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15.8C: The Human Central Nervous System - Biology

15.8C: The Human Central Nervous System - Biology



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The central nervous system is made up of the spinal cord and brain. It also conducts motor information from the brain to our various effectors: skeletal muscles, cardiac muscle, smooth muscle, glands, and serves as a minor reflex center. The brain receives sensory input from the spinal cord as well as from its own nerves (e.g., olfactory and optic nerves) and devotes most of its volume (and computational power) to processing its various sensory inputs and initiating appropriate and coordinated motor outputs

White Matter vs. Gray Matter

Both the spinal cord and the brain consist of white matter (bundles of axons each coated with a sheath of myelin) and gray matter (masses of the cell bodies and dendrites each covered with synapses). In the spinal cord, the white matter is at the surface, the gray matter inside. In the brain of mammals, this pattern is reversed. However, the brains of "lower" vertebrates like fishes and amphibians have their white matter on the outside of their brain as well as their spinal cord.

The Meninges

Both the spinal cord and brain are covered in three continuous sheets of connective tissue, the meninges. From outside in, these are thedura mater — pressed against the bony surface of the interior of the vertebrae and the cranium, the arachnoid, nd the pia mater. The region between the arachnoid and pia mater is filled with cerebrospinal fluid (CSF).

The Interstitial Fluid of the Central Nervous System

The cells of the central nervous system are bathed in a fluid, called cerebrospinal fluid (CSF), that differs from that serving as the interstitial fluid (ISF) of the cells in the rest of the body. Cerebrospinal fluid leaves the capillaries in the choroid plexus of the brain. It contains far less protein than "normal" because of the blood-brain barrier, a system of tight junctions between the endothelial cells of the capillaries. This barrier creates problems in medicine as it prevents many therapeutic drugs from reaching the brain. CSF flows uninterrupted throughout the central nervous system through the central cerebrospinal canal of the spinal cord and through an interconnected system of four ventricles in the brain.

CSF returns to the blood through lymphatic vessels draining the brain.In mice, the flow of CSF increases by 60% when they are asleep. Perhaps one function of sleep is to provide the brain a way of removing potentially toxic metabolites accumulated during waking hours.

The Spinal Cord

31 pairs of spinal nerves arise along the spinal cord. These are "mixed" nerves because each contain both sensory and motor axons. However, within the spinal column, all the sensory axons pass into the dorsal root ganglion where their cell bodies are located and then on into the spinal cord itself. All the motor axons pass into the ventral roots before uniting with the sensory axons to form the mixed nerves.

The spinal cord carries out two main functions:

  • It connects a large part of the peripheral nervous system to the brain. Information (nerve impulses) reaching the spinal cord through sensory neurons are transmitted up into the brain. Signals arising in the motor areas of the brain travel back down the cord and leave in the motor neurons.
  • The spinal cord also acts as a minor coordinating center responsible for some simple reflexes like the withdrawal reflex.

The interneurons carrying impulses to and from specific receptors and effectors are grouped together in spinal tracts.

Crossing Over of the Spinal Tracts

Impulses reaching the spinal cord from the left side of the body eventually pass over to tracts running up to the right side of the brain and vice versa. In some cases this crossing over occurs as soon as the impulses enter the cord. In other cases, it does not take place until the tracts enter the brain itself.

The Brain

The brain of all vertebrates develops from three swellings at the anterior end of the neural tube of the embryo. From front to back these develop into the

  • forebrain (also known as the prosencephalon — shown in light color)
  • midbrain (mesencephalon — gray)
  • hindbrain (rhombencephalon — dark color) The human brain is shown from behind so that the cerebellum can be seen.

The human brain receives nerve impulses from the spinal cord and 12 pairs of cranial nerves:

  • Some of the cranial nerves are "mixed", containing both sensory and motor axons
  • Some, e.g., the optic and olfactory nerves (numbers I and II) contain sensory axons only
  • Some, e.g. number III that controls eyeball muscles, contain motor axons only.

The Hindbrain

The main structures of the hindbrain (rhombencephalon) are the medulla oblongata, pons and cerebellum.

Medulla oblongata

The medulla looks like a swollen tip to the spinal cord. Nerve impulses arising here rhythmically stimulate the intercostal muscles and diaphragm thus making breathing possible. It also regulate heartbeats and regulate the diameter of arterioles thus adjusting blood flow. The neurons controlling breathing have mu (µ) receptors, the receptors to which opiates, like heroin, bind. This accounts for the suppressive effect of opiates on breathing. Destruction of the medulla causes instant death.

Pons

The pons seems to serve as a relay station carrying signals from various parts of the cerebral cortex to the cerebellum. Nerve impulses coming from the eyes, ears and touch receptors are sent on the cerebellum. The pons also participates in the reflexes that regulate breathing.

The reticular formation is a region running through the middle of the hindbrain (and on into the midbrain). It receives sensory input (e.g., sound) from higher in the brain and passes these back up to the thalamus. The reticular formation is involved in sleep, arousal (and vomiting).

Cerebellum

The cerebellum consists of two deeply-convoluted hemispheres. Although it represents only 10% of the weight of the brain, it contains as many neurons as all the rest of the brain combined. Its most clearly-understood function is to coordinate body movements. People with damage to their cerebellum are able to perceive the world as before and to contract their muscles, but their motions are jerky and uncoordinated. So the cerebellum appears to be a center for learning motor skills (implicit memory). Laboratory studies have demonstrated both long-term potentiation (LTP) and long-term depression (LTD) in the cerebellum.

The Midbrain

The midbrain (mesencephalon) occupies only a small region in humans (it is relatively much larger in "lower" vertebrates). We shall look at only three features:

  • the reticular formation: collects input from higher brain centers and passes it on to motor neurons.
  • the substantia nigra: helps "smooth" out body movements; damage to the substantia nigra causes Parkinson's disease.
  • the ventral tegmental area (VTA): packed with dopamine-releasing neurons that are activated by nicotinic acetylcholine receptors and whose projections synapse deep within the forebrain.The VTA seems to be involved in pleasure: nicotine, amphetamines and cocaine bind to and activate its dopamine-releasing neurons and this may account at least in part for their addictive qualities.

The midbrain along with the medulla and pons are often referred to as the "brainstem".

The Forebrain

The human forebrain (prosencephalon) is made up of a pair of large cerebral hemispheres, called the telencephalon. Because of crossing over of the spinal tracts, the left hemisphere of the forebrain deals with the right side of the body and vice versa. A group of structures located deep within the cerebrum make up the diencephalon.

