Density Of Oligodendrocytes Research Articles

The Role of Transthyretin in Oligodendrocyte Development

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.

Numerical density of oligodendrocytes and oligodendrocyte clusters in the anterior putamen in major psychiatric disorders.

There is increasing evidence to support the notion that oligodendrocyte and myelin abnormalities may contribute to the functional dysconnectivity found in the major psychiatric disorders. The putamen, which is an important hub in the cortico-striato-thalamo-cortical loop, has been implicated in a broad spectrum of psychiatric illnesses and is a central target of their treatments. Previously we reported a reduction in the numerical density of oligodendrocytes and oligodendrocyte clusters in the prefrontal and parietal cortex in schizophrenia. Oligodendrocyte clusters contain oligodendrocyte progenitors and are involved in functionally dependent myelination. We measured the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters in the putamen in schizophrenia, bipolar disorder (BPD) and major depressive disorder (MDD) as compared to healthy controls (15 cases per group). Optical disector was used to estimate the Nv of oligodendrocytes and oligodendrocyte clusters. A significant reduction in both the Nv of oligodendrocytes (- 34%; p < 0.01) and the Nv of oligodendrocyte clusters (- 41%; p < 0.05) was found in the schizophrenia group as compared to the control group. Sexual dimorphism for both measurements was found only within the control group. The Nv of oligodendrocytes was significantly lower in male schizophrenia cases as compared to the male control cases. However, the Nv of oligodendrocyte clusters was significantly lower in all male clinical cases as compared to the male control group. The data suggest that lowered density of oligodendrocytes and oligodendrocyte clusters may contribute to the altered functional connectivity in the putamen in subjects with schizophrenia.

Cuprizone-induced oligodendrocyte loss and demyelination impairs recording performance of chronically implanted neural interfaces

Biological inflammation induced during penetrating cortical injury can disrupt functional neuronal and glial activity within the cortex, resulting in potential recording failure of chronically implanted neural interfaces. Oligodendrocytes provide critical support for neuronal health and function through direct contact with neuronal soma and axons within the cortex. Given their fundamental role to regulate neuronal activity via myelin, coupled with their heightened vulnerability to metabolic brain injury due to high energetic demands, oligodendrocytes are hypothesized as a possible source of biological failure in declining recording performances of intracortical microelectrode devices. To determine the extent of their contribution to neuronal activity and function, a cuprizone-inducible model of oligodendrocyte depletion and demyelination in mice was performed prior to microelectrode implantation. At 5 weeks of cuprizone exposure, mice demonstrated significantly reduced cortical oligodendrocyte density and myelin expression. Mice were then implanted with functional recording microelectrodes in the visual cortex and neuronal activity was evaluated up to 7 weeks alongside continued cuprizone administration. Cuprizone-induced oligodendrocyte loss and demyelination was associated with significantly reduced recording performances at the onset of implantation, which remained relatively stable over time. In contast, recording performances for mice on a normal diet were intially elevated before decreasing over time to the recording level of tcuprizone-treated mice. Further electrophysiological analysis revealed deficits in multi-unit firing rates, frequency-dependent disruptions in neuronal oscillations, and altered laminar communication within the cortex of cuprizone-treated mice. Post-mortem immunohistochemistry revealed robust depletion of oligodendrocytes around implanted microelectrode arrays alongside comparable neuronal densities to control mice, suggesting that oligodendrocyte loss was a possible contributor to chronically impaired device performances. This study highlights potentially significant contributions from the oligodendrocyte lineage population concerning the biological integration and long-term functional performance of neural interfacing technology.

Abstract TP112: Delayed Oligodendrocyte Maturation Corresponds to Myelin and Motor Recovery After Neonatal Stroke

