Increased Microglial Activity In The White Matter Tracts Of The Aged Mouse Brain
To investigate the effect of aging on the microglia phenotype, age-related changes in microglia morphology were visualized by staining with IBA1. During aging, IBA1 immunoreactivity particularly increased particularly in white matter regions, such as corpus callosum . Morphological changes were also visible in gray matter regions of the brain at 27 months . Microglia cell clusters and changes in microglia morphology were clearly observed at 24 months, particularly in white matter areas like corpus callosum, anterior commissure, dorsal fornix, and cerebellar white matter, compared to 4-month-old mice . In addition to white matter-enriched regions, the cortex, hippocampus , hypothalamus, and spinal cord gray matter regions also showed changes in microglia morphology in aged mouse brain. Microglia cell clusters and the presence of beaded structures in processes of IBA1-positive microglia were exclusively found in the aged mouse brain.
White Matter In Psychiatric Disease
Certain conditions have long been associated with damage to the myelin sheath. For instance, the immune systems of individuals with Guillain-Barré syndrome and multiple sclerosis attack myelin, causing a gradually worsening weakness that can end in paralysis.
But more recently, changes in myelin have been linked to a number of psychiatric conditions, such as schizophrenia, major depression, autism, post-traumatic stress disorder, Alzheimers disease, dyslexia, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourettes. White matter has even been implicated in stuttering and tone deafness.
One of the most studied psychiatric conditions in relation to white matter is schizophrenia. One
of oligodendrocytes in some regions of the brain.
In fact, more recently, it has been shown that white matter tracts across the majority of the brain are disrupted in schizophrenia.
Schizophrenia tends to develop during adolescence, a time when the forebrain is finally being given its myelin coating. Some scientists believe that this might be more than a coincidence.
Whether these changes are the cause of the condition or a consequence of the abnormal brain function is yet to be understood, but it is probably an intertwined two-way path. Evidence of this came in a paper published in 2007 by Dr. Gabriel Corfas. He showed that disrupting the genetic control of oligodendrocytes could produce striking behavioral changes similar to those seen in schizophrenia.
Wanted: A Behavioral Neurology Of White Matter
The study of higher functions in humans requires consideration of all the brains neural tissues. Long neglected as a contributor to the organization of cognitive and emotional operations, white matter is the object of intense, intriguing, and increasingly fruitful efforts to improve our understanding. Studying people with white matter disorders to correlate their brain lesions with specic behavior changes promises a wealth of insights. Increasingly, this method will be complemented by sophisticated neuroimaging techniques that yield detailed visualization of white matter tracts as they participate in the cognitive and emotional operations of distributed neural networks.
In practical terms, an appreciation of the brain-behavioral importance of white matter disorders can greatly benet patients, especially as early recognition and treatment often determine an outcome. In theoretical terms, further study of white matter and its disorders expands our knowledge of the brain as an extraordinarily complex structure in which the connectivity provided by white matter is central to cognition, emotion, and consciousness itself.
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Acute Isolation Of Microglia From Adult Mouse Brain
Animals were sacrificed by means of saline perfusion under inhalation anesthesia with 4% isoflurane in oxygen. The brains were isolated and kept in ice-cold dissection solution . For the isolation of microglia from white and gray matter regions, the forebrain and cerebellum were cut into approximately 1.5 mm thick coronal sections. Dissection was performed under magnifying glass with the tissue wet with medium A. Corpus callosum, cerebellar white matter were pooled from 2 to 3 animals of a particular age group and considered as one sample from that age group. From the collected tissue, microglia were isolated at high purity using a discontinuous Percoll gradient . All steps of the isolation and staining procedure were performed at 4°C. Briefly, the tissue was transferred to a tissue homogenizer , and mechanically dissociated. The brain homogenate was then filtered through a 70 m cell strainer, washed with medium A, and pelleted by centrifugation . The density gradient separation was done using Percoll solutions with different densities . To obtain a stock isotonic Percoll solution , nine volume parts of Percoll were mixed with one volume part of 10x HBSS. Percoll solutions with the appropriate concentration were prepared via dilution of 100% Percoll with 1x PBS.
White Matter Anisotropy Changes With Age In Prefrontal Regions
As children mature, they become more capable of executing tasks that require complex cognitive functioning. Contributing to this cognitive development are capabilities such as working memory, inhibition and attention. These capabilities improve with age , and have been attributed at least partially to prefrontal circuitry . Synaptic proliferation and pruning, as well as ongoing myelination, are assumed to be important mechanisms that shape cognitive development . Supporting this assumption, there is evidence for gray matter loss, beginning around puberty, in sensorimotor areas that spreads during late adolescence into higher-order cortical regions, including the dorsolateral prefrontal cortex . In another study, frontal cortical thinning was related to improved ability to retain and retrieve verbal and spatial information .
Our data suggest that beyond the processes that occur in the prefrontal cortex, cognitive improvement with age may be due to more coherent, or more myelinated, non-cortical white matter circuitry in prefrontal regions.