Diencephalon

We shall consider four of its structures:

  • Thalamus.
    • All sensory input (except for olfaction) passes through these paired structures on the way up to the somatic-sensory regions of the cerebral cortex and then returns to them from there.
    • Signals from the cerebellum pass through them on the way to the motor areas of the cerebral cortex.
  • Lateral geniculate nucleus (LGN). All signals entering the brain from each optic nerve enter a LGN and undergo some processing before moving on the various visual areas of the cerebral cortex.
  • Hypothalamus.
    • The seat of the autonomic nervous system. Damage to the hypothalamus is quickly fatal as the normal homeostasis of body temperature, blood chemistry, etc. goes out of control.
    • The source of 8 hormones, two of which pass into the posterior lobe of the pituitary gland.
  • Posterior lobe of the pituitary.
    Receives vasopressin and oxytocin from the hypothalamus and releases them into the blood.

The Cerebral Hemispheres

Each hemisphere of the cerebrum is subdivided into four lobes visible from the outside:

  • frontal
  • parietal
  • occipital
  • temporal

Hidden beneath these regions of each cerebral cortex is

  • An olfactory bulb; they receive input from the olfactory epithelia.
  • A striatum; they receive input from the frontal lobes and also from the limbic system (below). At the base of each striatum is a nucleus accumbens (NA).

The pleasurable (and addictive) effects of amphetamines, cocaine, and perhaps other psychoactive drugs seem to depend on their producing increasing levels of dopamine at the synapses in the nucleus accumbens (as well as the VTA).

  • a limbic system; they receives input from various association areas in the cerebral cortex and pass signals on to the nucleus accumbens. Each limbic system is made up of a:
    • hippocampus. It is essential for the formation of long-term memories.
    • The amygdala appears to be a center of emotions (e.g., fear). It sends signals to the hypothalamus and medulla which can activate the flight or fight response of the autonomic nervous system.In rats, at least, the amygdala contains receptors for
      • vasopressin whose activation increases aggressiveness and other signs of the flight or fight response
      • oxytocin whose activation lessens the signs of stress

      The amygdala receives a rich supply of signals from the olfactory system, and this may account for the powerful effect that odor has on emotions (and evoking memories).

Mapping the Functions of the Brain

It is estimated that the human brain contains some 86 billion (8.6 x 1010) neurons averaging 10,000 synapses on each; that is, almost 1015 connections. How to unravel the workings of such a complex system?

Several methods have been useful.

Histology

Microscopic examination with the aid of selective stains has revealed many of the physical connections created by axons in the brain.

The Electroencephalograph (EEG)

This device measures electrical activity (brain "waves") that can be detected at the surface of the scalp. It can distinguish between, for example, sleep and excitement. It is also useful in diagnosing brain disorders such as a tendency to epileptic seizures.

Damage to the Brain

Many cases of brain damage from, for example,

  • strokes (interruption of blood flow to a part of the brain)
  • tumors in the brain
  • mechanical damage (e.g., bullet wounds)

have provided important insights into the functions of various parts of the brain.

Example 1:

Battlefield injury to the left temporal lobe of the cerebrum interferes with speech.

Example 2: Phineas P. Gage

In 1848, an accidental explosion drove a metal bar completely through the frontal lobes of Phineas P. Gage. Not only did he survive the accident, he never even lost consciousness or any of the clearly-defined functions of the brain. However, over the ensuing years, he underwent a marked change in personality. Formerly described as a reasonable, sober, conscientious person, he became — in the words of those observing him — "thoughtless, irresponsible, fitful, obstinate, and profane". In short, his personality had changed, but his vision, hearing, other sensations, speech, and body coordination were unimpaired. (Similar personality changes have since been often observed in people with injuries to their prefrontal cortex.)

The photograph (courtesy of the Warren Anatomical Museum, Harvard University Medical School) shows Gage's skull where the bar entered (left) and exited (right) in the accident (which occurred 12 years before he died of natural causes in 1861).

Stimulating the exposed brain with electrodes

There are no pain receptors on the surface of the brain, and some humans undergoing brain surgery have volunteered to have their exposed brain stimulated with electrodes during surgery. When not under general anesthesia, they can even report their sensations to the experimenter. Experiments of this sort have revealed a band of cortex running parallel to and just in front of the fissure of Rolando that controls the contraction of skeletal muscles. Stimulation of tiny spots within this motor area causes contraction of the muscles.

The area of motor cortex controlling a body part is not proportional to the size of that part but is proportional to the number of motor neurons running to it. The more motor neurons that activate a structure, the more precisely it can be controlled. Thus the areas of the motor cortex controlling the hands and lips are much larger than those controlling the muscles of the torso and legs. A similar region is located in a parallel band of cortex just behind the fissure of Rolando. This region is concerned with sensation from the various parts of the body. When spots in this sensory area are stimulated, the patient reports sensations in a specific area of the body. A map can be made based on these reports. When portions of the occipital lobe are stimulated electrically, the patient reports light. However, this region is also needed for associations to be made with what is seen. Damage to regions in the occipital lobe results in the person's being perfectly able to see objects but incapable of recognizing them.

The centers of hearing — and understanding what is heard — are located in the temporal lobes.

CT = X-ray C omputed T omography

This is an imaging technique that uses a series of X-ray exposures taken from different angles. Computer software can integrate these to produce a three-dimensional picture of the brain (or other body region). CT scanning is routinely used to quickly diagnose strokes.

PET = P ositron-E mission T omography

This imaging technique requires that the subject be injected with a radioisotope that emits positrons.

  • Water labeled with oxygen-15 (H215O) is used to measure changes in blood flow (which increases in parts of the brain that are active). The short half-life of 15O (2 minutes) makes it safe to use.
  • Deoxyglucose labeled with fluorine-18. The brain has a voracious appetite for glucose (although representing only ~2% of our body weight, the brain receives ~15% of the blood pumped by the heart and consumes ~20% of the energy produced by cellular respiration when we are at rest). When supplied with deoxyglucose, the cells are tricked into taking in this related molecule and phosphorylating it in the first step of glycolysis. But no further processing occurs so it accumulates in the cell. By coupling a short-lived radioactive isotope like 18F to the deoxyglucose and using a PET scanner, it is possible to visualize active regions of the brain.

The images in fig. 15.8.3.8 (courtesy of Michael E. Phelps from Science 211:445, 1981) were produced in a PET scanner. The dark areas are regions of high metabolic activity. Note how the metabolism of the occipital lobes (arrows) increases when visual stimuli are received.

Similarly, sounds increase the rate of deoxyglucose uptake in the speech areas of the temporal lobe.

The image in fig. 15.8.3.9 on the right (courtesy of Gary H. Duncan from Talbot, J. D., et. al., Science 251: 1355, 1991) shows activation of the cerebral cortex by a hot probe (which the subjects describe as painful) applied to the forearm.

