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Myelination: An Overlooked Mechanism of Synaptic Plasticity?
Abstract
Myelination of the brain continues through childhood into adolescence and early adulthood--the question is, Why? Two new articles provide intriguing evidence that myelination may be an underappreciated mechanism of activity-dependent nervous system plasticity: one study reported increased myelination associated with extensive piano playing, another indicated that rats have increased myelination of the corpus callosum when raised in environments providing increased social interaction and cognitive stimulation. These articles make it clear that activity-dependent effects on myelination cannot be considered strictly a developmental event. They raise the question of whether myelination is an overlooked mechanism of activity-dependent plasticity, extending in humans until at least age 30. It has been argued that regulating the speed of conduction across long fiber tracts would have a major influence on synaptic response, by coordinating the timing of afferent input to maximize temporal summation. The increase in synaptic amplitude could be as large as neurotransmitter-based mechanisms of plasticity, such as LTP. These new findings raise a larger question: How did the oligodendrocytes know they were practicing the piano or that their environment was socially complex?
... Myelination of cerebral axons begins in utero and continues into the second and third decades of life [1]. It advances particularly rapidly over the first 2 y of life following a specific posterior-to-anterior pattern and in close interplay with emerging neurobehavioral development [2][3][4][5][6][7]. ...
... To our knowledge, this is the first longitudinal association study describing nutrient-myelin windows and their dynamics in Recommendations for children aged 7-11 mo. 2 Recommendations for children aged 1-3 y. 3 Recommendations for children aged 4-8 y. 4 All macronutrient Dietary Recommended Intakes are from Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids [54]. 5 Dietary Recommended Intakes are from Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids [55]. 6 Dietary Recommended Intakes are from Dietary reference intakes for thiamine, riboflavin, niacin, vitamin B-6, folate, vitamin B-12, pantothenic acid, biotin, and choline [56]. ...
... Age window 1 from 6 to 20 mo, window 2 from 20 to 30 mo, and window 3 from 30 to 60 mo.2 Folic acid is the fully oxidized monoglutamate form of the vitamin that is used in fortified foods and most dietary supplements.3 Folate is the generic term for naturally occurring food folates and folates in dietary supplements and fortified foods, including folic acid.4 ...
Background:
Myelin imaging has increasingly been applied to study the impact of nutrition on brain development in recent years. Although individual dynamics for nutrient intakes and myelin trajectories previously have been investigated across childhood, the longitudinal interaction between both remains unclear in typically developed children.
Objectives:
The objective of this work was to explore the developmental dynamics of nutrient-myelin interactions from infancy to early childhood using myelin imaging as a marker for brain maturation.
Methods:
Brain neuroimaging (1 scan per child) and dietary nutrient intake data were analyzed for 88 nutrients from 293 children (127 female, 62% White) from a longitudinal cohort study in the United States. A sliding window approach was used to investigate correlations between nutrient intakes and brain myelination over a continuous set of age windows. Image processing techniques (Sobel-filter vertical edge detection) were applied to determine age windows with unique association profiles, providing novel insight into how these relationships change with child age.
Results:
We identified 3 nutrient-myelin windows covering the age range of 1-5 y: window 1 from 6 to 20 mo with 60% positive nutrient correlations, window 2 from 20 to 30 mo with 20% positive correlations, and window 3 from 30 to 60 mo with 37% positive correlations. The windows are aligned with reported myelin and white matter dynamics that change in the first 5 y from fast and steep (window 1) to continued but slower growth (window 3), with window 2 possibly representing the inflection period.
Conclusions:
To our knowledge, this is the first study in typically developing children demonstrating the developmental dynamics between early life nutrient intakes and brain maturation in toddlerhood. The knowledge can be applied for identifying targeted and brain-stage-appropriate nutritional interventions for this critical stage of brain development.
... It has recently been suggested that the myelination of axons may be a point of regulation for activity-dependent plasticity due to its capacity to change conductance speed in axons (Fields, 2005). This form of structural plasticity would therefore contribute to synaptic efficacy by increasing the duration, strength, and possibly timing of synaptic inputs (Fields, 2005). ...
... It has recently been suggested that the myelination of axons may be a point of regulation for activity-dependent plasticity due to its capacity to change conductance speed in axons (Fields, 2005). This form of structural plasticity would therefore contribute to synaptic efficacy by increasing the duration, strength, and possibly timing of synaptic inputs (Fields, 2005). ...
... This illustrates the extent that molecular events at the synapse can reach out beyond the synapse. However, activity-dependent myelination can also occur through generation of nascent oligodendrocytes from progenitor cells (Fields, 2005). This phenomenon is part of the wider topic of activity-dependent changes in cellular phenotype, which will be discussed in the next section. ...
p>Expression analysis of the whole MAST family has been performed using reverse-transcriptase PCR (RT-PCR), northern blot analysis and in situ hybridisation. RT-PCR using cDNA derived from multiple mouse tissues has shown an overlapping expression pattern for MAST1 and 2, and a more distinct expression pattern for MAST3, 4 and MAST-like. MAST1-4 were expressed in brain. The expression of MAST1-4 in brain has been investigated using in situ hybridisation. Again, MAST1 and 2 have been shown to have an overlapping pattern, which is in the cortex, hippocampus and cerebellum. MAST 3 is expressed more strongly in the hippocampus, and it also shows a more distinct expression in the striatum. MAST4 is expressed in both non-neuronal oligodendrocyte cells as well as hippocampal and cerebellar granule neurons. The activity-dependent expression of MAST4 in the dentate gyrus has also been confirmed. Although MAST1 and 2 have been shown to interact with group I and II metabotropic glutamate receptors via their PDZ domains this interaction does not appear to occur for MAST4.
MAST4 contains a noticeable extension of its C-terminus that is unique to this family member. This ‘C-domain’ does not contain any identifiable domains and may contribute a novel function to this family member, which supports the known PDZ and kinase domain.
A model is proposed whereby MAST4 may contribute to transcription and/or alternative mRNA splicing following synaptic activity. Based on these studies, possible new routes have been opened up to investigate the molecular mechanisms underlying neural signalling and plasticity.</p
... Moreover, a growing body of literature suggests Alzheimer's disease is associated with atypical patterns of myelination (Ota et al. 2019), and that changes in myeloarchitecture may correlate with the onset of Alzheimer's symptomatology (Maitre et al. 2023). The clear relationships between myeloarchitecture and experience-dependent plasticity/disease etiology (Fields 2005(Fields , 2008 underscore the important role that myelin quantification may play in tracking the anatomical status of cortical regions, surgical planning, and in predicting associated functional change following therapeutic interventions. ...
... In part, the hierarchical gradient of myelin density presented here likely reflects regional differences in neuronal density (and thus, differences in the number of myelinated axons per unit volume; see Table 1). However, regional differences may also be related to the time course of neural development, and may play an important role in regional differences in experience-dependent plasticity (Fields 2005(Fields , 2008. As a general principle, myelination ascends along a hierarchical order of increasing functional complexity (Yakovlev and Lecours 1967), and axons in regions that are myelinated early are also myelinated more rapidly and more completely (Stadelmann et al. 2019). ...
The cerebral cortex comprises many distinct regions that differ in structure, function, and patterns of connectivity. Current approaches to parcellating these regions often take advantage of functional neuroimaging approaches that can identify regions involved in a particular process with reasonable spatial resolution. However, neuroanatomical biomarkers are also very useful in identifying distinct cortical regions either in addition to, or in place of functional measures. For example, differences in myelin density are thought to relate to functional differences between regions, are sensitive to individual patterns of experience, and have been shown to vary across functional hierarchies in a predictable manner. Accordingly, the current study provides quantitative stereological estimates of myelin density for each of the 13 regions that make up the feline auditory cortex. We demonstrate that significant differences can be observed between auditory cortical regions, with the highest myelin density observed in the regions that comprise the auditory core (i.e., the primary auditory cortex and anterior auditory field). Moreover, our myeloarchitectonic map suggests that myelin density varies in a hierarchical fashion that conforms to the traditional model of spatial organization in auditory cortex. Taken together, these results establish myelin as a useful biomarker for parcellating auditory cortical regions, and provide detailed estimates against which other, less invasive methods of quantifying cortical myelination may be compared.
... Brain plasticity is the capacity of the central nervous system (CNS) to change structurally and functionally to gain its normal functions during normal brain development, or to gain new functions in response to experience or trauma [8,15]. The ability of CNS to undergo plasticity involves the regulation of neural circuit formation or synaptic connections at genetic, cellular, and molecular levels [7,8,12,15]. While the normal brain development occurs primarily during prenatal and postnatal periods and to a lesser degree adolescence and adulthood, a multilayered, versatile and an overlapping mechanism takes place controlled by intrinsic homeostatic mechanisms with the in uence of extrinsic environmental experiences [7,8,12,15]. ...
... The ability of CNS to undergo plasticity involves the regulation of neural circuit formation or synaptic connections at genetic, cellular, and molecular levels [7,8,12,15]. While the normal brain development occurs primarily during prenatal and postnatal periods and to a lesser degree adolescence and adulthood, a multilayered, versatile and an overlapping mechanism takes place controlled by intrinsic homeostatic mechanisms with the in uence of extrinsic environmental experiences [7,8,12,15]. Although brain plasticity is a natural process and can be adaptive and evolutionary advantageous event of the CNS as in developmental, reactive, and adaptive plasticity, in some cases plasticity becomes a liability for the person in question causing epilepsy and disorders such as Tuberous sclerosis complex or Rett syndrome [9,27]. ...
Background: The functional reorganization of motor functions is a sign of adaptive brain plasticity to brain damage and understanding its mechanisms may be a key role to many treatment models for brain damage in childhood and even in adults. Our aim is to show an electrophysiological evidence of brain plasticity regarding motor functions in early brain damaged patients.
Methods: We retrospectively analyzed four patients with some extremity motor functions shifting to unusual brain areas who were diagnosed with childhood epilepsy and underwent epilepsy surgery. We analyzed their clinical and surgical data particularly including intraoperative neuromonitorization (IONM) results.