This typical brain development may be altered in developmental disorders that cause impairments in working memory, attention or inhibition . Interestingly, prefrontal white matter has been implicated in these disorders .
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How Could This Be Diagnosed
Your primary care physician can make an analysis of white matter disease by examining your manifestations and utilizing imaging tests. Numerous individuals with white matter disease go to their primary care physician grumbling of equilibrium issues. In the wake of posing you some particular inquiries about your side effects, your primary care physician will probably arrange an X-ray.
An X-ray is an output of your mind utilizing attractive reverberation. To see the white matter of your mind, your primary care physician may utilize a particular kind of X-ray called T2 Flair. This kind of X-ray helps your primary care physician see the subtleties of the white matter in your cerebrum, just as distinguish any anomalies inside the white matter.
These anomalies appear as spots that are more brilliant than their environmental factors. Both the measure of these unusual brilliant spots just as where the white matter irregularities are found will help your PCP make a conclusion.
The last analysis is made after your primary care physician thinks about the X-ray, your cardiovascular wellbeing, and any manifestations you have.
White Matter Anisotropy Changes With Age In The Basal Ganglia And Between The Basal Ganglia And Thalamus
Previous research has shown that the striatum undergoes structural changes during childhood and adolescence . These changes are thought to result from normal dendritic pruning, myelination, and changes in iron deposition. Our study complements these findings and suggests that white matter tracts originating or terminating in the basal ganglia and thalamus also show temporal maturation during childhood and adolescence. The basal ganglia and thalamus have extensive reciprocal connections with the frontal cortex and the anterior cingulate . These pathways have an important regulatory influence on the cortex and are known to be involved in emotional, behavioral, cognitive, and motor functions as well as in attention, learning and memory .
The increases in anisotropy with age we observed in the basal ganglia, thalamus and prefrontal cortex may reflect maturation of these basal-ganglia-thalamo-cortical pathways. Accordingly, during normal development, improvement in attention, motor skills, cognitive ability and memory, as well as in the modulation of behavior, may be a result of white matter maturation and improved signal transmission in brain circuits connecting the prefrontal cortex and the basal ganglia.
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Phase Diagram Of Optimal Designs
In previous sections we derived conditions under which various designs are optimal in terms of minimizing conduction delays. Specifically, HD is optimal if ND2 2 and PD is optimal if ND2 2 and 1. Next, we illustrate these results on a phase diagram in terms of basic network parameters such as the local wire diameter d, the number of local connections per neuron n, global axon diameter D, and the total number of neurons in the brain N. To obtain the phase diagram, in the first-order perturbation theory, we substitute the expression for into ND2 2, and find that PD is optimal when 1/2D/n1/6d 1. In the linear-log space of Figure 6, this expression corresponds to the regime above the thick green line.
In this phase diagram, we show parameter regimes in which HD or PD are optimal in terms of the global axon diameter D, local wire diameter d, total neuron number N, and the number of local connections per neuron n. We assume n = 104 and d = 1 m for all empirical data points. Values of D in mammalian brains are from S. S. H. Wang and , and values of N in the neocortex are from . Value of N in rat neostriatum is from . For birds, we assume N = 107.
White Matter Density Changes With Age
Within the regions of interest derived from the FA analysis results, there were prominent white matter density increases with age in the internal capsule, in inter-thalamic pathways, and in the corpus callosum. Additional white matter density increases with age were observed in prefrontal regions, in the arcuate fasciculus, and in visual pathways .
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Late Infantile Metachromatic Leukodystrophy
This condition occurs between 12 and 18 months of age and causes deterioration in thinking skills, speech, and coordination.
Within 2 years, children can develop gait and posture problems, as well as blindness and paralysis. It is not possible to stop disease progression, and it is typically fatal within 6 months to 4 years of symptom onset.
People with the juvenile form of metachromatic leukodystrophy, which develops between the age of 4 and adolescence, may live for many years after diagnosis.
Postmortem Human Brain Tissues
Postmortem human brain samples used for studying the aging effect were obtained from the Department of Pathology, VU University . The rapid autopsy regimen of the Netherlands Brain Bank in Amsterdam was used to acquire subcortical white matter samples from 15 control donors without any known neurodegenerative condition , with the approval of the medical ethical committee of the VU University Medical Center, and specific approval for the present study. All patients and control donors had given informed consent for autopsy and the use of brain tissue for research purposes.
TABLE 1. Patient data.
TABLE 3. Antibodies for flow cytometry.
TABLE 5. Antibodies for Immunohistochemistry.
Brain samples from patients who died of acute inflammatory diseases were used as positive controls for detecting neuroinflammation. Seven brain samples were obtained from the Pathology division of the Department of Pathology and Medical Biology, University Medical Center Groningen . All donors had given written informed consent for autopsy and use of their brain tissue for research purposes. The use of samples were approved by the medical committee of University Medical Center Groningen.
