Understanding neuroanatomy, histology, and physiology are integral for medical students who are laying the foundation of neurology. For residents and fellows, reviewing such material serves as a refresher of topics not regularly confronted in clinical practice but are often seen on in-service and board examinations. In this section, we will cover CNS histology, anatomy as well as briefly mention some associated neurological syndromes.

Authors: James Eaton MD, Steven Tessier, Brian Hanrahan MD

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Central Nervous System Histology

Illustration and microscope slide with H&E stain showing glial cells and neurons
Illustration (left) and microscope slide with H&E stain (right) showing glial cells and neurons

Glial cells

  • May be classified as macroglia (which include astrocytes, oligodendrocytes, and ependymal cells) and microglia.
  • Provide support and protection for neurons.
  • Glial cells outnumber neurons 10 to 1 in the central nervous system.

Astrocytes

  • The largest glial cell.
  • Support function of neurons in multiple ways:
      • Regulates interstitial fluid.
      • Modulates signals that regulate blood flow in response to neuronal activity.
      • Provides structural support; astrocytes are essential components of the blood-brain barrier and of glial-limiting membranes (aka glial limitans) that line the pia matter and parenchymal vasculature.
      • Provides nutritional support via glycogen storage.
      • Protects against the death of neurons by activating antioxidant pathways.

  • Immunohistochemical staining for glial fibrillary acidic protein (GFAP) can be used to identify astrocytes.
  • Glial fibrillary acid proteins (GFAP) make up intracellular intermediate filaments located in astrocytic processes.
  • Astrocytes become reactive and hypertrophic from injury, infection, or chronic neurodegeneration. Reactive hypertrophic astrocytes upregulate GFAP, proliferate, and form a glial scar that surrounds damaged CNS tissue.

    • Microscopic images of astrocytes

    Oligodendrocytes

    • Responsible for the formation of myelin in the central nervous system
      • Myelin provides electrical insulation that allows for saltatory conduction, the speed of which is determined by the length of the internodal myelin segments. Larger axonal diameters conduct faster than smaller diameters.
      • Oligodendrocytes have condensed, rounded nuclei and unstained cytoplasm.

  • Leukodystrophies typically involve metabolic and lysosomal pathways that are necessary for normal oligodendrocyte function.
  • Progressive Multifocal Leukoencephalopathy (PML) likely involves lytic infection of oligodendrocytes to induce demyelination.
  • Oligodendrogliomas are primary brain tumors with a classic ‘chicken wire’ appearance on histopathology.

    • Oligodendrocytes vs. Oligodendroglioma

    Astrocyte-Oligodendrocyte crosstalk

    • Communication occurs by direct cell-cell gap junctions, as well as secreted signaling molecules.
    • The importance of astrocyte-oligodendrocyte communication is made apparent in primary astrocytopathies such as Alexander disease, and osmotic demyelination syndrome.

    Ependymal cells

    • Produces and facilitates the movement of cerebrospinal fluid (CSF).
    • Lines the ventricles and central canal of the spinal cord.
    • Resembles simple cuboidal or columnar epithelium with some cilia and microvilli on histopathology.

    Microglia

    • The primary immune cell of the central nervous system.
      • Responsible for antigen presentation,
      • Activates in response to tissue damage and ischemic injury. Once activated, becomes a motile, phagocytic cell (adept for neuronophagia) which forms reactive oxygen species and secretes cytokines and proteases.
    • The smallest and rarest glial cell.
    • Derived from bone marrow/monocytes and enter the CNS in the perinatal period.
      • All other glial cells and neuronal cells are derived from neural tube cells.

    Neuronal cells

    • Responsible for receiving, integrating, and propagating information to other cells.
    • Contains three parts; dendrites, cell body, and axon(s).
      • Dendrites
        • Receive information from other neurons at synapses.
        • Changes in dendritic spines are critical for neural plasticity that occurs during development and learning.
      • Cell body
        • The main synthetic and trophic center of the cell, it contains the nucleus and most organelles.
        • Easily identified by a large central and euchromatic nucleus with a prominent nucleolus.
        • Basophilic clumps of polyribosomes are called Nissl bodies.
      • Axons
        • Conducts information to muscles, glands, or neurons.
        • Axons terminate at synapses.
    • There are a few named neurons to be aware of:
      • Pyramidal Cells: The prototype cerebral neuron, present in the cortex and hippocampus, with large triangular cell bodies.
      • Stellate Cells: Described as GABAergic inhibitory interneurons that control Purkinje cell activity in the cerebellum.