Results: Patients’ preoperative data showed some motor representation of extremities was located somewhere else than the expected brain areas due to perinatal damage. In first patient right hand presentation was shifted to the right hemisphere and in second patient right hand was represented on both hemispheres. In the remaining two patients, all the motor functions of epileptogenic hemisphere were shifted to the contralateral side. IONM proved the neuroplasticity of the patients with previously crossed motor functions and was in line with preoperative functional Magnetic Resonance Imaging data.
Conclusion: Brain plasticity can alter the motor reorganization of the healthy hemisphere by taking upon the functions of the pathological hemisphere.
... Concurrent with this parcellation and functional localization theme has been an evolving exploration of how brain systems change across the lifespan in response to aging, learning, or environmental exposures (Davison and Dobbing, 1966;Weiss and Landrigan, 2000;Fields, 2005;Casey et al., 2005b). It is increasingly recognized that environmental influences, both positive and negative, can shape developing brain structures, networks, and connectivity (Fields, 2005;Casey et al., 2005a;Ishibashi et al., 2006). ...
... Concurrent with this parcellation and functional localization theme has been an evolving exploration of how brain systems change across the lifespan in response to aging, learning, or environmental exposures (Davison and Dobbing, 1966;Weiss and Landrigan, 2000;Fields, 2005;Casey et al., 2005b). It is increasingly recognized that environmental influences, both positive and negative, can shape developing brain structures, networks, and connectivity (Fields, 2005;Casey et al., 2005a;Ishibashi et al., 2006). Neural plasticity in response to specific skill training is a basic foundation of rehabilitation sciences (Kleim and Jones, 2008) and a growing body of literature has focused on identifying changes in white and gray matter structure (Draganski et al., 2004;Sampaio-Baptista and Johansen-Berg, 2017) and functional connectivity (Taubert et al., 2011;Moore et al., 2014) in individuals associated with learning, skill development, or during recovery from injury (e.g., stroke). ...
Three important themes in neuroscience are parcellation, structure-function specificity, and neural plasticity. These themes relate to: 1. The ability to delineate brain regions, for example on the basis of their cellular composition, myeloarchitecture, microstructural architecture, and/or connectivity profiles; 2. Relate parcellations to specific cognitive functions or behaviors; and 3. The ability of the tissue microstructure and architecture to adaptively change in response to environmental influences, with concurrent functional consequences. Neural plasticity suggests that any regional delineation scheme is likely to change with age and functional development, which we can exploit to identify functionally relevant regions and their development with age. From a large longitudinal cohort of neurotypically-developing children, 0 to 13 years of age, we used a data-driven approach to subdivide the cortex based on cortical myelination patterns. Next, we quantified the relationships between rates of myelination across each region and rates of functional development (including motor, language, visuospatial, executive, and academic ability). Linking these evolving processes, we identified unique and overlapping cortical regions that underly diverse skill development, providing new insight into how the cortical myeloarchitecture develops throughout early childhood and its importance to developing cognitive functioning.
... Clinical data also support the importance of experience-dependent myelin formation. Indeed, structural MRI studies have shown that white matter changes are required for the acquisition of both new motor and cognitive skills (e.g learning to read, juggling, piano playing) [58][59][60] . Moreover, cognitive deficits have been associated with (dys)function of the oligodendrocyte lineage and alterations in myelin content and ultrastructure [50][51][52] . ...
Early life events shape neuronal networks, and prime juvenile and adult behavior. Severely aversive, early experiences can interfere with brain development and enhance the risk for the onset of psychiatric illnesses. Recent evidence has implicated oligodendrocyte precursor cells (OPCs) in the pathophysiology of stress-related mental disorders. Historically classified as precursors of myelinating oligodendrocytes, OPCs are now known to fine-tune neuronal activity and modify their proliferation-maturation dynamics in response to environmental challenges. However, the underlying mechanisms are still elusive. OPCs express the glucocorticoid receptor (GR) for glucocorticoids (GCs), mediating the response to aversive challenges. To decipher the role of early postnatal GCs on OPCs proliferation-maturation dynamics, behavior and neuronal network activity in adulthood, we conditionally deleted GR in postnatal OPCs. Such deletion led to hippocampus-specific reduction of oligodendrocytes, sex-specific alteration of hippocampal activity and impairment in the formation of non-aversive and aversive memories in adulthood. Our findings disclosed a novel OPC-specific role for GRs, establishing the importance of postnatal GCs for modulating OPC maturation, fine-tuning the excitability of neuronal networks in response to a challenge and in adult memory formation. This provides the first evidence for a new dual role of GR-signaling in both the canonical and non-canonical functions of OPCs.
... The function of mRNA localization in astrocytes is being actively investigated (Boulay et al., 2017;Mazaré et al., 2020;Oudart et al., 2020;Sapkota et al., 2022). Oligodendrocytes are thought to modulate synaptic plasticity via myelination (Bacmeister et al., 2020;de Faria et al., 2021;Fields, 2005Fields, , 2008Fields and Bukalo, 2020;Pan et al., 2020) and are one of the glial cell types where the importance of mRNA localization has been extensively studied, leading to several groundbreaking discoveries of numerous transport mechanisms and localization elements (Ainger et al., 1997;Carson et al., 2008;White et al., 2008;Yergert et al., 2021). Microglia can preferentially phagocytose synaptic endings and modulate connectivity in the visual cortex (Andoh and Koyama, 2021;Graeber, 2010;Morris et al., 2013;Schafer et al., 2012;Vasek et al., 2023). ...
The polarization of cells often involves the transport of specific mRNAs and their localized translation in distal projections. Neurons and glia are both known to contain long cytoplasmic processes, while localized transcripts have only been studied extensively in neurons, not glia, especially in intact nervous systems. Here, we predict 1,740 localized Drosophila glial transcripts by extrapolating from our meta-analysis of seven existing studies characterizing the localized transcriptomes and translatomes of synaptically associated mammalian glia. We demonstrate that the localization of mRNAs in mammalian glial projections strongly predicts the localization of their high-confidence Drosophila homologs in larval motor neuron–associated glial projections and are highly statistically enriched for genes associated with neurological diseases. We further show that some of these localized glial transcripts are specifically required in glia for structural plasticity at the nearby neuromuscular junction synapses. We conclude that peripheral glial mRNA localization is a common and conserved phenomenon and propose that it is likely to be functionally important in disease.
... По данным различных авторов, в лобных долях головного мозга, отвечающих за регуляцию поведения, сложные рассуждения, планирование действий, этот процесс может завершаться в возрасте от 20 до 27 лет. Считается, что длительность этого процесса определяет то, что в связи с недостаточной зрелостью лобных долей подростки не способны принимать ответственные решения на уровне взрослых [13][14][15]. ...
... 5,6 At the same time, myelination is also activity-dependent: the glial cells (oligodendrocytes) that constitute the myelin sheath around neuronal axons respond to electrical activity in the neurons, preferentially myelinating electrically active axons. [7][8][9][10][11][12][13] Furthermore, properties of brain connections, such as their level of myelination, can adapt to external stimuli, exhibit plasticity induced by learning, and are sensitive to brain disease. [14][15][16] Injury to these connections can lead to significant brain dysfunction, resulting in neurological, psychiatric, and neurodevelopmental syndromes. ...
Diffusion-weighted MRI (dMRI) provides a unique non-invasive view of human brain tissue properties. The present review article focuses on tractometry analysis methods that use dMRI to assess the properties of brain tissue within the long-range connections comprising brain networks. We focus specifically on the major white matter tracts that convey visual information. These connections are particularly important because vision provides rich information from the environment that supports a large range of daily life activities. Many of the diseases of the visual system are associated with advanced aging, and tractometry of the visual system is particularly important in the modern aging society. We provide an overview of the tractometry analysis pipeline, which includes a primer on dMRI data acquisition, voxelwise model fitting, tractography, recognition of white matter tracts, and calculation of tract tissue property profiles. We then review dMRI-based methods for analyzing visual white matter tracts: the optic nerve, optic tract, optic radiation, forceps major, and vertical occipital fasciculus. For each tract, we review background anatomical knowledge together with recent findings in tractometry studies on these tracts and their properties in relation to visual function and disease. Overall, we find that measurements of the brain's visual white matter are sensitive to a range of disorders and correlate with perceptual abilities. We highlight new and promising analysis methods, as well as some of the current barriers to progress toward integration of these methods into clinical practice. These barriers, such as variability in measurements between protocols and instruments, are targets for future development.
... Myelination is a hallmark of neurodevelopment and critical for information processing, cell communication, and brain plasticity important for learning and development [15,28,29]. Our findings add to the previous observations displaying a steep increase in myelin during, particularly, the first 2 to 3 years of life [16] by showing that a specific blend of nutrients can support that trajectory. ...
Observation studies suggest differences in myelination in relation to differences in early life nutrition. This two-center randomized controlled trial investigates the effect of a 12-month nutritional intervention on longitudinal changes in myelination, cognition, and behavior. Eighty-one full-term, neurotypical infants were randomized into an investigational (N = 42) or a control group (N = 39), receiving higher versus lower levels of a blend of nutrients. Non-randomized breastfed infants (N = 108) served as a reference group. Main outcomes were myelination (MRI), neurodevelopment (Bayley-III), social-emotional development (ASQ:SE-2), infant and toddler behavior (IBQ-R and TBAQ), and infant sleep (BISQ) during the first 2 years of life. The full analysis set comprised N = 67 infants from the randomized groups, with 81 myelin-sensitive MRI sequences. Significantly higher myelination was observed in the investigational compared to the control group at 6, 12, 18, and 24 months of life, as well as significantly higher gray matter volume at 24 months, a reduced number of night awakenings at 6 months, increased day sleep at 12 months, and reduced social fearfulness at 24 months. The results suggest that brain development may be modifiable with brain- and age-relevant nutritional approaches in healthy infants and young children, which may be foundational for later learning outcomes.
