 1/2a from OL precursors) crucial Wnt signalling to maintain migration VEGF-A Xia and Fancy 2021, Wolf et al. 2021, Su et al. 2022 cellular interaction for myelination microglia neuron astrocyte iron folate vitamin B112 phagocytosis of excess myelin fatty acids <— IGF1 leads developmental myelination connexins thyroxine (MCT8 transporter)