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Is It Really That Simple
Not quite. Whilst the above division is physiologically accurate on a system level, there are a mix of cell types present in both gray and white matter.Gray matter also contains:
- Neuropil a mix of dendrites, unmyelinated axons, and glia
White matter also contains:
- Oligodendrocytes glial cells which produce myelin
Comparison Of Microglia Activation Upon Systemic Inflammation And Load
To evaluate the neuroinflammation status in aging and AD, we first investigated brain sections from people who died of acute inflammatory diseases, which were used as positive controls for the further study. In addition, we compared a young non-demented control group and a group of LOAD tissue samples . For each group, we compared the expression of IBA1, HLA-DR, and CD68 between the patients who died of acute inflammatory disease and those who died without systemic inflammation . In the non-demented group, white-matter microglia of samples with acute infection showed deramified morphology and expressed significantly higher levels of IBA1 and CD68. However, the expression of HLA-DR did not change significantly in the white matter between acute-inflammation- and non-inflammation groups . In the LOAD group, the expression of IBA1, HLA-DR, and CD68 was not significantly different between inflammation- and non-inflammation groups . In conclusion, these data indicate that acute inflammation in addition to neurodegeneration did not further alter microglial morphology.
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How Does The Brain Work
The brain sends and receives chemical and electrical signals throughout the body. Different signals control different processes, and your brain interprets each. Some make you feel tired, for example, while others make you feel pain.
Some messages are kept within the brain, while others are relayed through the spine and across the bodys vast network of nerves to distant extremities. To do this, the central nervous system relies on billions of neurons .
White Matter Consists Mainly Of Nerve Fibers
White matter appears white because the protective wrapping around nerve fibers, or axons, is a pale, fatty tissue called myelin.
Axons are like the electric wires of the brain,” says Rhonda Voskuhl, MD, professor of neurology at the UCLA Brain Research Institute and director of the UCLA Multiple Sclerosis Program in Los Angeles.
In MS, the immune system attacks the myelin in the brain, spinal cord, and optic nerves. The attack causes inflammation that eventually leads to sclerosis, which is the medical term for scarring.
“When MS attacks these parts of the brain, it’s like stripping the rubber off the wires. That slows down conduction speed and causes the types of MS symptoms that come and go, says Dr. Voskuhl. An attack may last for weeks or months, but then the inflammation cools off, and the area recovers completely or partially.
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Lobes Of The Brain And What They Control
Each brain hemisphere has four sections, called lobes: frontal, parietal, temporal and occipital. Each lobe controls specific functions.
- Frontal lobe. The largest lobe of the brain, located in the front of the head, the frontal lobe is involved in personality characteristics, decision-making and movement. Recognition of smell usually involves parts of the frontal lobe. The frontal lobe contains Brocas area, which is associated with speech ability.
- Parietal lobe. The middle part of the brain, the parietal lobe helps a person identify objects and understand spatial relationships . The parietal lobe is also involved in interpreting pain and touch in the body. The parietal lobe houses Wernickes area, which helps the brain understand spoken language.
- Occipital lobe. The occipital lobe is the back part of the brain that is involved with vision.
- Temporal lobe. The sides of the brain, temporal lobes are involved in short-term memory, speech, musical rhythm and some degree of smell recognition.
Combining Local And Global Connections Increases Conduction Delays
After having considered conduction delays in local and global connections separately, now we are in a position to analyze how they are combined in the brain. Here we argue that the main difficulty in integration arises when introducing global connections into local networks.
We adopt a model combining both local and global connections proposed by Ruppin et al. and Murre and Sturdy . In this model, each neuron connects with n local neurons and sends a global axon to another arbitrarily chosen local network in the brain. For simplicity, we neglect specificity and assume that local connections are made with nearest n neurons located in a sphere of radius centered on a given neuron, where is given by Equation 4. Although local and global connections may be highly specific , this approximation is sufficient to understand brain segregation into white and gray matter.
where t is conduction delay in unperturbed local circuits given by Equation 6. As before, numerical factors are neglected in the spirit of the scaling estimate.
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Scaling Of The Mammalian Neocortex
The theoretical framework developed in this paper allows us to derive several scaling laws for the neocortex. Provided our perturbation theory is valid, the total neocortical volume G should be proportional to the total nonwire volume. Assuming that nonwire contains mostly synapses, we have
First, from Equation 62, we find that the synaptic density, s, is a constant, since s ~ Nn/G ~ 1/vs, where the average synapse volume vs is assumed to be a constant in different cortical areas and across different species. The prediction of constant synapse density is supported by experimental observations from a small number of taxa so far, and was used as a starting point to derive scaling laws of the mammalian brains in several theoretical papers .
Second, we find the neuronal density ~ N/G ~ N/ ~ 1/n. Since scales inversely as the cubic root of total brain volume V across different mammalian species , and the cortical volume is loosely proportional to the brain volume , we find n ~ V1/3, N ~ V2/3, and n ~ N1/2. We note that Braintenberg has previously proposed the square-root relationship between n and N. He assumed that the cerebral cortex could be divided into N1/2 compartments and each compartment contains N1/2 neurons. The local connectivity within a compartment is almost all-to-all, and every compartment is connected to every other one by a global axon.