... El secreto se encuentra en la mielina, sustancia producida por las células de Schwann presentes en las neuronas conectivas y motoras y que se enrollan a través del axón; esta es una sustancia aislante que se encuentra relacionado con las raíces biológicas del aprendizaje y desórdenes cognitivos (Coyle, 2009). Es así, como Bengtsson et al., (2005) asociaron en un estudio con niños, un incremento del coeficiente intelectual, con un incremento en la organización y la densidad de la materia blanca y Fields (2005Fields ( , 2008 afirma que en cuanto mayor es la cantidad de mielina que lo envuelve, más deprisa viajan las señales, aumentando la velocidad hasta cien veces más que en el caso de una fibra que no haya sido aislada (Ishibashi et al., 2006). La habilidad es un aislamiento que envuelve circuitos neuronales y crece de acuerdo con determinadas señales, como puede ser el entrenamiento táctico basado en principios ofensivos. ...
The objective is to determine the effect of a training program using an active method in youth football. The study had a unique case design with pretest and post-test measurements. The participants were 18 soccer players under 15 from a club in the city of Medellin (14,94±0,4 years; 166,33±0,05 cm; 54,09±5,96 kg; 19,52±1,56 Kg/m2; 0,98±1,15 years of experience). The intervention was carried out during 20 training units in 10 weeks, which had as learning contents the offensive tactical principles of evolution. The evaluations were following up of friendly football matches with a control group that had characteristics similar to the experimental group. The games were recorded and analyzed using a previously validated observation protocol. The analysis unit was made up of 605 ball recoveries and 301 offensive sequences in total. Pearson's chi-squared test (x2) was applied for the analysis of pre-post test differences. The results indicate a statistically significant increase in offensive performance (p = 0, 04) among the number of post-test offensive sequences compared to the pretest of the experimental group. It is recommended to use a training program based on the tactical component using the active method to increase offensive performance.
... Oligodendrocytes are thought to modulate synaptic plasticity via myelination (Fields, 2005;Fields, 2008;de Faria et al., 2021;Bacmeister et al., 2020;Pan et al., 2020;Fields and Bukalo, 2020). Microglia can preferentially phagocytose synaptic endings and modulate connectivity in the visual cortex (Andoh and Koyama, 2021;Graeber, 2010;Morris et al., 2013;Schafer et al., 2012;Vasek et al., 2021). ...
The polarization of cells often involves the transport of specific mRNAs and their localized translation in distal projections. Neurons and glia both contain long cytoplasmic processes with important functions. While mRNA localization has been studied extensively in neurons, little is known in glia, especially in intact nervous systems. Here, we predicted 1700 localized Drosophila glial transcripts by extrapolating from our meta-analysis of 8 existing studies characterizing the localized transcriptomes and translatomes of synaptically-associated mammalian glia. We tested these predictions in glia of the neuromuscular junction of Drosophila larvae and found that localization to vertebrate glia is a strong predictor of mRNA localization of the high confidence Drosophila homologues. We further showed that some of these localized transcripts are required in glia for plasticity of neuromuscular junction synapses. We conclude that peripheral glial mRNA localization is a common and conserved phenomenon and propose that it is likely to be functionally important.
... This partial myelination in the CNS opens up a window for the formation of new myelin sheaths on unmyelinated axonal segments. Newly layered myelin extends metabolic support to neurons 6 , fine-tunes conduction velocity of individual axons and consequently influence neural circuit function 7,8 . Hence, myelin remodeling is thought to be yet another form of long-term plasticity contributing to adaptive changes in brain function 9 . ...
Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca ²⁺ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca ²⁺ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca ²⁺ signals and their cell-fate progression. We found Ca ²⁺ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca ²⁺ microdomains. Microdomain Ca ²⁺ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca ²⁺ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca ²⁺ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca ²⁺ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate.
... Experience-dependent changes in white matter organization and structure are an important mechanism of neuroplasticity (Fields, 2005). White matter tracts connect brain regions and play a crucial role in efficient neural communication. ...
Background: Early childhood neglect can impact brain development across the lifespan. Using voxel-based approaches we recently reported that severe and time-limited institutional deprivation in early childhood was linked to substantial reductions in total brain volume in adulthood, more than twenty years later. Here we extend this analysis to explore deprivation-related regional white matter volume and microstructural organization using diffusion-based techniques.
Methods: A combination of tensor-based morphometry analysis and tractography was conducted on diffusion weighted imaging data from 59 young adults who spent between 3 and 41 months in the severely depriving Romanian institutions of the 1980’s before being adopted into UK families, and 20 non-deprived age-matched UK controls.
Results: Independent of total volume, institutional deprivation was associated with smaller volumes in localized regions across a range of white matter tracts including (1) long-ranging association fibers such as bilateral inferior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus, left superior longitudinal fasciculi, and left arcuate fasciculus; (2) tracts of the limbic circuitry including fornix and cingulum; and (3) projection fibers with the corticospinal tract particularly affected. Tractographic analysis found no evidence of altered microstructural organization of any tract in terms of hindrance modulated orientational anisotropy (HMOA), fractional anisotropy (FA) or mean diffusivity (MD).
Discussion: We provide further evidence for the effects of early neglect on brain development and their persistence in adulthood despite many years of environmental enrichment associated with successful adoption. Localized white matter effects appear limited to volumetric changes with microstructural organization unaffected.<br/
... SC evolves, rearranges, and strengthens in developmental stages, after brain injuries as well as across the lifespan as a result of, for example, learning processes (Fields, 2005;Salat, 2011;Yeatman et al., 2014). However, in older ages, increases in SC are rather unlikely and may point to yet unresolved methodological constraints. ...
In the normal aging process, the functional connectome restructures and shows a shift from more segregated to more integrated brain networks, which manifests itself in highly different cognitive performances in older adults. Underpinnings of this reorganization are not fully understood, but may be related to age-related differences in structural connectivity, the underlying scaffold for information exchange between regions. The structure-function relationship might be a promising factor to understand the neurobiological sources of interindividual cognitive variability, but remain unclear in older adults. Here, we used diffusion weighted and resting-state functional magnetic resonance imaging as well as cognitive performance data of 573 older subjects from the 1000BRAINS cohort (55-85 years, 287 males) and performed a partial least square regression on 400 regional functional and structural connectivity (FC and SC, respectively) estimates comprising seven resting-state networks. Our aim was to identify FC and SC patterns that are, together with cognitive performance, characteristic of the older adults aging process. Results revealed three different aging profiles prevalent in older adults. FC was found to behave differently depending on the severity of age-related SC deteriorations. A functionally highly interconnected system is associated with a structural connectome that shows only minor age-related decreases. Because this connectivity profile was associated with the most severe age-related cognitive decline, a more interconnected FC system in older adults points to a process of dedifferentiation. Thus, functional network integration appears to increase primarily when SC begins to decline, but this does not appear to mitigate the decline in cognitive performance.
... However, neuroregeneration is defined as the ability to generate new neurons (neurogenesis) and, consequently, new connections. In addition to this difference, neuroplasticity consists of short/medium-term functional recovery, while neuroregeneration promotes long-term functional recovery [1][2][3][4][5]. ...
... Moreover, estimating the z-coordinate (the height above the electrode plane) in addition to the x-y coordinates of an axon is a complicated inverse problem. While the amplitude of the recorded axonal signal is known to depend on the position relative to the recording electrode, various other biophysical factors, such as ion-channel densities and kinetics, membrane capacitances, axial resistances, and axon geometries, can influence axonal AP conduction velocities in unmyelinated axons [45,46,47,48,49,50]. In order to use the signal amplitude to correct for z-modulation, one would need to make assumptions about these other biophysical factors. ...
Objective: Neurons communicate with each other by sending action potentials (APs) through their axons. The velocity of axonal signal propagation describes how fast electrical APs can travel. This velocity can be affected in a human brain by several pathologies, including multiple sclerosis, traumatic brain injury and channelopathies. High-density microelectrode arrays (HD-MEAs) provide unprecedented spatio-temporal resolution to extracellularly record neural electrical activity. The high density of the recording electrodes enables to image the activity of individual neurons down to subcellular resolution, which includes the propagation of axonal signals. However, axon reconstruction, to date, mainly relies on manual approaches to select the electrodes and channels that seemingly record the signals along a specific axon, while an automated approach to track multiple axonal branches in extracellular action-potential recordings is still missing. Approach: In this article, we propose a fully automated approach to reconstruct axons from extracellular electrical-potential landscapes, so-called ‘electrical footprints’ of neurons. After an initial electrode and channel selection, the proposed method first constructs a graph based on the voltage signal amplitudes and latencies. Then, the graph is interrogated to extract possible axonal branches. Finally, the axonal branches are pruned, and axonal action-potential propagation velocities are computed. Main results: We first validate our method using simulated data from detailed reconstructions of neurons, showing that our approach is capable of accurately reconstructing axonal branches. We then apply the reconstruction algorithm to experimental recordings of HD-MEAs and show that it can be used to determine axonal morphologies and signal-propagation velocities at high throughput. Significance: We introduce a fully automated method to reconstruct axonal branches and estimate axonal action-potential propagation velocities using HD-MEA recordings. Our method yields highly reliable and reproducible velocity estimations, which constitute an important electrophysiological feature of neuronal preparations.
... Rather, according to grounded cognition theory, children's sensorimotor experiences, environmental affordances, and sociocultural contexts play a key role in children's global development (Barsalou, 2008;Gibson, 1988;Piaget, 1953). For instance, on the cellular level, early sensorimotor stimulation promotes neuronal connectivity, myelination of axons, and an increase in gray matter (Driemeyer, Boyke, Gaser, Büchel, & May, 2008;Fields, 2005;Milgrom et al., 2010). On the organismal level, early sensorimotor experiences advance children's motor skills, memory, learning, problem solving, language, and social competency (Cunha et al., 2018;Heathcock, Bhat, Lobo, & Galloway, 2004;Iverson, 2010;Mundy & Newell, 2007;Smith, 2005;Soska, Adolph, & Johnson, 2010). ...