Most cancers consume large amounts of glucose (cellular respiration is less efficient than in normal cells so they must rely more on the inefficient process of glycolysis). Therefore PET scanning with 18F-fluorodeoxyglucose is commonly used to monitor both the primary tumor and any metastases.

MRI = M agnetic R esonance I maging

This imaging technique uses powerful magnets to detect magnetic molecules within the body. These can be endogenous molecules or magnetic substances injected into a vein.

FMRI = Functional Magnetic Resonance Imaging

fMRI exploits the changes in the magnetic properties of hemoglobin as it carries oxygen. Activation of a part of the brain increases oxygen levels there increasing the ratio of oxyhemoglobin to deoxyhemoglobin.

The probable mechanism:

  • The increased demand for neurotransmitters must be met by increased production of ATP.
  • Although this consumes oxygen (needed for cellular respiration),
  • it also increases the blood flow to the area.
  • So there is an increase and not a decrease in the oxygen supply to the region, which provides the signal detected by fMRI.

Magnetoencephalography (MEG)

MEG detects the tiny magnetic fields created as individual neurons "fire" within the brain. It can pinpoint the active region with a millimeter, and can follow the movement of brain activity as it travels from region to region within the brain. MEG is noninvasive requiring only that the subject's head lie within a helmet containing the magnetic sensors.


Functions of the Central Nervous System

The central nervous system consists of the brain and the spinal cord. It is part of the overall nervous system that also includes a complex network of neurons, known as the peripheral nervous system. The nervous system is responsible for sending, receiving, and interpreting information from all parts of the body. The nervous system monitors and coordinates internal organ function and responds to changes in the external environment.

The central nervous system (CNS) functions as the processing center for the nervous system. It receives information from and sends information to the peripheral nervous system. The brain processes and interprets sensory information sent from the spinal cord. Both the brain and spinal cord are protected by a three-layered covering of connective tissue called the meninges.

Within the central nervous system is a system of hollow cavities called ventricles. The network of linked cavities in the brain (cerebral ventricles) is continuous with the central canal of the spinal cord. The ventricles are filled with cerebrospinal fluid, which is produced by specialized epithelium located within the ventricles called the choroid plexus. Cerebrospinal fluid surrounds, cushions, and protects the brain and spinal cord from trauma. It also assists in the circulation of nutrients to the brain.


Basic biology of coronaviruses

Coronaviruses are a large and expanding family of membrane-enveloped, positive sense, single-strand RNA viruses, with genomes ranging in molecular weight from 25 to 32 kb. They are roughly 120 to 140 nm in diameter, inclusive of spike (S) proteins that protrude from their envelopes to a height of approximately 20 nm, producing the corona-like appearance on electron microscopy (EM) that gives the family its name. An excellent review of the viral and cellular biology of coronaviruses can be found in Fields Virology (Perlman and Masters, 2020). Within the subfamily Coronavirinae, there are four genuses—alpha, beta, gamma, and delta—defined by intra-genus conservation of seven domains in the viral replicase/transcriptase within each genus, species are defined by a minimum of 90% amino acid sequence homology in these conserved regions (Perlman and Masters 2020).

Currently, with one exception, mammalian coronaviruses are members of the alpha and beta genuses (Table 1). The global distribution of coronavirus species is “driven” by bat populations, which constitute the major viral reservoir. In regions of the world where bats are highly diverse, such as portions of Asia and Africa, host switching is the dominant mechanism of viral evolution (Anthony et al. 2017). Thus, zoonotic transmission to man has higher likelihood in these geographic areas, as host switching is its predicate. There are currently seven known human coronaviruses (Table 1) almost all have zoonotic origins, or are known to circulate in animals (Anthony et al. 2017 Andersen et al. 2020). Animal surveillance has been suggested as a useful technique in combatting epidemic viruses: for example, both SARS-CoV and SARS-CoV-2 can infect and replicate in domestic cats, with transmission from infected to uninfected cats occurring through respiratory droplets (Martina et al. 2003 Shi et al. 2020). As these common pets may be in community as well as in close contact with their owners at home, they may conceivably provide an adjunctive mechanism for virus tracking.

Canonical features of coronaviruses include a large RNA molecule with 5′ capping and polyadenylated tail and an invariant order of major genes encoding (from 5′ to 3′): the replicase/transcriptase complex–spike (S) protein–envelope (E) protein–membrane (M) protein–nucleocapsid (N) protein. The S, E, and M proteins are embedded in the viral envelope, with M being most abundant, whereas N is the sole protein of the helical viral nucleocapsid (Fig. 1). As the genome is capped and polyadenylated, it is ready for translation once introduced into cell cytoplasm. Dependent upon viral species, a variety of smaller open reading frames (ORFs) for accessory genes are found within intergenic regions of the structural proteins. In a subset of betacoronaviruses (murine hepatitis virus (MHV), bovine CoV, and human viruses HCoV-OC43 and HCoV-HKU1), a fifth major protein, hemagglutinin-esterase (HE), may be encoded. The HE protein, expressed on the viral membrane envelope, is capable of binding sialic acid residues on cell surface glycoproteins and glycolipids and has acetylesterase activity it is a close relative of the influenza C virus HE and is thought to reflect a shared common ancestor (Perlman and Masters 2020). In mice inoculated with some strains of MHV, an important animal model of neuropathogenesis, HE mediates enhanced neurovirulence, and higher HE expression is associated with neuronal infection and more severe pathology (Lai and Stohlman 1992). Importantly, through adaptation to human infection, the HEs found in HCoVs OC43 and HKU1 are thought to have lost their receptor/lectin binding functions (Bakkers et al. 2017). The HE protein is not found in SARS viruses.

a Canonical organization of the coronavirus genome. Major genes present in all coronaviruses, from 5′ to 3′, encode the replicase/transcriptase complex, the spike (S) protein, the envelope (E) protein, the membrane (M) protein, and the nucleocapsid protein (N). In some variants, a fifth major protein, the hemagglutinin-esterase (HE), is represented proximal to the spike protein. b Organization of the coronavirus virion. S, E, and M proteins are embedded in the membrane envelope, whereas the N protein encases the viral genome