Introduction: Neonatal stroke is a common cause of lifelong neurologic disability. White matter repair after neonatal stroke has been understudied. Objective: Characterize acute myelin injury within striatal white matter and determine if endogenous remyelination occurs chronically. Methods: Postnatal day 10 (p10) mice underwent MCAO for 60 minutes, followed by reperfusion, and animals were sacrificed on post-op day (POD) 3, 14 or 28. Immunohistochemistry (IHC) was used to assess oligodendrocyte maturation, and white matter integrity. Gait was assessed on POD 14 or 30. Results: On POD3 there is a significant decrease in neuronal density in the ipsilateral striatum compared to contralateral. There is also a significant reduction in mature oligodendrocytes density. At this timepoint, axons are preserved (measured as %SMI34 + pixels), but there is significant myelin loss (measured as %MBP + pixels) in the ipsilateral striatum (fig 1A-D). On POD 14 there is persistently decreased myelin density in ipsilateral striatum compared to contralateral, and the proportion of oligodendrocytes with a mature phenotype (Olig2 + CC1 + /Olig2 + ) is significantly lower. Both myelin density and maturational index of oligodendrocytes recover by POD 28. At fourteen days after MCAO there is a significant reduction in gait length on the left side, which recovers by 28 days (fig1 E-G). Conclusions: 60 minute MCAO in neonatal mice produces striatal injury with oligodendrocyte and myelin loss but preservation of axons, providing a substrate for repair. Myelin deficit persists at 14 days, and there is an oligodendrocyte maturational delay at this same time. Myelination and oligodendrocyte maturation recover between 14 and 28 days, corresponding to recovery of motor function. Future studies will focus on whether interventions that accelerate oligodendrocyte maturation and re-myelination can improve early functional outcome.

Global boundedness and stability for a chemotaxis model of Boló's concentric sclerosis.

Baló's concentric sclerosis (BCS) is considered a variant of inflammatory demyelinating disease closely related to multiple sclerosis characterized by a discrete concentrically layered lesion in the cerebal white matter. Khonsari and Calvez (Plos ONE. 2(2007)) proposed a parabolic-elliptic-ODE chemotaxis model for BCS which describes the evolution of the densities of activated macrophages, cytokine and apoptotic oligodendrocytes. Because "classically activated" M1 microglia can produce cytotoxicity, we introduce a linear production term from the activated microglia in the ODE for pro-inflammatory cytotoxic. For the new BCS chemotaxis model, we first investigate the uniform boundedness and global existence of classical solutions, and then get a range of the chemosensitive rate χ where the unique positive equilibrium point is exponentially asymptotically stable.

Trust the heart to save the brain: changes in heart rate patterns have the potential to be a biomarker for hypoxic ischaemic brain injury.

Trust the heart to save the brain: changes in heart rate patterns have the potential to be a biomarker for hypoxic ischaemic brain injury.

Reduced density of oligodendrocytes and oligodendrocyte clusters in the caudate nucleus in major psychiatric illnesses

Functional dysconnectivity in schizophrenia and affective disorders may be associated with myelin and oligodendrocyte abnormalities. Altered network integration involving the caudate nucleus (CN) and metabolic abnormalities in fronto-striatal-thalamic white matter tracts have been reported in schizophrenia and impaired patterns of cortico-caudate functional connectivity have been found in both bipolar disorder (BPD) and schizophrenia compared to healthy controls. Postmortem studies have found ultrastructural dystrophy and degeneration of oligodendrocytes and dysmyelination in the CN in schizophrenia and BPD. We aimed to test the hypothesis that oligodendrocyte density may be reduced in the CN in major psychiatric disorders and may thereby form the cellular basis for the functional dysconnectivity observed in these disorders. Optical disector was used to estimate the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters (OLC) in the CN of cases with schizophrenia, BPD and major depressive disorder (MDD) and in normal controls (15 cases per group). A significant reduction in the Nv of oligodendrocytes was found in schizophrenia and BPD as compared to the control group (p < 0.05), and the Nv of OLC was significantly lowered in schizophrenia and BPD compared to controls (p < 0.05). There were no significant differences between MDD and control groups. The Nv of OLC was significantly decreased in the left hemisphere in schizophrenia as compared to the left hemisphere of the control group (−52%, p < 0.01). The data indicates that a decreased density of oligodendrocytes and OLC could contribute to the altered functional connectivity of the CN in subjects with severe mental illnesses.

Enhanced mitochondrial autophagy (mitophagy) in oligodendrocytes might play a role in white matter pathology in schizophrenia

Disrupted white matter integrity is a typical feature of brain pathologic alterations in schizophrenia, which includes impaired myelination, decreased oligodendrocyte densities, distortion of their spatial distribution and deviations from normal oligodendrocyte cell morphology. While most genes expressed “in the remaining” oligodendrocytes are downregulated in schizophrenia, only a few are upregulated. To the latter group belong prohibitin 2 and DISC 1, which were recently identified as mitochondria-located mitophagy receptors. Their overexpression, together with greatly reduced numbers and densities of oligodendroglial mitochondria and the structurally “normal appearance of the remaining mitochondria” in these cells as reported by Uranova’s group (Uranova et al., 2001, 2004, 2018), point to enhanced mitophagy in oligodendrocytes in schizophrenia, which is possibly even cell protective by preventing apoptosis. Since massive loss of white matter oligodendrocytes is a characteristic feature of schizophrenia, we assume that increased mitophagy is a late event in the development and/or further progression of white matter pathologic changes. Moreover, altered oligodendroglial mitophagy might in part result from antipsychotic treatment. Further studies are clearly needed to substantiate our hypothesis on enhanced mitochondrial autophagy in schizophrenia, whereby the “drug-naïve state” and the possible influence of antipsychotic treatment could be elegantly simulated using animal models of the disease.