Children born with a variety of environmental or medical risk factors may exhibit delays in global development. Very often, such delays are identified at preschool or school age, when children are severely overdue for effective early interventions that can alleviate the delays. This chapter proposes a conceptual model of child development to inform the creation of interventions and rehabilitative technologies that can be provided very early in development, throughout the first year of life, to optimize children's future developmental outcomes. The model suggests that early sensorimotor skills are antecedent and foundational for future motor, cognitive, language, and social development. As an example, this chapter describes how children's early postural control and exploratory movements facilitate the development of future object exploration behaviors that provide enhanced opportunities for learning and advance children's motor, cognitive, language, and social development. An understanding of the developmental pathways in the model can enable the design of effective intervention programs and rehabilitative technologies that target sensorimotor skills in the first year of life with the goal of minimizing or ameliorating the delays that are typically identified at preschool or school age. Specific examples of early interventions and rehabilitative technologies that have effectively advanced children's motor and cognitive development by targeting early sensorimotor skills and behaviors are provided.
... Recent studies have uncovered a surprising role for oligodendrocytes and the myelin they produce in stress, behavior, and experience-dependent plasticity [8][9][10][11][12][13]. Namely, neuronal activity and hormonal signaling can induce the proliferation of oligodendrocyte precursor cells and the remodeling of existing myelin in regions such as the corpus callosum, somatosensory cortex, and premotor cortex [14][15][16][17][18][19]. ...
Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.
... Using the same social delay discounting task, during functional imaging, we have shown that mPFC expresses neuronal plasticity that predicts preference malleability 36 . Myelin maturation unfolds throughout adolescence and into young adulthood and is a key mechanism underlying neuronal plasticity 37,68 . This motivated a hypothesis that a marker of myelin in the mPFC would relate to developmental effects on preference uncertainty. ...
Adolescents are prone to social influence from peers, with implications for development, both adaptive and maladaptive. Here, using a computer-based paradigm, we replicate a cross-sectional effect of more susceptibility to peer influence in a large dataset of adolescents 14 to 24 years old. Crucially, we extend this finding by adopting a longitudinal perspective, showing that a within-person susceptibility to social influence decreases over a 1.5 year follow-up time period. Exploiting this longitudinal design, we show that susceptibility to social influences at baseline predicts an improvement in peer relations over the follow-up period. Using a Bayesian computational model, we show that in younger adolescents a greater tendency to adopt others' preferences arises out of a higher uncertainty about their own preferences in the paradigmatic case of delay discounting (a phenomenon called 'preference uncertainty'). This preference uncertainty decreases over time and, in turn, leads to a reduced susceptibility of one's own behaviour to an influence from others‟. Neuro-developmentally, we show that a measure of myelination within medial prefrontal cortex, estimated at baseline, predicts a developmental decrease in preference uncertainty at follow up. Thus, using computational and neural evidence, we reveal adaptive mechanisms underpinning susceptibility to social influence during adolescence.
... Rather, we underline the fact that, despite undoubted improvements concerning technological advances allowing the establishment and maintenance of neural circuit architecture [106,107], it is very difficult to quantify such processes among different species, brain regions, and ages. Another important chapter of postnatal brain maturation is linked to myelination, a process which contributes to critical periods and crystallized circuits [108,109]. The division of oligodendrocyte progenitor cells plays a role in myelination, which is a widespread phenomenon across the CNS and is more common than neuron production during postnatal development [79]. ...
Plasticity, and in particular, neurogenesis, is a promising target to treat and prevent a wide variety of diseases (e.g., epilepsy, stroke, dementia). There are different types of plasticity, which vary with age, brain region, and species. These observations stress the importance of defining plasticity along temporal and spatial dimensions. We review recent studies focused on brain plasticity across the lifespan and in different species. One main theme to emerge from this work is that plasticity declines with age but that we have yet to map these different forms of plasticity across species. As part of this effort, we discuss our recent progress aimed to identify corresponding ages across species, and how this information can be used to map temporal variation in plasticity from model systems to humans.
... Evolving alongside the white matter, maturation of the cortical myeloarchitecture also advances rapidly over the first 2 years of life, and in association with evolving neurobehavioral functions. The ontogenic pattern of myelination is tightly regulated by neural activity (Ishibashi et al., 2006;Fields, 2005;Demerens et al., 1996) and coincides with the emergence of cognitive skills and abilities (van der Knaap et al., 1991;Nagy et al., 2004;Casey et al., 2005;Fornari et al., 2007;Fields, 2008), and contributes to developmental plasticity. Preceding myelination, the growth of new synaptic connections (synaptogenesis) begins by the 5th week of gestation and drives the enlargement of the fetal and infant brain, which reaches 80 % of its adult size by age 2yrs (Gilmore et al., 2012;Knickmeyer et al., 2008). ...
A major challenge in designing large-scale, multi-site studies is developing a core, scalable protocol that retains the innovation of scientific advances while also lending itself to the variability in experience and resources across sites. In the development of a common Healthy Brain and Child Development (HBCD) protocol, one of the chief questions is “is fetal MRI ready for prime-time?” While there is agreement about the value of prenatal data obtained non-invasively through MRI, questions about practicality abound. There has been rapid progress over the past years in fetal and placental MRI methodology but there is uncertainty about whether the gains afforded outweigh the challenges in supporting fetal MRI protocols at scale. Here, we will define challenges inherent in building a common protocol across sites with variable expertise and will propose a tentative framework for evaluation of design decisions. We will compare and contrast various design considerations for both normative and high-risk populations, in the setting of the post-COVID era. We will conclude with articulation of the benefits of overcoming these challenges and would lend to the primary questions articulated in the HBCD initiative.
... Using the same social delay discounting task, during functional imaging, we have shown that mPFC expresses neuronal plasticity that predicts preference malleability 36 . Myelin maturation unfolds throughout adolescence and into young adulthood and is a key mechanism underlying neuronal plasticity 37,68 . This motivated a hypothesis that a marker of myelin in the mPFC would relate to developmental effects on preference uncertainty. ...
Adolescents are prone to social influence from peers, with implications for development, both adaptive and maladaptive. Here, using a computer-based paradigm, we replicate a cross-sectional effect of more susceptibility to peer influence in a large dataset of adolescents 14 to 24 years old. Crucially, we extend this finding by adopting a longitudinal perspective, showing that a within-person susceptibility to social influence decreases over a 1.5 year follow-up time period. Exploiting this longitudinal design, we show that susceptibility to social influences at baseline predicts an improvement in peer relations over the follow-up period. Using a Bayesian computational model, we demonstrate that in younger adolescents a greater tendency to adopt others’ preferences arises out of a higher uncertainty about their own preferences in the paradigmatic case of delay discounting (a phenomenon called ‘preference uncertainty’). This preference uncertainty decreases over time and, in turn, leads to a reduced susceptibility of one’s own behaviour to an influence from others. Neuro-developmentally, we show that a measure of myelination within medial prefrontal cortex, estimated at baseline, predicts a developmental decrease in preference uncertainty at follow-up. Thus, using computational and neural evidence, we reveal adaptive mechanisms underpinning susceptibility to social influence during adolescence.
... Moreover, estimating the z-coordinate (the height above the electrode plane) in addition to the x-y coordinates of an axon is a complicated inverse problem. While the amplitude of the recorded axonal signal is known to depend on the position relative to the recording electrode, various other biophysical factors, such as ion-channel densities and kinetics, membrane capacitances, axial resistances, and axon geometries, can influence axonal AP conduction velocities in unmyelinated axons [43,44,45,46,47,48]. In order to use the signal amplitude to correct for z-modulation, one would need to make assumptions about these other biophysical factors. ...
Neurons communicate with each other by sending action potentials through their axons. The velocity of axonal signal propagation describes how fast electrical action potentials can travel, and can be affected in a human brain by several pathologies, including multiple sclerosis, traumatic brain injury and channelopathies. High-density microelectrode arrays (HD-MEAs) provide unprecedented spatio-temporal resolution to extracellularly record neural electrical activity. The high density of the recording electrodes enables to image the activity of individual neurons down to subcellular resolution, which includes the propagation of axonal signals. However, axon recon-struction, to date, mainly relies on a manual approach to select the electrodes and channels that seemingly record the signals along a specific axon, while an automated approach to track multiple axonal branches in extracellular action-potential recordings is still missing.
In this article, we propose a fully automated approach to reconstruct axons from extracellular electrical-potential landscapes, so-called “electrical footprints” of neurons. After an initial electrode and channel selection, the proposed method first constructs a graph, based on the voltage signal amplitudes and latencies. Then, the graph is interrogated to extract possible axonal branches. Finally, the axonal branches are pruned and axonal action-potential propagation velocities are computed.
We first validate our method using simulated data from detailed reconstructions of neurons, showing that our approach is capable of accurately reconstructing axonal branches. We then apply the reconstruction algorithm to experimental recordings of HD-MEAs and show that it can be used to determine axonal morphologies and signal-propagation velocities at high throughput.
We introduce a fully automated method to reconstruct axonal branches and estimate axonal action-potential propagation velocities using HD-MEA recordings. Our method yields highly reliable and reproducible velocity estimations, which constitute an important electrophysiological feature of neuronal preparations.
Le système somatosensoriel, sensoriel somatique ou somesthésique est un système qui collecte toutes les informations sensorielles provenant du corps.
Une classification purement anatomique permet de définir plusieurs sortes de sensibilités :
la sensibilité somatique au sens strict :
la sensibilité superficielle ou extéroceptive provenant de la peau par les extérocepteurs,
la sensibilité profonde ou proprioceptive qui nous renseigne sur notre position, nos sensations musculaires et squelettiques par les propriocepteurs,
la sensibilité viscérale qui provient de récepteurs de l'appareil digestif, du coeur, des poumons et des glandes endocrines par les intérocepteurs.
Fonctionnellement, le système somatosensoriel fait partie du SN sensoriel ou voie sensitive.
Educational games and enriched environments can potentially significantly impact neural development and cognitive functions. This article explores the empirical data from MRI studies on how these interventions promote brain plasticity and enhance learning capabilities. I examine various studies focusing on board games, social interaction games, and educational games, linking them to enriched environments to understand their combined effects. The results demonstrate substantial improvements in memory, attention, problem-solving skills, and overall cognitive development, emphasising the importance of incorporating these strategies into educational practices.