Cell tropism is an essential aspect of establishing CNS disease and, for coronaviruses, the S protein dominates this characteristic (albeit not exclusively, as demonstrated by the HE protein). It is the major cell surface binding molecule, responsible for membrane fusion and viral genome entry into the cell. The S protein is a homotrimer, with each of its polypeptides containing a large, bipartite ectodomain: S1, which is highly variable and mediates receptor binding, and S2, which is more conserved and functions in membrane fusion between virus and host cell (Perlman and Masters 2020). Virus entry into the cell occurs either in an “early” pathway of direct fusion between viral envelope and the cell membrane or a “late” pathway in which receptor binding leads to endocytosis in clathrin-coated pits, which then transition to acidified endosomes (Fig. 2). Proteolytic priming of the S protein is an essential step in the viral life cycle, both at cell entry and upon maturation and egress large conformational changes on cell entry are needed to expose the S2 fusion peptide. This occurs through two cleavages, at the boundary of S1/S2 and at a second S2’ site. Thus, cell entry requires not only S protein binding to its cognate receptor but also exposure to a cellular protease for priming, either in the context of the cell membrane or the endosome. While cathepsins provide this proteolytic processing in the endosome, a variety of proteases may be active at the cell surface. The cell surface serine protease TMPRSS2 can provide priming function for all human coronaviruses, and there is evidence to suggest that wild type viruses prefer the TMPRSS2-mediated cell surface pathway to cathepsin-mediated endosomal pathways of cell entry (Shirato et al. 2018 Kleine-Weber et al. 2018 Hoffmann et al. 2020). TMPRSS2 is not expressed in human brain, and it is unclear what impact this absence might have on neurotropism (Jacquinet et al. 2001). Of interest, SARS-CoV-2 has acquired a polybasic site at the S1–S2 junction that allows for effective cleavage by furin, an endoprotease abundantly expressed in CNS, located on cell membranes, in endosomes, and also cleaved and secreted (Andersen et al. 2020 Thomas 2002 Braun and Sauter 2019).

Cell entry pathways utilized by coronaviruses. Coronaviruses enter cell cytoplasm via two receptor-mediated pathways that require proteolytic processing of the S protein this priming exposes the S2 domain, which participates in membrane fusion and allows injection of viral genome into the cell. The “early pathway” occurs exclusively at the cell membrane, and the “late pathway” entails viral internalization via clathrin-coated pits that transition to acidified endosomes. In the late pathway, S antigen priming occurs both at the cell membrane (via proteases such as TMPRSS2 and furin), as well as in the endosome, utilizing endosomal proteases (cathepsins) and potentially furin. Therapies that interfere with acidification of the endosome, such as hydroxychloroquine, interfere with this pathway. In the early pathway, viral binding to the receptor and proteolytic processing of the S protein are accomplished entirely by proteases at the cell surface, which allows direct entry of the viral genome into cytoplasm.

The major cell receptors for epidemic human coronaviruses are for SARS-CoV and SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) and for MERS, dipeptidyl peptidase 4 (DPP4) (Table 1). For continuously circulating human species, HCoV-NL63 uses the ACE2 receptor, and neutralizing antibodies to HCoV-NL63 have been found in virtually all adults (Hofmann et al. 2005). Furthermore, HCoV-NL63 and SARS-CoV recognize the same motifs in ACE2 with their receptor binding domains (Perlman and Masters 2020). While sharing a common receptor, characteristics of viral–host cell interactions vary between species: SARS-CoV binds and downregulates ACE2 with greater efficiency than HCoV-NL63, and SARS-CoV-2 demonstrates even greater binding efficiency for ACE2 than SARS-CoV (Hofmann et al. 2005 Glowacka et al. 2010 Wang et al. 2020). HCoV-229E uses aminopeptidase N (APN, also known as CD13) as its major receptor, and binding motifs for HCoVs OC43 and HKU1 are N-acetyl-9-O-acetylneuraminic acids (9-O-acetylsialic acids) (Hulswit et al. 2019 Perlman and Masters 2020).

The importance of cell receptor expression to neuropathogenesis is demonstrated by transgenic animal models. Mice can be infected with SARS-CoV and support viral replication, but generally fail to develop the severe disease seen in humans. When mice are made transgenic for human ACE2 (hACE2), their disease becomes lethal, characterized by severe pulmonary and extra-pulmonary infection, including the brain (McCray et al. 2007). When hACE2 transgenic mice are inoculated intranasally with SARS-CoV, virus spreads through the olfactory bulbs into the brain and then rapidly disseminates via trans-neuronal pathways, with viral protein detected in brain regions with first- and second-order connections to the olfactory system (McCray et al. 2007). Neuronal infection is subsequently followed by neuronal loss (McCray et al. 2007 Netland et al. 2008). This model is remarkable in that expression of the transgene is very low in brain, contrasting with the extensive neuronal infection (McCray et al. 2007). Furthermore, the model does not demonstrate a cellular immune response—that is, inflammatory cell infiltration/meningoencephalitis does not develop (Netland et al. 2008). A similar model featuring brain infection has been created for MERS-CoV, with mice transgenic for human DPP4 (hDPP4) (Li et al. 2016a). In contrast to mouse models of SARS, hDPP4 transgenics have high levels of receptor expression in brain and, when inoculated intranasally with MERS-CoV, show viropathic effects in neurons with most significant early damage in regions unrelated to olfaction these mice also demonstrate perivascular inflammatory cell infiltrates (Li et al. 2016a). Both SARS-CoV and MERS-CoV transgenic mouse models highlight the importance of receptor expression to neuropathogenesis, raising the important question of whether HCoV receptors are found in human brain.

While present on pulmonary, nasopharyngeal, and gastrointestinal epithelia, the ACE2 protein was not described in human brain parenchyma in the single publication documenting its distribution (Hamming et al. 2004). However, ACE2 was demonstrated in brain vascular (arterial and venous) endothelia and smooth muscle, as well as systemic vasculature (Hamming et al. 2004). In human heart, vascular pericytes demonstrate abundant ACE2 expression (Chen et al. 2020). While reports of brain parenchymal ACE2 are often cited in the literature, none have entailed analysis of human tissue. Neuronal cytoplasmic ACE2 has been described in a rabbit model of heart failure and in a transgenic mouse model of hypertension with human renin and angiotensin transgenes, with no explanation regarding its cytosolic localization (Kar et al. 2010 Doobay et al. 2007). In a study of ontogeny, ACE2 immunoreactivity was detected in mouse ependyma at E18.5, with no mention of neuronal staining (Song et al. 2012). ACE2 activity and mRNA have been detected in mouse and rat brain tissues without cellular localization, and cultured rat astrocytes can express ACE2 mRNA and protein (Sakima et al. 2005 Gallagher et al. 2006 Elased et al. 2008). Thus, it remains an open question whether ACE2 is sufficiently expressed and can act as a SARS receptor in non-vascular human brain parenchyma, both under normal conditions and in disease states known to regulate ACE2 expression and/or activity, such as diabetes and hypertension (Batlle et al. 2010 South et al. 2020).