White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study.

Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.

TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Corpus Callosum.

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

Impact of High-Dose Caffeine on the Preterm Ovine Cerebrum and Cerebellum.

Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28–33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V–VI projection neurons (p = 0.02), Tbr1-positive layers V–VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II–IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.

The effects of a combination of ion channel inhibitors on pathology in a model of demyelinating disease

BackgroundMultiple sclerosis (MS) has been shown to feature oxidative damage, which can be modelled using the cuprizone model of demyelinating disease. Oxidative damage can occur as a result of excessive influx of calcium ions (Ca2+) and oligodendroglia are particularly vulnerable. However, the effects of limiting excess Ca2+ influx on oxidative damage, oligodendroglia and myelin structure are unknown. ObjectiveThis study investigated the effects of limiting excess Ca2+ flux on oxidative damage and associated changes in oligodendroglial densities and Node of Ranvier structure in the cuprizone model. MethodsThe effects of three weeks of cuprizone administration and of treatment with a combination of three ion channel inhibitors (Lomerizine, Brilliant Blue G (BBG) and YM872), were semi-quantified immunohistochemically. Outcomes assessed were protein nitration (3-nitrotyrosine (3NT)) oxidative damage to DNA (8-hydroxy deoxyguanosine (8OHDG)), advanced glycation end-products (carboxymethyl lysine (CML)), immunoreactivity of microglia (Iba1) and astrocytes (glial acidic fibrillary protein (GFAP)), densities of oligodendrocyte precursor cells (OPCs) (platelet derived growth factor alpha receptor (PDGFαR) with olig2) and oligodendrocytes (olig2 and CC1), and structural elements of the Node of Ranvier (contactin associated protein (Caspr)). ResultsThe administration of cuprizone resulted in increased protein nitration, DNA damage, and astrocyte and microglial immunoreactivity, a decrease in the density of oligodendrocytes and OPCs, together with altered structure of the Node of Ranvier and reduced myelin basic protein immunoreactivity. Treatment with the ion channel inhibitor combination significantly lowered protein nitration, increased the density of OPCs and reduced the number of atypical Node of Ranvier complexes; other outcomes were unaffected. ConclusionOur findings suggest that excess Ca2+ influx contributes to protein nitration, and associated changes to OPC densities and Node of Ranvier structure in demyelinating disease.

Genetic Elimination of Connective Tissue Growth Factor in the Forebrain Affects Subplate Neurons in the Cortex and Oligodendrocytes in the Underlying White Matter.

Connective tissue growth factor (CTGF) is a secreted extracellular matrix-associated protein, which play a role in regulating various cellular functions. Although the expression of CTGF has been reported in the cortical subplate, its function is still not clear. Thus, to explore the significance of CTGF in the brain, we created a forebrain-specific Ctgf knockout (FbCtgf KO) mouse model. By crossing Ctgffl/fl mice with Emx1-Cre transgenic mice, in which the expression of Cre is prenatally initiated, the full length Ctgf is removed in the forebrain structures. In young adult (2–3 months old) FbCtgf KO mice, subplate markers such as Nurr1 and Cplx3 are still expressed in the cortical layer VIb; however, the density of the subplate neurons is increased. Interestingly, in these mutants, we found a reduced structural complexity in the subplate neurons. The distribution patterns of neurons and glial cells, examined by immunohistochemistry, are comparable between genotypes in the somatosensory cortex. However, increased densities of mature oligodendrocytes, but not immature ones, were noticed in the external capsule underneath the cortical layer VIb in young adult FbCtgf KO mice. The features of myelinated axons in the external capsule were then examined using electron microscopy. Unexpectedly, the thickness of the myelin sheath was reduced in middle-aged (>12 months old), but not young adult FbCtgf KO mice. Our results suggest a secretory function of the subplate neurons, through the release of CTGF, which regulates the density and dendritic branching of subplate neurons as well as the maturation and function of nearby oligodendrocytes in the white matter.