Цель обзора: представить новые литературные данные об участии олигодендроцитов и миелина в когнитивной дисфункции при шизофрении. Материал и метод: систематический обзор литературы. Результаты: настоящий обзор посвящен роли олигодендроцитов и миелина в когнитивных функциях мозга, патологии олигодендроцитов и миелина в мозге при шизофрении, связи нарушений олигодендроцитов и миелина с когнитивной дисфункцией у больных шизофренией и влиянию лечения на олигодендроциты и когнитивные нарушения. Важное значение нарушений структуры и функций олигодендроцитов и миелинизации мозга в патогенезе когнитивных расстройств при шизофрении подтверждены результатами нейровизуализационных, генетических, биохимических и морфометрических исследований мозга больных шизофренией. Заключение: стимуляция олигодендроглиогенеза и миелиногенеза в коре больших полушарий может стать новой стратегией в лечении когнитивных расстройств у больных шизофренией.
Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity, accomplished by oligodendrocytes (OLs), has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that OLs use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OLs play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL's transient intracellular responses to neural spikes is between 10 and 40 ms and the firing rates in individual axons are relatively low (⪅ 10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.
Microglia-the resident immune cells of the central nervous system-sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from microglia in mouse organotypic brain tissue cultures of both sexes, while no significant changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice of both sexes. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.
Significance Statement:
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that induces cortical plasticity. Despite its wide use in neuroscience and clinical practice (e.g., depression treatment) the cellular and molecular mechanisms of rTMS-mediated plasticity remain not well understood. Herein, we report an important role of microglia and plasticity-promoting cytokines in synaptic plasticity induced by 10 Hz rTMS in organotypic slice cultures and anesthetized mice, thereby identifying microglia-mediated synaptic adaptation as a target of rTMS-based interventions.
Objective:
Morphometric estimation of the numerical density of oligodendrocytes (NcOl) and numerical density of oligodendrocyte clusters (NvOlC) in the rostral part of the caudate head nucleus associated with the cortical regions of the default network in the norm and in schizophrenia.
Material and methods:
NcOl and NvOlC were determined in the gray matter of the rostral part of the head of the caudate nucleus in Nissl-stained sections using optical dissector in postmortem brains in 18 schizophrenia and 18 healthy control cases.
Results:
The NvOl (-20%, p<0.001) and NvOlC (-28%, p<0.001) were decreased in the schizophrenia group as compared to the control groups. The NvOl correlated with the NvOlC (R≥0.88, p<0.001) in both groups while a lack of correlations was previously found in the central part of the caudate head.
Conclusion:
The detected deficits of the NcOl and NvOlC is an agreement with prominent suppressing of cortico-striatal connections and reduced density of gray matter in this part of the caudate in schizophrenia. The differences in the pattern of correlations as compared to the central part of this structure might be associated with the specific features of functional activity of default-mode and fronto-parietal networks associated with these parts of caudate nucleus.
Neurons and glia are highly polarized cells, whose distal cytoplasmic functional subdomains require specific proteins. Neurons have axonal and dendritic cytoplasmic extensions containing synapses requiring mRNA transport and localized translation to regulate synaptic plasticity efficiently. The principles behind these mechanisms are equally attractive for explaining rapid local regulation of distal glial cytoplasmic projections, independent of their cell nucleus. However, in contrast to neurons, this topic has received little experimental attention in glia. Nevertheless, there are many functionally diverse glial sub-types, containing extensive networks of long cytoplasmic projections with likely localized regulation that influence neurons and their synapses. Moreover, glia have many other neuron-like properties, including electrical activity, secretion of gliotransmitters and calcium signaling, influencing for example synaptic transmission, plasticity and axon pruning. Here, we review previous studies concerning glial transcripts with important roles in influencing synaptic plasticity, focusing on a few cases involving localized translation. We discuss a variety of important questions about mRNA transport and localized translation in glia that remain to be addressed using cutting-edge tools already available for neurons.
This resource is the long-awaited new revision of the most highly regarded reference volume on glial cells, and has been completely revised, greatly enlarged, and enhanced with full color figures throughout. Neglected in research for years, it is now evident that the brain only functions in a concerted action of all the cells, namely glia and neurons. Seventy one chapters comprehensively discuss virtually every aspect of normal glial cell anatomy, physiology, biochemistry and function, and consider the central roles of these cells in neurological diseases including stroke, Alzheimer disease, multiple sclerosis, Parkinson's disease, neuropathy, and psychiatric conditions. With more than 20 new chapters it addresses the massive growth of knowledge about the basic biology of glia and the sophisticated manner in which they partner with neurons in the course of normal brain function.
Abuse of toluene-containing volatile inhalants, particularly among youth, is of significant medical and social concern worldwide. Teenagers constitute the most abundant users of toluene and the majority of adult abusers of toluene started as teenagers. Although the euphoric and neurotoxic effects of acute toluene have been widely studied, lasting effects of chronic toluene exposure, especially in various age groups, have not been well investigated. In this study, we used adolescent and adult male Wistar rats to evaluate the short- and long-term effects of chronic toluene on various behaviors including cognitive function. Daily exposure to toluene (2000 ppm) for 40 days (5 min/day) resulted in age-dependent behavioral impairments. Specifically, adolescent animals showed recognition memory impairment the day after the last exposure, which had normalized by day 90 post- exposure, whereas such impairment in adult animals was still evident at day 90 post-exposure. Our data suggest that age-dependent responses should be taken into consideration in interventional attempts to overcome specific detrimental consequences of chronic toluene exposure.
Myelination of the brain’s white and cortical gray matter is a critical neurodevelopmental process that underpins efficient brain messaging and communication and, accordingly, contributes to the development and refinement of cognitive skills and abilities. While this is conceptually supported by the concurrent timelines of myelination derived from histological assays and cognitive development from behavioral studies, in vivo demonstration of myelin-cognitive associations across human infancy and childhood is limited. From histological studies, myelination proceeds in a known and characteristic caudal-cranial and posterior-to-anterior arc, driven by the increasingly coherent synaptic activity associated with emerging cognitive and behavioral functions. Patterns of myelination, therefore, may intrinsically inform on the rate and sequence of these developing skills and abilities, as well as the brain regions that contribute to them. In this work, we used longitudinal and myelin-sensitive MRI measures from a large cohort of neurotypical children to examine patterns of myelination throughout the brain and link these patterns to concurrently evolving motor, visual, and language skills. Results revealed a core system of central brain regions that contributed broadly across cognitive domains as well as individual and domain-specific regions that align with known functional specialization. These results provide important new insight into the sequence of emerging skills and the underlying myeloarchitectural changes that support them. This information provides context and reference for how early alterations may affect cognitive outcomes depending on their timing and anatomical location.
It is a book about the different advances in clinical research and pathologies. The chapter I authored (Chapter 15) is in my profile available for reading, it is a comprehensive review on neuroplasticity in spinal cord injury and various forms of treatment that are being proposed for it. If you want the complete book, go to the B P International website to get access.
Neurodevelopmental disabilities are a group of disorders that result from injury to the developing nervous system causing functional impairment. Multiple diagnoses are the rule because brain dysfunctions in childhood are the results of etiologies that have wide-ranging effects. The functional limitations may result directly from a primary injury, from secondary effects related to that injury, or from arrested brain development. While the functional limitations have been the historical focus of these disorders, new advances in genetics and neuroscience offer the potential for amelioration, cure, or both.
Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood,and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.
Despite substantial evidence that mechanical variables play a crucial role in transmembrane voltage regulation, most research efforts focus mostly on the nerve cell's biochemical or electrophysiological activities. We propose an electromechanical model of a nerve in order to advance our understanding of how mechanical forces and thermodynamics also regulate neural electrical activities. We explore the spatiotemporal dynamics of the transmembrane potential using the proposed nonlinear model with a sinusoid as the initial transmembrane potential and periodic boundary conditions. The localized wave from our numerical simulation and transmembrane potentials in nerves are solitary and show the three stages of action potential (depolarization, repolarization, and hyperpolarization), as well as threshold and saturation effects. We show that the mechanical properties of membranes affect the localization of the transmembrane potential. According to simulation data, mechanical pulses of sufficient magnitude can modulate a transmembrane voltage. The current model could be used to describe the dynamics of a transmembrane potential modulated by sound. Mechanical perturbations that modulate an electrical signal have a lot of clinical potential for treating pain and other neurological diseases.
Early pediatric neurodevelopment is marked by rapid growth and development of every structural and functional brain system and network. Fundamental processes, including synaptogenesis and synaptic pruning, and myelination work in competitive collaboration to build functional brain networks that support nearly every cognitive function and behavioral skill. MRI provides a noninvasive means with which to measure these evolving structural and functional connections and networks. Techniques such as quantitative relaxation time measurement, magnetization transfer imaging, and multicomponent water imaging provide important and quantitative insight into the maturing tissue microstructure and myelination processes. In this chapter, we outline these quantitative techniques, including methods to collect the data and potential pitfalls and areas of opportunity and forth advancement.
Spatiotemporal patterns, such as words in speech, are rarely precisely the same duration, yet a word spoken faster or slower is still easily recognisable. Neural mechanisms underlying this ability to recognise stretched or compressed versions of the same spatiotemporal pattern are not well understood. Recognition of time-varying patterns is often studied at the network level, however here we propose a single neuron using learnable spike delays for the task. We characterise the response of a single neuron to stretched and compressed versions of a learnt pattern and show that using delays leads to pattern recognition above 99% accuracy for patterns morphed by up to 50%. Additionally, we demonstrate a significantly reduced response when the pattern is reversed, a property that is often difficult to reproduce in synaptic efficacy (synaptic weight) based learning systems. With appropriate settings of the neuron membrane time constant and spike threshold, we show that a single neuron is able to generalise to time-warped patterns while discriminating temporally reversed patterns. Together, these results highlight the potential of synaptic delay-based learning rules as a robust mechanism for learning time-warped spatiotemporal patterns.