In contrast, DPP4 (also known as T cell activation antigen CD26) can more confidently be localized to human CNS in an age-dependent manner and is a protein implicated in immunologic signaling, processing/inactivation of neuropeptides, and glucose homeostasis. It is the target for inhibition by gliptin therapies in diabetes, which are also in trial for dementia and stroke (Wicinski et al. 2019). The DPP4 protein has been detected in abundance in human fetal and perinatal brains and in neuroblasts and neurons, capillaries, ependyma, and choroid plexus (Bernstein et al. 1987). With maturation, its expression decreases and, in adult brain, appears largely confined to vascular structures this is in contrast to a study in normal mice, which detected protein in cortical astrocytes (Bernstein et al. 1987 Mentzel et al. 1996). Only small amounts of DPP4 mRNA are detected in adult human brain relative to other tissues such as the placenta, kidney, lung, and liver (Abbott et al. 1994). Detection in brain parenchyma is also described in human disease: in progressive multiple sclerosis (MS), DPP4 is upregulated in microglia of normal appearing white matter, whereas within MS plaque, expression is in monocytes/macrophages (Elkjaer et al. 2019). One report of increased DPP4 in neurons and plaques of Alzheimer’s disease is published, but is restricted to immunohistochemical analysis without other means of confirmation (Bernstein et al. 2018).

Whereas ACE2 and DPP4 are primarily vascular in the healthy adult human brain, strong expression of APN (CD13) is seen both in mature brain parenchyma and vasculature (Larrinaga et al. 2005 Smyth et al. 2018). In cerebral cortex, APN activity can be isolated in diverse subcellular fractions, including nuclei and synaptic membranes the protein is a component of the system regulating neuropeptide activity (Larrinaga et al. 2005). In brain vasculature, APN is a marker of pericytes and smooth muscle cells (Smyth et al. 2018). APN has also been identified in primary cultures of human olfactory neuroepithelia, which by virtue of their location offer a potential CNS portal for respiratory viruses (Vawter et al. 1996). It is currently hypothesized, but not proven, that transaxonal spread from infected olfactory neuroepithelium is a CNS portal for HCoVs, as has been described in animal models of diverse viral pathogens and in SARS-HCoV-infected hACE2 transgenic mice (Van Riel et al. 2015 McCray et al. 2007). Finally, the human brain contains the highest concentration of sialic acids of any organ, found predominantly as sialoglycolipids (Wang and Brand-Miller 2003 Schnaar et al. 2014). O-Acetylated forms constitute several percent of total brain gangliosides, although 9-O forms may be specific for neurogenesis and migrating neuroblasts and, thus, not generally available for binding in adults (Schnaar et al. 2014).

While expression of most major coronavirus receptors may not be significant in adult human brain parenchyma, another consideration for viral neurotropism is the fact that viruses commonly exploit alternate receptors to gain cell access, albeit with lesser efficiency. For example, human CD209L (L-SIGN), expressed on endothelial cells of liver and lymph node and also on primary isolated human brain microvascular endothelia, can act as a receptor for SARS-CoV (Jeffers et al. 2004 Mukhtar et al. 2002). It is currently unclear if SARS-CoV-2 is capable of exploiting L-SIGN, and alternate receptor mechanisms are not thoroughly investigated for HCoVs only receptor motifs are available for two human species (OC43 and HKU1) (Table 1). A clinical isolate of one of those species, HCoV-OC43-Paris, can infect murine olfactory bulbs with dissemination throughout brain the cell receptor mediating this neurovirulence is unknown (St-Jean et al. 2004).

It is also important to recognize that direct infection of neurons, glia, and/or olfactory neuroepithelia is not a necessary predicate for neuropathogenesis (Table 2). In addition to direct parenchymal infection, mechanisms that can contribute to CNS damage are direct infection of endothelial cells increased thrombophilia with vascular occlusion in the absence of direct infection para-infectious immune-mediated damage as in acute disseminated necrotizing or demyelinating encephalopathy and in the course of inflammatory cell migration across the blood–brain and blood–CSF barriers, meningoencephalitis. Many viruses gain access to the CNS via immune cell trafficking across the blood–brain and blood–CSF barriers.

SARS and MERS coronaviruses are both capable of infecting human monocyte-derived macrophages and dendritic cells however, with SARS, in vitro infections are abortive and do not support production of virions, whereas with MERS, productive infections and rising viral titers are seen (Zhou et al. 2015 Cheung et al. 2005 Tseng et al. 2005). In vitro, different characteristics of monocyte-derived cell infection are associated with differences in the pattern of immune response and cytokine elaboration (Zhou et al. 2015 Perlman and Dandekar 2005 Law et al. 2005). Whether these differences have nervous system relevance is unclear (Zhou et al. 2015 Cameron et al. 2008). SARS and MERS also directly infect T lymphocytes (Perlman and Dandekar 2005 Zhou et al. 2015). In tissue samples of individuals with SARS-CoV, virions, viral proteins, and nucleic acids have been identified in macrophages, T lymphocytes, granulocytes, and, to lesser degrees, B lymphocytes and NK cells (Gu et al. 2005 Shi et al. 2005 Nicholls et al. 2006). In contrast, a single autopsy report of an individual dying with MERS-CoV failed to demonstrate viral antigen in pulmonary macrophages despite detection in pneumocytes (Ng et al. 2016). Finally, non-epidemic HCoVs are also capable of infecting human monocyte/macrophages in vitro, with variable abilities to replicate (Desforges et al. 2007 Cheung et al. 2005). Thus, regardless of systemic pathogenicity, for human coronaviruses, immune cell trafficking is a potential mechanism for establishing CNS disease.


Systems Biology: BAC to the Future

In a step forward into the future of gene expression research, molecular biologists and neurobiologists have joined forces to map the genes that control brain structure and neural circuits. The project, called the Gene Expression Nervous System Atlas, or GEN-SAT, maps mouse genes that are also present in the human genome as expressed in the central nervous system. According to project director Nathaniel Heintz, head of the Laboratory of Molecular Biology at The Rockefeller University, New York, GENSAT means that researchers studying degenerative conditions such as Parkinson disease can now have access to gene expression within the brain without having to do their own molecular genetics from scratch. Some unexpected insights have already come to light, giving neuroscientists new places to search for the roots of cognitive impairment.

GENSAT is sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and is based at The Rockefeller University, although prescreening of candidate genes is conducted by Tom Curran, chair of developmental neurobiology at St. Jude Children’s Research Hospital in Memphis, Tennessee. In situ hybridization is used to screen thousands of candidates to find genes that are active in the central nervous system. Of these, an advisory committee selects 250 genes each year for in-depth analysis by the Rockefeller group. Says Heintz, “Having an advisory committee means this research is done with consensus from many parts of the neuroscience community.”

Information gathered through the project is posted in a public database at http://www.gensat.org/. Started in 2003, the GENSAT database contains detailed information for 300 genes and is updated regularly. With the goal of analyzing 250 genes yearly, the project is planned to run for at least several more years, according to Heintz.