Abnormalities of oligodendrocyte clusters in supra- and infragranular layers of the prefrontal cortex in schizophrenia

A deficit of cortical gray matter myelination in the frontal lobes has been reported in schizophrenia in neuroimaging studies. Previously the decrease in the numerical density (Nv) of oligodendrocytes (NvOl) in layers 3 and 5 in area 10 of the prefrontal cortex (PFC) has been reported in schizophrenia. Oligodendrocyte progenitors proliferate in the adult human brain and form oligodendrocyte clusters for functional-dependent adaptive myelination. We aimed to estimate the NvOl and Nv of oligodendrocyte clusters (NvOlC) in supra- and infragranular sublayers of the PFC in schizophrenia and healthy controls. 17 chronic schizophrenia subjects and 20 healthy matched controls were studied in Nissl-stained sections in sublayers 3a- 3c and 5a of the PFC by stereological optical dissector method. The NvOl and the NvOlC were significantly decreased in supra- (32%, p<0.02) and infragranular sublayers (50%, p<0.001) of the PFC in the schizophrenia group as compared to controls. The Nv OlC/Nv Ol ratio decreased significantly in the schizophrenia group only in sublayers 3a (p=0.015) and 5a (p<0.001). In the control group, the NvOlC was positively correlated with the NvOl in sublayers 3b, 3c and 5a (R≥0.59; p≤0.006). In the schizophrenia group, a significant correlation between the parameters was found only in sublayer 5a (R=0.8; p<0.001). The deficit of oligodendrocyte clusters might be associated with altered proliferation and/or maturation of oligodendrocyte progenitors in schizophrenia. Specific alterations of the Nv OlC/Nv Ol ratio might be due to different connectivity of supra- and infragranular sublayers of the PFC and their disturbances in schizophrenia.

Ultrastructural pathology of oligodendrocytes adjacent to microglia in prefrontal white matter in schizophrenia

Microglial activation has been proposed to be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that dystrophic alterations of oligodendrocytes previously reported in the prefrontal white matter in SCZ might be associated with microglial activation in the acute state of SCZ. White matter of the prefrontal cortex (BA10) was studied in post-mortem brain tissue from 21 SCZ cases and 20 normal controls. The SCZ group included 12 subjects with predominantly positive symptoms and 9 subjects with predominantly negative symptoms. Electron microscopy was applied to estimate cell density, size, volume fraction (Vv) and the number (N) of organelles in oligodendrocytes adjacent to microglia and in oligodendrocytes adjacent to myelin, neurons and capillaries and not adjacent to microglia. Cell density of oligodendrocytes was not changed in the SCZ group as compared to controls. Vv and N of mitochondria were significantly decreased, while Vv of vacuoles of endoplasmic reticulum and lipofuscin granules were significantly increased in oligodendrocytes adjacent to either microglia or myelin in the SCZ group and in patients displaying predominantly positive symptoms as compared to the control group. There were no significant differences between oligodendrocytes adjacent to microglia and to myelin. Vv and N of lipofuscin were also increased in peri-capillary oligodendrocytes. There was no effect of clinical subgroups on the parameters of peri-capillary and peri-neuronal oligodendrocytes. Though many ameboid and dystrophic microglia adjacent to oligodendrocytes were found in the SCZ samples, we provide no quantitative evidence that oligodendrocyte dystrophy is associated with microglial activation in white matter in SCZ.

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Major deficits arise in MS patients due to an inability to repair damaged myelin sheaths following CNS insult, resulting in prolonged axonal exposure and neurodegeneration. The TAM receptors (Tyro3, Axl, and Mertk) have been implicated in MS susceptibility, demyelination and remyelination. Previously, we have shown that Tyro3 regulates developmental myelination and myelin thickness within the optic nerve and rostral region of the corpus callosum (CC) of adult mice. In this study we have verified and extended our previous findings via a comprehensive analysis of axonal ensheathment and myelin thickness in the CC of unchallenged mice, following demyelination and during myelin repair. We show that the loss of the Tyro3 receptor correlates with significantly thinner myelin sheaths in both unchallenged mice and during remyelination, particularly in larger caliber axons. The hypomyelinated phenotype observed in the absence of Tyro3 occurs independently of any influence upon oligodendrocyte precursor cell (OPC) maturation, or density of oligodendrocytes (OLs) or microglia. Rather, the primary effect of Tyro3 is upon the radial expansion of myelin. The loss of Tyro3 leads to a reduction in the number of myelin lamellae on axons, and is therefore most likely a key component of the regulatory mechanism by which oligodendrocytes match myelin production to axonal diameter.