Hyperserotonemia and brain-specific autoantibodies are detected in some autistic children. Nerve growth factor (NGF) stimulates the proliferation of B lymphocytes with production of antibodies and also increases mast cell serotonin release. This work was the first to investigate the relationship between plasma NGF and both hyperserotonemia and the frequency of serum anti-myelin basic protein (anti-MBP) auto-antibodies in 22 autistic children aged between 4 and 12 years and 22 healthy-matched controls. Levels of NGF, serotonin and anti-MBP were significantly higher in autistic children than healthy control children (P < 0.001). There was a significant positive correlation between NGF and serotonin levels in autistic patients (P < 0.01). In contrast, there was a non-significant correlation between NGF and anti-MBP levels (P > 0.05). In conclusions, serum NGF levels were elevated and significantly correlated to hyperserotonemia found in many autistic children.
Differentiation of oligodendrocyte progenitor cells (OPCs) into myelination-capable mature oligodendrocytes is essential for proper function of the central nervous system. OPCs are tissue-resident stem cells that populate all regions of the central nervous system and exist beyond development into adulthood. Disorders that lead to disruption of this critical cell state change cause devastating myelin diseases that are often associated with shortened life span. Recent findings have also provided support for a newly appreciated contribution of perturbed OPC differentiation to neurodegenerative and psychiatric diseases. These findings emphasize the need for a more complete understanding of OPC differentiation in health and disease. Here, we review recent molecular and functional findings revealing new roles of OPCs. It is our hope that this review provides readers with an enticing snapshot of current OPC research and highlights the potential of controlling OPC fate and function to treat diseases of the brain.
The sural sensory nerve, which innervates the lower extremities, is a useful model for studying the structural and functional characteristics of peripheral sensory nerves. Its development and myelination extends across the early postnatal through to the juvenile stage. Myelination of the sural nerve depends on interactions between axons and Schwann cells and requires a variety of factors including hormones, neurotrophic factors, nerve impulses, and transcription factors. Maternal deprivation or malnutrition during early life reduces the thickness of myelin and decreases the area and amplitude of the compound action potential of the sural nerve. Importantly, the replacement of tactile or social stimuli during experimental maternal isolation in rats prevents such effects. Electrical stimulation or neurotrophic factors favor the remyelination and regeneration of nerves damaged by crushing or neuropathies derived from genetic, infectious, or metabolic diseases such as diabetes mellitus.
Electric organs in Sternarchidae are of neural origin, in contrast to electric organs in other fish, which are derived from muscle. The electric organ in Sternarchus is composed of modified axons of spinal neurons. Fibers comprising the electric organ were studied by dissection and by light- and electron microscopy of sectioned material. The spinal electrocytes descend to the electric organ where they run anteriorly for several segments, turn sharply, and run posteriorly to end blindly at approximately the level where they enter the organ. At the level of entry into the organ, and where they turn around, the axons are about 20 micro in diameter; the nodes of Ranvier have a typical appearance with a gap of approximately 1 micro in the myelin. Anteriorly and posteriorly running parts of the fibers dilate to a diameter of approximately 100 micro, and then taper again. In proximal and central regions of anteriorly and posteriorly running parts, nodal gaps measure approximately 1 micro along the axon. In distal regions of anteriorly and posteriorly running parts are three to five large nodes with gaps measuring more than 50 micro along the fiber axis. Nodes with narrow and with wide gaps are distinguishable ultrastructurally; the first type has a typical structure, whereas the second type represents a new nodal morphology. At the typical nodes a dense cytoplasmic material is associated with the axon membrane. At large nodes, the unmyelinated axon membrane is elaborated to form a closely packed layer of irregular polypoid processes without a dense cytoplasmic undercoating. Electrophysiological data indicate that typical nodes in proximal regions of anteriorly and posteriorly running segments actively generate spikes, whereas large distal nodes are inactive and act as a series capacity. Increased membrane surface area provides a morphological correlate for this capacity. This electric organ comprises a unique neural system in which axons have evolved so as to generate external signals, an adaptation involving a functionally significant structural differentiation of nodes of Ranvier along single nerve fibers.
Development of the mammalian nervous system is regulated by neural impulse activity, but the molecular mechanisms are not well understood. If cell recognition molecules [for example, L1 and the neural cell adhesion molecule (NCAM)] were influenced by specific patterns of impulse activity, cell-cell interactions controlling nervous system structure could be regulated by nervous system function at critical stages of development. Low-frequency electrical pulses delivered to mouse sensory neurons in culture (0.1 hertz for 5 days) down-regulated expression of L1 messenger RNA and protein (but not NCAM). Fasciculation of neurites, adhesion of neuroblastoma cells, and the number of Schwann cells on neurites was reduced after 0.1-hertz stimulation, but higher frequencies or stimulation after synaptogenesis were without effect.
Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer "games" designed to drive improvements in their "temporal processing" skills. With 8 to 16 hours of training during a 20-day period, LLI children improved markedly in their abilities to recognize brief and fast sequences of nonspeech and speech stimuli.
The oligodendrocyte is the myelin-forming cell in the central nervous system. Despite the close interaction between axons and oligodendrocytes, there is little evidence that neurons influence myelinogenesis. On the contrary, newly differentiated oligodendrocytes, which mature in culture in the total absence of neurons, synthesize the myelin-specific constituents of oligodendrocytes differentiated in vivo and even form myelin-like figures. Neuronal electrical activity may be required, however, for the appropriate formation of the myelin sheath. To investigate the role of electrical activity on myelin formation, we have used highly specific neurotoxins, which can either block (tetrodotoxin) or increase (alpha-scorpion toxin) the firing of neurons. We show that myelination can be inhibited by blocking the action potential of neighboring axons or enhanced by increasing their electrical activity, clearly linking neuronal electrical activity to myelinogenesis.
A cell culture preparation equipped with stimulating electrodes was used to investigate whether action potential activity can influence myelination of mouse dorsal root ganglia axons by Schwann cells. Myelination was reduced to one-third of normal by low-frequency impulse activity (0.1 Hz), but higher-frequency stimulation (1 Hz) had no effect. The number of Schwann cells and the ultrastructure of compact myelin were not affected. The frequency of stimulation that inhibited myelination decreased expression of the cell adhesion molecule L1, and stimulation under conditions that prevented the reduction in L1 blocked the effects on myelination. This link between myelination and functional activity in the axon at specific frequencies that change axonal expression of L1 could have important consequences for the structural and functional relationship of myelinating axons.
Structural maturation of fiber tracts in the human brain, including an increase in the diameter and myelination of axons,
may play a role in cognitive development during childhood and adolescence. A computational analysis of structural magnetic
resonance images obtained in 111 children and adolescents revealed age-related increases in white matter density in fiber
tracts constituting putative corticospinal and frontotemporal pathways. The maturation of the corticospinal tract was bilateral,
whereas that of the frontotemporal pathway was found predominantly in the left (speech-dominant) hemisphere. These findings
provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting
motor and speech functions.
Two-way communication between neurons and nonneural cells called glia is essential for axonal conduction, synaptic transmission,
and information processing and thus is required for normal functioning of the nervous system during development and throughout
adult life. The signals between neurons and glia include ion fluxes, neurotransmitters, cell adhesion molecules, and specialized
signaling molecules released from synaptic and nonsynaptic regions of the neuron. In contrast to the serial flow of information
along chains of neurons, glia communicate with other glial cells through intracellular waves of calcium and via intercellular
diffusion of chemical messengers. By releasing neurotransmitters and other extracellular signaling molecules, glia can affect
neuronal excitability and synaptic transmission and perhaps coordinate activity across networks of neurons.
Childhood abuse has been associated with abnormalities in brain development, particularly corpus callosum (CC) morphology. The impact of neglect has not been assessed, though it is the most prevalent form of childhood maltreatment.
Regional CC area was measured from magnetic resonance imaging scans in 26 boys and 25 girls admitted for psychiatric evaluation (28 with abuse or neglect) and compared with CC area in 115 healthy control subjects. Data were analyzed by multivariate analysis of covariance, with age and midsagittal area as covariates.
Total CC area of the abused/neglected patients was 17% smaller than in control subjects (p =.0001) and 11% smaller than in psychiatric patients who had not been abused or neglected (contrast group; p =.01). Control subjects and the contrast group did not differ in total CC area. Neglect was the strongest experiential factor and was associated with a 15%-18% reduction in CC regions 3, 4, 5, and 7 (all p <.02). In contrast, sexual abuse seemed to be the strongest factor associated with reduced CC size in girls.
These data are consistent with animal research that demonstrated reduced CC size in nursery-reared compared with semi-naturally reared primates. Early experience might also affect the development of the human CC.
Using diffusion tensor imaging, we investigated effects of piano practicing in childhood, adolescence and adulthood on white matter, and found positive correlations between practicing and fiber tract organization in different regions for each age period. For childhood, practicing correlations were extensive and included the pyramidal tract, which was more structured in pianists than in non-musicians. Long-term training within critical developmental periods may thus induce regionally specific plasticity in myelinating tracts.
Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2(A) adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.
Neuronal activity influences myelination of the brain, but the molecular mechanisms involved are largely unknown. Here, we report that oligodendrocyte progenitor cells (OPCs) express functional adenosine receptors, which are activated in response to action potential firing. Adenosine acts as a potent neuron-glial transmitter to inhibit OPC proliferation, stimulate differentiation, and promote the formation of myelin. This neuron-glial signal provides a molecular mechanism for promoting oligodendrocyte development and myelination in response to impulse activity and may help resolve controversy on the opposite effects of impulse activity on myelination in the central and peripheral nervous systems.
Changes in brain through experience, demanded by learning theories, are found in experiments with rats.