The main tools of GENSAT are bacterial artificial chromosomes (BACs), which are simple loops of bacterial DNA that reproduce outside the cell. BACs adeptly incorporate chunks of introduced DNA from other species, which are preserved and duplicated along with the BACs. The Human Genome Project relied on BACs to help map the human genome.

To measure gene activity and patterns of gene expression in the brain, the GEN-SAT team inserts a reporter gene for enhanced green fluorescent protein into each BAC. When genes are active, the enhanced green fluorescent protein glows bright green. Each BAC is then inserted into eggs harvested from mice, and the eggs are implanted into foster mothers.

The resulting offspring carry the BAC throughout their bodies in all of the cells that express the corresponding gene. Groups of mice are sacrificed at three time points—two of which correspond to critical periods of human central nervous system development𠅊nd their brains and spinal cords are analyzed. Mapping gene activity at three different points reveals how the cells migrate and interact.

The first samples are taken when the mouse embryos are 15 days old, which corresponds to the sixth to seventh month of human gestation. 𠇍uring this period the cortex forms, and defects that lead to malformations occur,” explains project codirector Mary Beth Hatten, head of the Laboratory of Developmental Neurobiology at Rockefeller. The second time point, at 7 days after birth, is equivalent to 6𠄸 months of age in humans. At this age, interconnections form in the cerebellum, which controls movement, and in the hippocampus, which controls short-term memory. The final observations are made on adult mouse brains at age 7 months, which are similar to those of 30-year-old humans.

Findings published in the 30 October 2003 issue of Nature reveal some of the surprising connections the GENSAT project is uncovering. For example, people with DiGeorge syndrome, a congenital condition marked by heart defects and learning disorders, lack a gene called Gscl. Heintz, Hatten, and other GENSAT researchers discovered that Gscl is produced by neurons in the interpeduncular nucleus, the brain region that also regulates rapid-eye-movement sleep. Another finding reported in this paper relates to the striatum, which degenerates in patients with Parkinson disease. In end-stage Parkinson disease, up to 95% of so-called spiny neurons are lost. Until recently, the striatum had been the only place where spiny neurons were found, says Hatten. Yet, the BAC method identified vectors that can be used to separately analyze spiny neurons that project to the substantia nigra and the globus pallidus.

The GENSAT methods can also monitor the effects of environmental toxicants, such as lead, on brain development. “You can expose the BAC mice to any environmental condition you want, to see how the migration and maturation of neurons changes,” says Hatten.

“The tools and mouse lines provided by this project allow the neuroscience community to perform detailed studies of each gene,” says Laura Mamounas, the GEN-SAT project officer at the NINDS. “GEN-SAT also may serve as a model for future gene expression projects.”

Indeed, BAC mice can be used to screen gene activity in other organs. The BAC mice are made available to other researchers who are interested in performing systematic studies of gene expression. Scientists in other specialties are “just starting to bootstrap our efforts to get their particular information,” says Heintz.


2.12.1 Human Nervous System

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1 . Question

Which of the following statement is meant by body coordination?

  • Coordination of the organs and systems in the body to produce appropriate response.
  • Coordination of the body by peripheral nervous system.
  • The response of the organs to external stimuli.
  • The response of the body that is controlled by endocrine system.

Well done! You are correct.

The correct answer is ”
Coordination of the organs and systems in the body to produce appropriate response”.

2 . Question

The diagram shows the composition of the human nervous system.

  • Endocrine system
  • Peripheral system
  • Lymphatic system
  • Respiratory system

Well done! You are correct.

The correct answer is “Peripheral system”.

3 . Question

The diagram shows the human nervous system.

Well done! You are correct.

The correct answer is “Spinal nerve”.

4 . Question

The diagram below shows a motor neurone.

The part label X and Y are?

  • X = Dendron, Y = Axon
  • X = Dendrite, Y = Dendron
  • X = Axon, Y = Dendrite
  • X = Dendron, Y = Dendrite

Well done! You are correct.

The correct answer is “X = Dendron, Y = Axon”.

5 . Question

The diagram below shows a type of neurone.

What is the function of this neurone?

  • Carry impulse from the sensory neurone to the motor neurone across the spinal cord.
  • Carry impulse from the sensory organ to the brain.
  • Carry impulse from the relay neurone going out to the effectors.
  • Carry impulse from the effectors to the central nervous system.

Well done! You are correct.

Carry impulse from the sensory neurone to the motor neurone across the spinal cord”.

6 . Question

The diagram shows a type of neurone.

Well done! You are correct.

The correct answer is “Sensory neurone”.

7 . Question

The diagram shows a gap between two neurones.

What is the name of the gap labelled M?

Well done! You are correct.

The correct answer is “Synapse”.

8 . Question

The diagram shows the human nervous system.

Which of the parts A, B, C or D is a spinal cord?

Well done! You are correct.

9 . Question

The diagram shows three types of neurone.

  • P: Sensory neurone Q: Relay neurone R: Motor neurone
  • P: Relay neurone Q: Motor neurone R: Sensory neurone
  • P: Motor neurone Q: Sensory neurone R: Relay neurone
  • P: Relay neurone Q: Sensory neurone R: Motor neurone

Well done! You are correct.

The correct answer is:
P: Relay neurone
Q: Motor neurone
R: Sensory neurone

10 . Question

The diagram shows a type of neurone.

What is the function of this neurone?

  • Carries impulse from central nervous system to effector
  • Carries impulse from sensory organ to central nervous system
  • Transmit impulses from sensory neurone to motor neurone
  • Carry impulse from the effectors to the central nervous system

Well done! You are correct.

The correct answer is “Carries impulse from central nervous system to effector”.

11 . Question

The diagram shows a type of neurone.

What is the function of the part labeled X?

  • Increase the speed of impulse transmission
  • Carry impulses away from the cell body
  • Carry impulses towards the cell body
  • Controls all activities of the neurone

Well done! You are correct.

The correct answer is “Increase the speed of impulse transmission”.

12 . Question

The diagram shows a type of neurone.

What is the function of this neurone?

  • Carry impulse from the sensory organ to the central nervous system.
  • Carry impulse from the sensory neurone to the motor neurone across the spinal cord.
  • Carry impulse from the relay neurone going out to the effectors.
  • Carry impulse from the effectors to the central nervous system.

Well done! You are correct.

The correct answer is “Carry impulse from the sensory organ to the central nervous system.”

13 . Question

What is the function of synapse?

  • Allow impulse to be transmitted in one direction
  • Prevents the leakage of impulses
  • Speed up of impulses transmission
  • Transmit impulses from other neurone to cell body

Well done! You are correct.

The correct answer is “Allow impulse to be transmitted in one direction”.