      • Purkinje cells: Large distinct neurons in the cerebellum with a prominent pink cell body and extensive dendritic tree.
        • These degenerate in various cerebellar degeneration syndromes (e.g. alcohol, chronic phenytoin use, or anti-Yo paraneoplastic syndromes).

    Anatomy of the Neuron

    Neuron Axon Dendrite Myelin and Nodes of Ranvier Neurology Anatomy Diagram for Board Exam Review

     

    Normal neuron on a microscope specimen
    Normal Neuron (arrow)
    • Most neurons contain multiple dendrites and only one axon.
    • Neurons can be easily identified with silver staining on microscopic slides which impregnate neurofilaments.
      • Intracellular neurofibrillary tangles can suggest a neurodegenerative disease such as Alzheimer’s disease.
    • When the axons of a nerve are severely damaged, Wallerian degeneration occurs.
      • Axonal fibers distal to the area of injury degenerate, while proximal fibers survive.

    Neuron Action Potential

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    Neuron Action Potential

    Normal neurons vs. an Alzheimer’s disease patient with neurofibrillary tangles

    • Neurofibrillary tangles tend to occur in the amygdala, hippocampus, and temporal association cortices.
    • Senile (amyloid) plaques tend to occur in the neocortex of the frontal, parietal, and temporal lobes.

    The Blood-Brain Barrier

    Diagram of The blood-brain barrier
    The Blood-Brain Barrier
    • The blood-brain barrier is a highly selective barrier that maintains CNS homeostasis.
    • CNS microvasculature contains continuous non-fenestrated blood vessels that tightly regulate the flow of proteins, ions, and cells between blood and parenchyma. It is responsible for the influx of nutrients and the efflux of waste, toxins, and drugs.
      • The integrity of the barrier depends on the close apposition of the astrocytic endfeet to blood capillaries, endothelial cells, and a thick basement membrane.
        • Endothelial cells form the inner walls of the blood vessel and create tight junctions which function as a fairly impermeable barrier. Transport occurs via either active or passive transport.
          • Gases (CO2, O2), water, and non-polar, small, lipophilic molecules (ethanol, nicotine, diazepam) are able to pass into the brain via simple diffusion.
          • Larger, polar, and/or hydrophilic molecules such as glucose, electrolytes, and amino acids require transport into the brain.
        • The aquaporin 4 channels targeted in Neuromyelitis Optica (NMO) are present in the astrocytic foot processes.
    • Integral neighboring cells include pericytes and smooth muscle cells.
    • Damage to the blood-brain barrier can occur secondary to ischemic, traumatic, inflammatory, infectious, or metabolic derangements and leads to vasogenic edema.
      • Cytotoxic edema results from cellular swelling, membrane breakdown, and cell death.
        • These types of edema are sometimes seen together. In the case of ischemic stroke, cytotoxic edema is seen in the hyperacute/acute phase, but vasogenic edema due to consequent damage to the blood-brain barrier can develop as soon as 6+ hours later, and reaches its peak at 1-2 days post-insult.
    • Areas in the brain which lack a blood-brain barrier:
      • Area postrema
        • The chemoreceptor trigger zone for vomiting.
        • Found in the dorsomedial medulla oblongata.
      • Pineal gland
        • A solid organ that is located in the roof of the third ventricle and secretes melatonin.
        • Cysts are commonly found in the pineal gland.
          • Can lead to obstructive hydrocephalus.
      • Posterior pituitary
        • Responsible for the secretion of oxytocin and vasopressin.
      • Choroid plexus
        • See below.

    Cerebral Spinal Fluid and the Ventricular System

    • CSF is produced from the choroid plexus and is reabsorbed by arachnoid granulations.
      • Ependymal cells lining the lateral and third ventricles form the choroid plexus and are responsible for CSF production.
        • Pathologies associated with ependymal cells include malignancy (ependymomas/subependymomas), ependymal cysts, and infection (ependymitis). 
      • Arachnoid granulations are small pouches of arachnoid mater that project through the dural wall of the major venous sinuses.
        • Most CSF is reabsorbed into the superior sagittal sinus.