Electric organs are specialized for the production of an electric field outside the body. The study of electric organs and electrocytes has illuminated many aspects of membrane physiology. They are found only in fish but apparently have evolved independently in some six different groups. Their primary usefulness is a result of evolution that has exaggerated different membrane functions in different electrocytes. For example, the concept of independent sites that pass different ions or groups of ions becomes more reasonable given that specific kinds of permeability can occur in isolation in different regions of a single cell or in different cells. Examples are the isolated occurrence of membrane generating postsynaptic potentials (in Astroscopus and torpedinids), of membrane exhibiting delayed rectification, and of the electrically excitable sodium system without delayed rectification (in the electric eel). This macroscopic separation suggests microscopic separation, which in many single membranes can only be inferred from functional arguments or pharmacological data. These specializations of different kinds of membrane cannot really be said to have been responsible for major advances in electrophysiological knowledge. As new morphological, biochemical, and biophysical techniques become available, electrocytes may provide the best tissues for their evaluation.
Recent studies on Schwann cells at the neuromuscular junction and non-synaptic regions of premyelinated axons indicate that extracellular ATP can act as an activity-dependent signaling molecule in communication between neurons and glia. Several mechanisms have been observed for the regulated release of ATP from synaptic and non-synaptic regions, and a diverse family of receptors for extracellular ATP has been characterized. The findings suggest functional consequences of neuron–glial communication beyond homeostasis of the extracellular environment surrounding neurons, including regulating synaptic strength, gene expression, mitotic rate, and differentiation of glia according to impulse activity in neural circuits.
Cells of origin of the corpus callosum (callosal efferent neurons) in prelunate gyrus (area OA) of the rhesus monkey were studied using electrophysiological techniques. Monkeys were chronically prepared and callosal efferent neurons were identified by their antidromic activation following electrical stimulation of the contralateral prelunate gyrus and/or the splenium of the corpus callosum. Interhemispheric antidromic latencies ranged from 2.6--18.0 ms (median = 7.0 ms) while the conduction velocity along the length of the axon ranged from 2.8 to 22.5 M/s (median = 7.4 M/s) while the conduction velocity along the length of the axon ranged from 2.8 to 22.5 M/s (median = 7.4 M/s. Following the relative refractory period of a single prior impulse, all but one of 61 callosal efferent neurons studied showed a supernormal period of increased axonal conduction velocity and excitability. Following several prior impulses, the supernormal period was followed by a subnormal period of decreased axonal conduction velocity and excitability, which, depending on the number of prior impulses, lasted from several hundred ms to nearly 2 min.
The cell populations of the occipital cortex were examined in young rats subjected to different sensory experiences. In one series recently weaned animals were reared in enriched, impoverished or control environments. The enriched environment was obtained by keeping the animals among “toys” and other rats; the impoverished environment, by rearing the animals one pr cage in a darkened, quiet room; and the control environment, by housing the animals three per cage under animal room conditions. Six recently weaned rats were kept ini each environment for 30 days and ten, for 80 days. In a second series suckling rats for 15 minutes per day during the first ten days after birth; twelve rats were studied, six handled and six unhandled controls. In the two series, the animals were sacrificed under anesthesia by perfusion with mixed aldehydes. Semithin epon sections of occipital cortex ere stained with toluidine blue; neurons and the three main types of glia were enumerated. In addition, the thickness of the cortex was measured and the glial cells of corpus callosum counted in the animals exposed to the three environments for 80 days.
Under the influence of the enriched environment , the occipital cortex enlarged, the number of oligodendrocytes increased over the controls by 27‐33% in the 30‐ and 80‐day groups and the number of astrocytes, by 13% in the 80‐day grup. Within the cortex, only certain layers showed the increase in glial numbers. In the corpus callosum, however, the numbers of glial cells did not differ from those in controls. In the animals exposed to the impoverished environment , neither the size of the cortex nor the number of oligodendrocytes and astrocytes differed from controls.
The animals subjected to handling also showed evidence of cortical enlargement, but the only significant change in glial cells was a 12% increase in astrocytes.
It is concluded that handling and enrichment produce changes in anatomical indices of neural function including depth of cortex and numbers of glial cells. The glial response was specific to the type of manipulation since astrocytes were predominantly affected by handling and oligodendrocytes, by enrichment. The effect of handling on astrocytes may be attributed to the stimulation being applied at a time of astrocyte proliferation, whereas the effect of the enriched environment on oligodendrocytes occurred at a time of active production of these cells. The differences in cell numbers were explained by changes in the rate of cell population growth; since the impoverished did not differ from the control animals, the changes probably consisted of growth acceleration in the enriched animals rather than dimiution in the impoverished ones.
A contested report of sex differences in the size of the splenium of the corpus callosum in humans prompted the present examination of the corpus callosum in the rat. We have previously found that sex differences can vary with the rearing environment. Consequently, male and female rats were raised from weaning to 55 days of age in either a complex or an isolated environment. There were no sex differences in the size of the corpus callosum in sagittal cross section in these rats; however, rats of both sexes had a larger posterior third of the corpus callosum if they were raised in the complex environment. Because the corpus callosum continues to grow in size past 55 days of age, we examined socially housed rats at 113 days and again found no sex differences. The splenium was examined with electron microscopy in complex and isolation reared rats at 55 days of age. The ultrastructural analysis revealed differences that were not apparent from gross size measures. Females had more unmyelinated axons regardless of environment, and females from the complex environment had more myelinated axons than comparably housed males. In contrast, males in the complex environment had larger myelinated axons than females. Rats of both sexes from the complex environment had larger and more unmyelinated axons than isolated rats. In addition in myelinated axons, plasticity in the females occurred through changes in axon number and in males, through axon size. Thus sex differences exist in axonal number and size and the environment influences these differences.
The visual system is able to accurately represent the spatiotemporal relations among the elements of a changing visual scene as the image moves across the retinal surface. This precise spatiotemporal mapping occurs despite great variability in retinal position and conduction velocity even among retinal ganglion cells of the same physiological class-a variability that would seem to reduce the precision with which spatiotemporal information can be transmitted to central visual areas. There was a strong negative relation between the intraretinal and extraretinal conduction time for axons of individual ganglion cells of the X-cell class. The effect of this relation was to produce a nearly constant total transmission time between the soma of a retinal X cell and its central target site. Thus, the variation in the conduction velocities of retinal ganglion cell axons may ensure that, regardless of the constraints imposed by retinal topography, a precise spatiotemporal central representation of the retinal image is maintained.
Morphological measures of neurons, astrocytes, oligodendrocytes, presynaptic boutons, dendrites and capillaries were examined in the upper 4 layers of occipital cortex in rats reared for 30 days postweaning in complex (EC), social (SC) or individual cage (IC) environments. EC rats had a lower numerical density of neuronal nuclei with a comparable volume fraction to SC and IC rats. The volume fraction of astrocyte and oligodendrocyte nuclei was significantly greater for EC rats than IC littermates, and IC rats also had more synapses and neurons/micron3 of glial nuclei. Environmental groups did not differ in the numerical density of presynaptic boutons but the number of boutons per neuron was greater in EC than in IC or SC rats. This result parallels the findings that EC rats have more synapses per neuron than IC rats. Electron microscopic estimates of dendritic volume fraction confirmed estimates from Golgi-impregnated neurons that there is more dendrite per neuron in the occipital cortex of EC rats than IC or SC rats. EC rats also had a larger capillary volume than SC or IC and these capillaries were closer together and had fewer synapses/micron3 of capillary in ECs. Another indicator of metabolic activity, mitochondria volume per neuron, gave similar results with ECs having a greater volume than ICs and SCs intermediate. These results indicate that not only are there more synapses per neuron in the visual cortex of rats from more complex environments but also that the brain appears to adjust to the metabolic requirements of its synapses or neurons, in terms of vascular, mitochondrial and glial support.
The splenium of the corpus callosum of a primate (Macaca mulatta), examined with the electron microscope, was found to contain both myelinated and nonmyelinated axons. The majority of nonmyelinated axons had diameters of less tha 0.25 micron. On the basis of this diameter distribution, it is expected that many callosal axons conduct impulses at velocities of less than 1 m/s and that interhemispheric conduction times for some callosal axons are at least 30 ms and possibly much longer.
1. The issue of isochronicity of olivocerebellar fibre conduction time as a basis for synchronizing complex spike activity in cerebellar Purkinje cells has been addressed by latency measurement, multiple-electrode recording and Phaseolus vulgaris leucoagglutinin (PHA-L) tracing of climbing fibres in the adult rat. 2. The conduction time of the olivocerebellar fibres was measured by recording Purkinje cell complex spike (CS) responses from various areas of the cerebellum. The CSs were evoked by stimulating the olivocerebellar fibres near the inferior olive. In spite of a difference in length, as determined directly by light microscopy, the conduction times of different climbing fibres were quite uniform, 3.98 +/- 0.36 ms (mean +/- S.D., n = 660). 3. Multiple-electrode recording of spontaneous Purkinje cell CS activity was employed to study the spatial extent of CS synchronicity in the cerebellar cortex. Recordings of CS were obtained from Purkinje cells located on the surface and along the walls of lobule crus 2a. The rostrocaudal band-like distribution of simultaneous (within 1 ms) CS activity in Purkinje cells extended down the sides of the cerebellar folia to the deepest areas recorded (1.6-2.6 mm deep). As shown in previous experiments, the distribution of simultaneous CS activity did not extend significantly (500 microns) in the mediolateral axis of the cerebellar cortex. 4. In two animals a detailed determination of the length of the olivocerebellar fibre bundles was performed by staining the fibres with PHA-L injected into the contralateral inferior olive. This measurement included fibre bundles terminating in twenty-six different areas, ranging from the tops of the various folia to the bottoms of the fissures in both the hemisphere and the vermis. There was a 47.5% difference between the length of the longest measured fibre bundle (15.8 mm, terminating in lobule 6b, zone A) and the length of the shortest measured fibre bundle (8.3 mm, terminating in the cortex at the base of the primary fissure, zone D), after correction for tissue shrinkage. To attain an isochronous conduction time the conduction velocities for these two fibre bundles were calculated to be 4.22 m/s and 2.37 m/s, respectively. 5. By interpolating between measured points a simple formula was derived to estimate the average length of olivocerebellar fibres terminating in any given area of the cerebellar cortex, excluding the paraflocculus, the flocculus and the most lateral regions of the hemisphere. 6. We investigated the most likely mechanisms by which conduction velocity variations with length could result in global isochronicity.(ABSTRACT TRUNCATED AT 400 WORDS)
This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.