Corpus Callosum Vasculature Predicts White Matter Microstructure Abnormalities after Pediatric Mild Traumatic Brain Injury.

Emerging data suggest that pediatric traumatic brain injury (TBI) is associated with impaired developmental plasticity and poorer neuropsychological outcomes than adults with similar head injuries. Unlike adult mild TBI (mTBI), the effects of mTBI on white matter (WM) microstructure and vascular supply are not well understood in the pediatric population. The cerebral vasculature plays an important role providing necessary nutrients and removing waste. To address this critical element, we examined the microstructure of the corpus callosum (CC) following pediatric mTBI using diffusion tensor magnetic resonance imaging (DTI), and investigated myelin, oligodendrocytes, and vasculature of WM with immunohistochemistry (IHC). We hypothesized that pediatric mTBI leads to abnormal WM microstructure and impacts the vasculature within the CC, and that these alterations to WM vasculature contribute to the long-term altered microstructure. We induced in mice a closed-head injury (CHI) mTBI at post-natal day (P) 14; then at 4, 14, and 60 days post-injury (DPI) mice were sacrificed for analysis. We observed persistent changes in apparent diffusion coefficient (ADC) within the ipsilateral CC following mTBI, indicating microstructural changes, but surprisingly changes in myelin and oligodendrocyte densities were minimal. However, vascular features of the ipsilateral CC such as vessel density, length, and number of junctions were persistently altered following mTBI. Correlative analysis showed a strong inverse relationship between ADC and vessel density at 60 DPI, suggesting increased vessel density following mTBI may restrict WM diffusion characteristics. Our findings suggest that WM vasculature contributes to the long-term microstructural changes within the ipsilateral CC following mTBI.

Axonal myelin decrease in the splenium in major depressive disorder

The corpus callosum has become a key area of interest for researchers in severe mental illness. Disruptions in fractional anisotropy in the callosum have been reported in schizophrenia and major depressive disorder. No change has been reported in oligodendrocyte density and overall size of the callosum in either illness, suggesting that gross morphology is unchanged, but subtler organisational disruption may exist within this structure. Using high-resolution oil immersion microscopy, we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath; and using standard high-resolution light microscopy, we measured the density of myelinated axons. These measurements were made in the splenium of the corpus callosum. Measures were taken in the sagittal plane in the callosal splenium to contrast with the previous similar examination of the callosal genu. Cases of major depressive disorder had significantly decreased mean myelin cross-sectional area (p = 0.014) per axon in the splenium than in controls or schizophrenia groups. There was no significant change in the density of myelinated axons. The results suggest a clear decrease of myelin in the axons of the callosal splenium in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. In contrast with increased myelin in the callosal genu, this result suggests a longitudinal change in callosal myelination in major depressive disorder not present in normal or schizophrenic brains.

Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia.

Neuroimaging and post-mortem studies have implicated altered myelin integrity and oligodendrocyte abnormalities in the dysfunction of neuronal network in schizophrenia, including the prefrontal cortex, Brodmann area (BA) 10. Pyramidal neurons in layer 5 of BA10 are the important link of reciprocal frontal cortical-basal ganglia-thalamic circuits altered in schizophrenia. Previously, we found ultrastructural dystrophic and degenerative alterations of oligodendrocytes in layer 5 of BA10 in schizophrenia. The aim of the study was to estimate the numerical density (Nv) of oligodendrocytes in layer 5 of BA10 in schizophrenia as compared to normal controls. 17 chronic schizophrenia subjects and 22 healthy matched controls were studied in Nissl-stained sections using optical disector method. Group differences were analyzed using ANCOVA followed by post hoc Duncan's test. The Nv of oligodendrocytes was significantly lower (- 32%, p < 0.001) in the schizophrenia group as compared to the control group. Young controls (age < 50years old) showed significantly higher Nv of oligodendrocytes as compared to elderly controls (age > 50years old). Young and elderly schizophrenia subgroups did not differ significantly. Both control subgroups have significantly higher Nv of oligodendrocytes as compared to the schizophrenia subgroups. Decreased Nv of oligodendrocytes found in layer 5 of BA10 may be the result of dystrophic and destructive alterations and/or disrupted development of oligodendrocytes in schizophrenia.