Abstract The human central nervous system CNS is very vulnerable

Abstract: The human central nervous system (CNS) is very vulnerable to perturbations, since it performs sophisticated biological processes and requires cooperation from multiple neural cell types. Subtle interference from exogenous chemicals may initiate severe developmental neural toxicity (DNT). Human pluripotent stem cells (hPSCs)-based neural differentiation assays provide effective and promising tools to help evaluate potential DNT caused by those toxicants. In fact, the specification of neural lineages in vitro recapitulates critical CNS developmental processes, such as patterning, differentiation, neurite outgrowth, synaptogenesis, myelination, etc.

Hence, the established protocols to generate a repertoire of neural derivatives from hPSCs greatly benefit the in vitro evaluation of DNT. In this review, we first dissect the various differentiation protocols inducing neural cells from hPSCs, with an emphasis on the signaling pathways and endpoint markers defining each differentiation stage. We then highlight the studies with hPSC-based protocols predicting developmental neural toxicants, and discuss remaining challenges. We hope this review can provide insights for the further progress of DNT studies.

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Keywords: Developmental neural toxicity (DNT) human pluripotent stem cells (hPSCs) neural differentiation neurons astrocytes oligodendrocytes.

Developmental neural disorders, such as autism, attention-deficit hyperactivity disorder, dyslexia, mental retardation, and other impairments of the nervous system, affect millions of children worldwide, and may cause lifelong disabilities (Grandjean and Landrigan, 2014 Landrigan et al., 2012). Although some of the developmental neural disorders may have a genetic origin, accumulating evidence suggests a significant contribution of industrial chemicals on the onset and/or progression of these medical conditions. For instance, environmental pollutants including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (BDEs), dioxins and phthalates, have been proved to cause developmental neural toxicity (DNT) in in vitro and in vivo studies (Colborn et al.

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, 1993 Costa and Giordano, 2007 Miodovnik et al., 2014). Because of that, many applications of these chemicals have been strictly limited or even abandoned. Nevertheless, these recognized developmental neural toxicants may just be the tip of the iceberg.

Several animal models based on rats, mice, zebrafish, rabbits, etc., have been used to represent humans for in vivo screening of toxicants causing developmental neural disorders. Though animal assays have played important roles in toxicology and provided abundant information on potential developmental neural toxicants, their ethical issues and innate drawbacks, such as interspecies variations, and being labor intensive and time consuming, make them defective (Faiola et al., 2015 Hartung, 2009 Hou et al., 2013). In vitro assays with human primary cells derived from individual donors, represent suitable alternatives to live animal experiments, to assess DNT (Moors et al., 2009 Schreiber et al., 2010). However, the availability of human primary cells is limited, making large-scale chemical screens impractical (Hou et al., 2013).

Pluripotent stem cells (PSCs), including mouse/human embryonic stem cells (ESCs) and mouse/human induced pluripotent stem cells (iPSCs), have the capacity to proliferate extensively and differentiate into multi-lineages, providing excellent alternative methods for DNT assays in vitro (Faiola et al., 2015 Yao et al., 2016). The very first well-known system applying PSCs for developmental toxicity assays was the embryonic stem cell test (EST). It consisted in cytotoxicity analyses of proliferating and differentiating mouse ESCs, as well as control embryonic fibroblasts, to predict potential embryo-toxicants (Genschow et al., 2004 Scholz et al., 1997). Inspired by the EST assay, the Embryonic Stem cell-based Novel Alternative Testing Strategies (ESNATS) project was launched in 2008, with the goal of establishing a battery of developmental toxicity tests in vitro with DNT as one of the major tasks (Rovida et al., 2014). Nowadays, the advances in our understanding of the molecular mechanisms of neural specification in vivo and in vitro, advocate for the use of hPSCs for developing and implementing accurate, high-performance and high-throughput methods to screen developmental neural toxicants. In this review, we analyze the various neural differentiation protocols from hPSCs, with a focus on their signaling pathways and endpoint markers defining each differentiation stage, and highlight their applications in developmental neural toxicants’ screenings, without forgetting the challenges we must overcome to allow these assays to become the gold standards for DNT evaluations.


Chapter Thirteen - Effects of Cannabis and Cannabinoids in the Human Nervous System

The endocannabinoid (EC) system, consisting of ECs, their synthesizing and degrading enzymes, specific transmembrane EC transporters and receptors, is located in both excitatory and inhibitory synapses of all the classical neurotransmitter types throughout the central and peripheral nervous systems, where it acts as a retrograde signaling mechanism to inhibit further release of transmitter. This form of synaptic plasticity is a major component of both rapid short-term and sustained long-term adaptive responses that underlie such processes as homeostasis, learning, memory, and extinction. The functional effects on any given pathway can be either inhibitory or excitatory, depending on whether excitatory (e.g., glutamatergic) or inhibitory (e.g., GABAergic) modulation normally predominates in that pathway. However, the dose-effect curves of EC activity are in many instances biphasic, because sustained strong activity leads to EC receptor desensitization and down-regulation, resulting in progressive loss or even reversal of the effect. Therefore the effects of cannabis and exogenous cannabinoids, of both plant and synthetic origin, are in many cases different from, or even opposite to, those of the EC system.

The functional effects of the EC system and of exogenous cannabinoids are compared with respect to neuronal growth and maturation, neuroprotection against toxic and traumatic damage, sensory pathways, nausea and vomiting, appetite and food intake, the sleep/wake cycle, affective responses and mood states, motor control, seizure activity and cognitive functions. Effects in laboratory animals are compared to those in humans, including both actual and potential therapeutic effects and adverse effects. The therapeutic effects in most instances correspond to the low-dose actions of the EC system, whereas the adverse effects generally correspond to the high-dose range. The exogenous cannabinoids are less selective in their actions than the EC system because they act on a much wider range of EC receptors throughout the nervous system. It is concluded that for most potential therapeutic applications the future will lie with the development of highly selective site-specific agents that act on individual components of the EC system, rather than on the whole system.


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Human Central Nervous System

This human anatomy ClipArt gallery offers 265 illustrations of the central nervous system, including external and dissected views of the brain and spinal cord.

Projection Fibers of the Cerebrum

Diagram of the projection fibers of the cerebrum. Labels: B, motor (pyramidal) tract C, body-sense…

Surface of the Cerebrum

The surface of the cerebrum.

Top View of the Cerebrum

"The cerebrum seen from above, showing the hemispheres." — Ritchie, 1918

Sections of Cervical Spinal Cord

Views of section of cervical cord. Labels: A, anterior surface B, right side C, upper surface D,…

Convolutions of the Brain

View of the appearance of the tortuous elevations (convolutions) of the brain, seen from above.