    Diagram of The Ventricular System
    The Ventricular system
    • After production, CSF enters the third ventricle through the interventricular foramen of Monro, then flows through the cerebral aqueduct and into the fourth ventricle.
      • CSF leaves the fourth ventricle into the subarachnoid space through the medial foramen of Magendie and the lateral foramina of Luschka.
        • Foramen of Magendie connects to the cisterna magna.
        • Foramen of Luschka connects to the cerebellopontine cistern.
    Diagram of The Ventricular system
    The Ventricular system

    Associated Syndromes

    Hydrocephalus

    • Hydrocephalus can occur with excess production of CSF, blockage of CSF circulation, or deficiency in CSF reabsorption.
    • Obstructive hydrocephalus occurs with mass lesions that compresses the flow of CSF.
      • Obstruction is the most common cause of hydrocephalus
      • Common causes include pineal region tumors, intraventricular lesions, Chiari malformations, and aqueductal stenosis.
    • Non-obstructive hydrocephalus occurs with impairment of CSF reabsorption through arachnoid granulations, this most often follows subarachnoid hemorrhage, venous sinus thrombosis, or meningitis.
      • Congenital aplasia of arachnoid granulations can also cause hydrocephaly in children with cranial dysplasia.

    Intraventricular lesions (by location)

    • Lateral ventricle: Subependymoma, choroid plexus tumors
    • Third ventricle: Colloid cyst, subependymal giant cell astrocytoma, central neurocytoma
    • Fourth ventricle: Ependymoma, medulloblastoma

    Ventriculitis

    • A possible complication of meningitis.
    • On MRI, ventriculitis appears as fluid levels within the cortical sulci and within the posterior horns of the lateral ventricles.
      • T1 sequences with contrast will show extensive enhancement of the ependyma.

    References

    1. Cinalli G, Spennato P, Nastro A, et al. Hydrocephalus in aqueductal stenosis. Childs Nerv Syst. 2011;27(10):1621-42.
    2. Hemphill, III J, Smith S, Josephson S, Gress DR. Severe Acute Encephalopathies and Critical Care Weakness. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill.
    3. Love, S, Perry, A, Ironside, J, Budka, H (Eds.). Greenfield’s Neuropathology – Two Volume Set. 9th ed. CRC Press; 2015.
    4. Neuwelt EA, Bauer B, Fahlke C, et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci. 2011;12(3):169-82.
    5. Mancall EL. Overview of the Microstructure of the Nervous System. In: Gray’s Clinical Neuroanatomy: The Anatomic Basis for Clinical Neuroscience. Philadelphia, PA: Elsevier; 2011:11-31.
    6. McKinley MJ, Clarke LJ, Oldfield BJ. Circumventricular Organs. In: Circumventricular Organs. 3rd ed. Waltham, MA: Elsevier; 2012:594-617.
    7. Mescher AL. Nerve Tissue & the Nervous System. In: Junqueira’s Basic Histology: Text and Atlas, 15e New York, NY: McGraw-Hill.
    8. Mtui E, Gruener G, Dockery P. Meninges. In: Fitzgerald’s Clinical Neuroanatomy and Neuroscience. 7th ed. Oxford, UK: Elsevier; 2016:40-49.
    9. Paulsen DF. Chapter 9. Nerve Tissue. In: Histology & Cell Biology: Examination & Board Review, 5e New York, NY: McGraw-Hill; 2010.
    10. Ropper AH, Samuels MA, Klein JP. Chapter 33. Viral Infections of the Nervous System, Chronic Meningitis, and Prion Diseases. In: Adams & Victor’s Principles of Neurology, 10e New York, NY: McGraw-Hill; 2014.
    11. Shakkottai VG, Lomen-Hoerth C. Nervous System Disorders. In: Hammer GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e New York, NY: McGraw-Hill.
    12. Vanderah TW, Gould DJ. Ventricles and Cerebrospinal Fluid. In: Nolte’s The Human Brain. 7th ed. Philadelphia, PA: Elsevier; 2016:103-125.
    13. Watts L, Jaramillo CA, Eapen BC. The Pathophysiology of Traumatic Brain Injury. In: Mitra R. eds. Principles of Rehabilitation Medicine New York, NY: McGraw-Hill.
    14. Waxman SG. Clinical Neuroanatomy, 27e. McGraw-Hill, 2013.
    15. Chen S, Shao L, Ma L. Cerebral Edema Formation After Stroke: Emphasis on Blood-Brain Barrier and the Lymphatic Drainage System of the Brain. Front Cell Neurosci. 2021 Aug 16;15:716825. doi: 10.3389/fncel.2021.716825. PMID: 34483842; PMCID: PMC8415457.
    16. Dostovic Z, Dostovic E, Smajlovic D, Ibrahimagic OC, Avdic L. Brain Edema After Ischaemic Stroke. Med Arch. 2016 Oct;70(5):339-341. doi: 10.5455/medarh.2016.70.339-341. Epub 2016 Oct 25. PMID: 27994292; PMCID: PMC5136437.

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