Sensory axons become functional late in development when Schwann cells (SC) stop proliferating and differentiate into distinct phenotypes. We report that impulse activity in premyelinated axons can inhibit proliferation and differentiation of SCs. This neuron-glial signaling is mediated by adenosine triphosphate acting through P2 receptors on SCs and intracellular signaling pathways involving Ca2+, Ca2+/calmodulin kinase, mitogen-activated protein kinase, cyclic adenosine 3',5'-monophosphate response element binding protein, and expression of c-fos and Krox-24. Adenosine triphosphate arrests maturation of SCs in an immature morphological stage and prevents expression of O4, myelin basic protein, and the formation of myelin. Through this mechanism, functional activity in the developing nervous system could delay terminal differentiation of SCs until exposure to appropriate axon-derived signals.
Despite significant gains in the fields of pediatric neuroimaging and developmental neurobiology, surprisingly little is known about the developing human brain or the neural bases of cognitive development. This paper addresses MRI studies of structural and functional changes in the developing human brain and their relation to changes in cognitive processes over the first few decades of human life. Based on post-mortem and pediatric neuroimaging studies published to date, the prefrontal cortex appears to be one of the last brain regions to mature. Given the prolonged physiological development and organization of the prefrontal cortex during childhood, tasks believed to involve this region are ideal for investigating the neural bases of cognitive development. A number of normative pediatric fMRI studies examining prefrontal cortical activity in children during memory and attention tasks are reported. These studies, while largely limited to the domain of prefrontal functioning and its development, lend support for continued development of attention and memory both behaviorally and physiologically throughout childhood and adolescence. Specifically, the magnitude of activity observed in these studies was greater and more diffuse in children relative to adults. These findings are consistent with the view that increasing cognitive capacity during childhood may coincide with a gradual loss rather than formation of new synapses and presumably a strengthening of remaining synaptic connections. It is clear that innovative methods like fMRI together with MRI-based morphometry and nonhuman primate studies will transform our current understanding of human brain development and its relation to behavioral development.
Vast amounts of neuropsychological evidence have been collected in recent years in support of the hypothesis that developmental dyslexia is caused not only by phonological deficits, but also by timing deficits that affect all senses (e.g., Tallal, Miller, & Fitch, 1995; Stein & Walsh, 1997). In parallel, recent developments in the study of Hebrew reading place heavy emphasis on root awareness in the mental lexicon and early root extraction in the process of word identification (e.g., Frost, Forster, & Deutch, 1997). The present study creates a link between the timing hypothesis and the special demands of Hebrew reading. The performance of dyslexics and normally reading children is compared on tasks requiring visual extraction of trigrams that approximates extracting roots out of Hebrew words. Partial findings show that dyslexics take longer and make more errors while performing trigram extractions on all levels examined, and that sequentiality in the task affects dyslexics and skilled readers in different ways.
Prior studies have demonstrated reduced frontal lobe volumes in depressed adolescents. In this study, frontal lobe gray and white matter volumes in adolescents with major depressive disorder were evaluated.
Nineteen depressed and thirty-eight healthy comparison adolescents were recruited for a magnetic resonance imaging study. Images were segmented into gray matter, white matter, and cerebrospinal fluid. Morphometric measurements of the whole brain and frontal lobe region were completed.
Whole brain volumes were significantly smaller in depressed subjects compared with the healthy comparison subjects. Significantly smaller frontal white matter volumes and significantly larger frontal gray matter volumes were found in the depressed subjects, after controlling for age and whole brain volume.
These results are consistent with the hypothesis that a deficit in frontal volume exists during cortical development in adolescents with depression. Further studies are needed to assess whether volume differences resolve over time and the extent to which these differences influence response to treatment.
Adolescent development is associated with progressive increases in the ratio of cerebral white-to-gray matter volume, but it is unclear how these changes relate to cognitive development and whether they are associated with sex-specific variability in cerebral maturation. We examined sex differences in the relation between cerebral tissue volume and cognitive performance in 30 healthy adolescents (ages 13 to 17 years using morphometric magnetic resonance imaging (MRI). In the 10 boys, greater white matter volume during adolescence was positively correlated with faster speed of information processing and better verbal abilities, while cerebrospinal fluid volume was negatively correlated with verbal abilities. No significant relations between cerebral tissue volume and cognitive abilities were found for the sample of 20 girls, raising the possibility of a different developmental trajectory for females that was not sampled in the age range of this study. Findings suggest sex-specific developmental differences in the relations between cerebral structure and function.
The role of glial cells in the thinking and learning process is highlighted. This theory of glial cells playing a role in the brain's working is in contrast to a half a century old belief that only neurons play an active role. However, recent research has indicated that astrocyte glia activate distant neurons to help form memories. Researchers have also indicated that Schwann glia could be the key to treating nerve diseases.
The importance of neural impulse activity in regulating neuronal plasticity is widely appreciated; increasingly, it is becoming apparent that activity-dependent communication between neurons and glia is critical in regulating many aspects of nervous system development and plasticity. This communication takes place not only at the synapse, but also between premyelinating axons and glia, which form myelin in the PNS and CNS. Recent work indicates that neural impulse activity releases ATP and adenosine from non-synaptic regions of neurons, which activates purinergic receptors on myelinating glia. Acting through this receptor system, neural impulse activity can regulate gene expression, mitosis, differentiation, and myelination of Schwann cells (SCs) and oligodendrocytes, helping coordinate nervous system development with functional activity in the perinatal period. ATP and adenosine have opposite effects on differentiation of Schwann cells and oligodendrocytes, providing a possible explanation for the opposite effects of impulse activity reported on myelination in the CNS and PNS.
Magnetic resonance imaging (MRI) provides accurate anatomical brain images without the use of ionizing radiation, allowing longitudinal studies of brain morphometry during adolescent development. Results from an ongoing brain imaging project being conducted at the Child Psychiatry Branch of the National Institute of Mental Health indicate dynamic changes in brain anatomy throughout adolescence. White matter increases in a roughly linear pattern, with minor differences in slope in the four major lobes (frontal, parietal, temporal, occipital). Cortical gray matter follows an inverted U-shape developmental course with greater regional variation than white matter. For instance, frontal gray matter volume peaks at about age 11.0 years in girls and 12.1 years in boys, whereas temporal gray matter volume peaks at about age at 16.7 years in girls and 16.2 years in boys. The dorsal lateral prefrontal cortex, important for controlling impulses, is among the latest brain regions to mature without reaching adult dimensions until the early 20s. The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.
Recent findings of spike timing-dependent plasticity (STDP) have stimulated much interest among experimentalists and theorists. Beyond the traditional correlation-based Hebbian plasticity, STDP opens up new avenues for understanding information coding and circuit plasticity that depend on the precise timing of neuronal spikes. Here we summarize experimental characterization of STDP at various synapses, the underlying cellular mechanisms, and the associated changes in neuronal excitability and dendritic integration. We also describe STDP in the context of complex spike patterns and its dependence on the dendritic location of the synapse. Finally, we discuss timing-dependent modification of neuronal receptive fields and human visual perception and the computational significance of STDP as a synaptic learning rule.
A possible relationship between cognitive abilities and white matter structure as assessed by magnetic resonance diffusion tensor imaging (DTI) was investigated in the pediatric population. DTI was performed on 47 normal children ages 5-18. Using a voxelwise analysis technique, the fractional anisotropy (FA) and mean diffusivity (MD) were tested for significant correlations with Wechsler full-scale IQ scores, with subject age and gender used as covariates. Regions displaying significant positive correlations of IQ scores with FA were found bilaterally in white matter association areas, including frontal and occipito-parietal areas. No regions were found exhibiting correlations of IQ with MD except for one frontal area significantly overlapping a region containing a significant correlation with FA. The positive direction of the correlation with FA is the same as that found previously with age, and indicates a positive relationship between fiber organization and/or density with cognitive function. The results are consistent with the hypothesis that regionally specific increased fiber organization is a mechanism responsible for the normal development of white matter tracts.
Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.
Neuronal activity influences myelination of the brain, but the molecular mechanisms involved are largely unknown. Here, we report that oligodendrocyte progenitor cells (OPCs) express functional adenosine receptors, which are activated in response to action potential firing. Adenosine acts as a potent neuron-glial transmitter to inhibit OPC proliferation, stimulate differentiation, and promote the formation of myelin. This neuron-glial signal provides a molecular mechanism for promoting oligodendrocyte development and myelination in response to impulse activity and may help resolve controversy on the opposite effects of impulse activity on myelination in the central and peripheral nervous systems.
The brain is remarkably responsive to its interactions with the environment, and its morphology is altered by experience in measurable ways. Histological examination of the brains of animals exposed to either a complex ('enriched') environment or learning paradigm, compared with appropriate controls, has illuminated the nature of experience-induced morphological plasticity in the brain. For example, this research reveals that changes in synapse number and morphology are associated with learning and are stable, in that they persist well beyond the period of exposure to the learning experience. In addition, other components of the nervous system also respond to experience: oligodendrocytes and axonal myelination might also be permanently altered, whereas changes in astrocytes and cerebrovasculature are more transient and appear to be activity- rather than learning-driven. Thus, experience induces multiple forms of plasticity in the brain that are apparently regulated, at least in part, by independent mechanisms.
A variety of anatomical features suggest that functional activity in the nervous system can influence the process of myelination, yet direct evidence of this is lacking. Research by Zalc and colleagues shows that myelination of optic nerve is inhibited by a neurotoxin that blocks action potential activity and is stimulated by a toxin that increases impulse activity, suggesting that impulse activity is necessary for initiating myelination during development of the optic nerve. Research by Fields and colleagues, using electrical stimulation of axons, shows that low frequency impulse activity inhibits myelination of dorsal root ganglion neurons, but high frequency impulse activity has no effect. This results from reduced expression of a cell adhesion molecule on the stimulated axons that is critical for inducing myelination. Together these studies support the conclusion that impulse activity can influence the process of myelination, probably through more than one molecular mechanism operating during discrete steps in the myelination process.
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