Corpus Callosum

Middle vertical section of the callous body (corpus callosum). The inner left side of the brain is also…

Corpus Collosum

The corpus callosum, exposed from above and the right half dissected to show the course taken by its…

Corpus Quadrigeminum

Section through anterior corpus quadrigeminum and part of optic thalamus. Labels: s, aqueduct of Sylvius…

Cortical Gray Matter of the Cerebrum

The five layers of the cortical gray matter of the cerebrum. 1, Superficial layer with abundance of…

Dura Mater and Cranial Sinuses

The dura mater and cranial sinuses. 1, falx cerebri 2, tentorium 3, superior longitudinal sinus 4,…

Dura of the Brain

Crucial prolongation of the dura. Frontal section passing through the tentorium cerebelli. The torcular…

Encephalon

"Diagram of Vertebrate Encephalon . in longitudinal vertical section. Mb, mid-brain in front of it…

Encephalon

"Diagram of Vertebrate Encephalon . in horizontal section. Mb, mid-brain in front of it all is forebrain,…

Outline of the Encephalon

Plan in outline of the encephalon, as seen from the right side. The parts are represented as separated…

Fissure of Rolando

Fissure of Rolando fully opened up, so as to exhibit the interlocking gyri and deep annectant gyrus…

Fornix

The fornix is a paired structure consisting of bilaterally symmetrical halves composed of longitudinally…

Profile View of Fornix

Diagrammatic profile view of the fornix.

Fourth Ventricle with the Medulla Oblongata and the Corpora Quadrigemina

Fourth ventricle with the medulla oblongata and the corpora quadrigemina. The roman numbers indicate…

Gray Matter of Cerebellum

Section through the gray matter of the human cerebellum.

The head is the part of the body that contains the brain and the organs of the special senses.

Cross Section of Head 1 cm above Orbit

Section of head 1 cm above orbit.

Cross Section of Head 2 cm above Supraorbital Orbit

Section of head 2 cm above orbit.

Cross Section of Head 3 cm above Supraorbital Border

Section of head 3 cm above supraorbital border.

Cross Section of Head 4 cm above Supraorbital Border

Section of head 4 cm above supraorbital border.

Head and Neck, Section of

Vertical middle section of head and neck showing the opening through the Eustachian tube, and its relations…

A Vertical Section of the Head and Neck

A vertical section of the head and neck through the mesial line, in order to show the opening of the…

Cross Section of Head at Supraorbital Margin

Section of the head at supraorbital margin.

Incision of the Head Showing Gasserian Ganglion

Exposure of the Gasserian ganglion and middle meningeal artery though a flap incision of the scalp and…

Cross Section of Head Through Lower Portion of Orbit

Section of the head through lower portion of orbit.

Cross Section of Head

Section two inches above supraorbital border. Upper surface. The (*) on right indicates subaponeurotic…

Frontal Section of the Head

Frontal section of the head passing through the parietal and occipital cerebral lobes and he cerebellar…

Head, Section of

Section of the head showing the greater scythe, the horizontal apophysis of the dura mater between the…

Sectional view of the Head

Section through the Head and Neck on the Median Line. 1. Medulla Oblongata 2. Pons 3. Right lobe of…

Frontal Section Through Hippocampus and Gyrus and Dentatus

Part of frontal section across left hippocampus and gyrus dentatus, showing arrangement of cell layers.

Human Brain

"The Brain is the encephalon, or center of the nervous system and the seat of consciousness and volition…

Internal Capsule

Diagrammatic representation of the internal capsule (as seen in horizontal section).

Medulla

Dorsal or posterior view of the medulla, fourth ventricle, and mesencephalon. Labels: p.n., line of…

Section Through Medulla in Olivary Region

Transverse section through the human medulla in the lower olivary region.

Section Through Medulla in Olivary Region

Transverse section through the the middle of the olivary region of the human medulla or bulb.

Medulla Oblongata

"The spinal cord and medulla oblongata. A, from the ventral, and B, from the dorsal aspect C to H,…

The Medulla Oblongata

The medulla oblongata (brain stem).

Medulla Oblongata

Anterior or dorsal section of the medulla oblongata in the region of the superior pyramidal decussation.…

Medulla Oblongata

Section of the medulla oblongata at about the middle of the olivary body. f.l.a., anterior median fissure…

Section of the Medulla Oblongata

Section of the medulla oblongata at the pyramidal tracts.

Section of the Medulla Oblongata

Section of the medulla oblongata at the lower end of the olives

Section of the Medulla Oblongata

Section of the medulla oblongata at about the middle of the olive.

Transverse Section Through Closed Part of Medulla

Transverse section through the closed part of the human medulla immediately above the decussation of…

Section of Mesencephalon at Inferior Quadrigeminal Body

Transverse section through the mesencephalon at the level of the inferior quadrigeminal body.

Section of Mesencephalon at Superior Quadrigeminal Body

Transverse section through the mesencephalon at the level of the superior quadrigeminal body.

Section of Mesencephalon

Diagrammatic view of the cut surface of a transverse section through the upper part of the mesencephalon.

Section Through the Midbrain

Section of the midbrain through the level of the inferior quadrigeminal body.

Section Through the Midbrain

Section of the midbrain through the level of the superior quadrigeminal body.

Muscle of the Hippocampus

Transverse section of one of the trunk muscles of the Hippocampus, stained in chloride gold.

Nerve Cells

Forms of nerve cells. Labels: A, from spinal ganglion B, from ventral horn of spinal cord C, pyramidal…

Nerve Cells from Spinal Ganglia

This illustration shows nerve cells from spinal ganglia.

Nerve Ganglia (Spinal)

Nerve Ganglia, or Knots (sing. Ganglion Knot) occur as collections of nerve cells on the course of…

Nerve Roots

"The spinal cord and nerve-roots. A, a small portion of the cord seen from the ventral side B, the…

Seventh Dorsal Nerve

Throughout the dorsal region, the spinal cord presents a uniform girth and a very nearly circular outline…

Nerves

The cord-like structures composed of delicate filaments by which sensation or stimulative impulses are…


NG2-positive glia in the human central nervous system

Cells that express the NG2 chondroitin sulfate proteoglycan and platelet-derived growth factor receptor alpha (NG2 glia) are widespread in the adult human cerebral cortex and white matter and represent 10–15% of non-neuronal cells. The morphology and distribution of NG2 glia are similar to, but distinct from, both microglia and astrocytes. They are present as early as 17 weeks gestation and persist throughout life. NG2 glia can be detected in a variety of human central nervous system (CNS) diseases, of which multiple sclerosis is the best studied. NG2 glia show morphological changes in the presence of pathology and can show expression of the Ki-67 proliferation antigen. The antigenic profile and morphology of NG2 glia in human tissues are consistent with an oligodendrocyte progenitor function that has been well established in rodent models. Most antibodies to NG2 do not stain formalin-fixed paraffin-embedded tissues. Advances in our understanding of NG2 glia in human tissues will require the development of more robust markers for their detection in routinely processed human specimens.