Why Do Not Nerve Cells Regenerate?

Why Aren’t We More Like Fish and Frogs?

The question of why the mammalian central nervous system does not regenerate after injury is of extra-ordinary interest at many levels. In terms of descriptive biology, it is remarkable how great the discrepancy is between nerve cells that can, and cannot repair their connections after their axons have been lesioned.

In an invertebrate such as the leech, in fishes and in frogs the central nervous system does show effective regeneration and restoration of function after complete transection. Thus, a leech can swim again after it’s nervous system has regenerated after being cut in two, and a frog can catch flies with it’s tongue after it’s optic nerve has grown back to the tectum(the dorsal portion of the midbrain, containing the superior colliculus and inferior colliculus).

In these “simple” animals the wiring is far more complex than in any man-made circuit, yet somehow fibres grow to find their targets and form effective synapses upon them. In this they resemble their counterparts in the mammalian peripheral nervous system.

What makes the mammalian central nervous system so different in this regard?

At the cellular and molecular level, differences between non-regenerating and regenerating neurons and the satellite cells that surround them are the focus of intense research. Detailed information is accumulating about molecules that enhance or inhibit growth, as well their receptors. And at the level of clinical medicine, there is the essential question about whether and when treatments can be devised for patients with central nervous system injuries so that functions can be restored.

Recent experiments at all of these levels have provided unexpected new findings and insights. Yet one of the most striking features of the field of regeneration today is how many key questions remain. For example, while we have clues, the mechanisms that prevent regeneration in mammalian CNS are still not fully known.

Why is the proportion of axons, that actually elongate, so small, even when the application of suitable techniques does give rise to successful growth across a lesion?

What changes in molecular mechanisms of growth occur in immature mammals during development, that later prevent regeneration in the adult?

While it seems reasonable to guess that understanding of growth promoting and inhibiting mechanisms will continue to proceed rapidly, a baffling question remains. It arises from our ignorance about normal development of the nervous system.



At present it is not known how specific synapses form, so that one type of cell is selected as a target while another one sitting just next door is ignored. 

If hope is to be offered to patients with spinal cord lesions, axons must not only grow (obviously a prerequisite for repair) but they must reform useful connections with the appropriate targets. In the best of all possible worlds no errors would be made. One also can imagine a scenario in which incorrect connections are formed and subsequently tuned by use; pain fibres would, one hopes, not re-form connections in patients.

All the neuroscientists who work on these problems have to face inevitable and quite natural questions about prospects for therapy.

A convenient analogy seems to me to be the repair of a watch. A desirable requirement would surely be to have an understanding of how the watch works and what the various components are doing. Without that knowledge one can still hope for some new insight or fluke that will allow the repair to be made. It would, however, be dangerous to promise how soon the watch will work again until the failure has been diagnosed and only one or two parts remain to be replaced. Because we are not even remotely at this stage in our knowledge of the nervous system, predictions about how and when seem unrealistic. (This analogy is of course flawed: the nervous system has to do the job on it’s own once one has provided the appropriate conditions).

In contrast to the plasticity of the brain, in the spinal cord the degree of plasticity is much less, although perhaps currently underestimated. Once the long tracts are severed or compressed to the point of axotomy, they will not recover and there is usually insufficient overlap in function in the spinal cord for the missing functions to be taken over by surviving tracts, should there indeed be any. The spinal cord is such a narrow structure, normally well protected by the bone forming the spinal canal, that any injury sufficient to damage it in part, may well be severe enough to damage it completely.

In the general strategy of devising spinal repair procedures that could eventually be applied in patients, there are at least four problems to be overcome:

  1. Central nervous system neurons show a variable response in their ability to produce neurites in response to injury, in contrast to peripheral nervous system, which show a consistent ability to do this.
  2. Following damage to the CNS, as for example in a spinal cord injury, any neurites that do appear at the site of injury are unable to cross it, which in patients may involve a substantial length of spinal cord.
  3. Once methods for promotion of growth of axons across the site of injury are available in a clinically applicable form, the axons may have to grow considerable distances to reach appropriate targets and may require specific guidance cues to direct them to functionally appropriate targets.
  4. Having reached appropriate targets, effective functional re-innervation of the targets should occur.

It is not entirely clear how separable are these four components of successful repair. There is increasing evidence that they may indeed be substantially separate processes and that achievement of one will not automatically lead to success with the others.

Thus the work described by Beazley & Dunlop on regeneration in the lizard shows clearly that while axotomised fibres can regrow to the appropriate targets in the visual systems in this species, no functionally effective innervation occurs.

Beazley and Dunlop describe different features of a wide range of species from cold-blooded vertebrates to mammals. Particularly with respect to effectiveness of target re-innervation, there appears to be a spectrum of regeneration. This goes from amphibia and lampreys (with particular respect to the underlying subcellular structures that may be responsible for regenerative outgrowth of injured axons) which can regenerate not only new axons but also functional connections with appropriate targets, through lizards that show excellent axonal growth, but inappropriate target innervation, to mammals in which neither regenerative axon growth nor appropriate target innervation normally occur. The evolutionary significance of this progressive loss of regenerative  ability (an ability which is even more marked in invertebrates) through the animal kingdom is unclear.

The central nervous system of adult mammals, including humans, recovers only poorly from injury. Once severed, major axon tracts (such as those in the spinal cord) never regenerate. The devastating consequences of these injuries—e.g., loss of movement and the inability to control basic bodily functions—has led many neuroscientists to seek ways of restoring the connections of severed axons. There is no a priori reason for this biological failure, since “lower” vertebrates—e.g., lampreys, fish, and frogs—can regenerate a severed spinal cord or optic nerve.

Even in mammals, the inability to regenerate axonal tracts is a special failing of the central nervous system; peripheral nerves can and do regenerate in adult animals, including humans.

Why, then, not the central nervous system?

Neuron injury

At least a part of the answer to this puzzle apparently lies in the molecular cues that promote and inhibit axon outgrowth.

In mammalian peripheral nerves, axons are surrounded by a basement membrane (a proteinaceous extracellular layer composed of collagens, glycoproteins, and proteoglycans) secreted in part by Schwann cells, the glial cells associated with peripheral axons. After a peripheral nerve is crushed, the axons within it degenerate; the basement membrane around each axon, however, persists for months.

One of the major components of the basement membrane is laminin, which (along with other growth promoting molecules in the basement membrane) forms a hospitable environment for regenerating growth cones. The surrounding Schwann cells also react by releasing neurotrophic factors, which further promote axon elongation.

This peripheral environment is so favourable to regrowth that even neurons from the central nervous system can be induced to extend into transplanted segments of peripheral nerve.


Albert Aguayo and his colleagues at the Montreal General Hospital found that grafts derived from peripheral nerves can act as “bridges” for central nervous system neurons (in this case, retinal ganglion cells), allowing them to grow for over a centimeter (Figure
A); they even form a few functional synapses in their target tissues (Figure B).

These several observations suggest that the failure of central neurons to regenerate is not due to an intrinsic inability to sprout new axons, but rather to something in the local environment that prevents growth cones from extending.

This impediment could be the absence of growth-promoting factors— such as the neurotrophins—or the presence of molecules that actively prevent axon outgrowth.

Studies by Martin Schwab and his colleagues point to the latter possibility. Schwab found that central nervous system myelin contains an inhibitory component that causes growth cone collapse in vitro and prevents axon growth in vivo. This component, recognized by a monoclonal antibody called IN-1, is found in the myelinated portions of the central nervous system but is absent from peripheral nerves.

IN-1 also recognizes molecules in the optic nerve and spinal cord of mammals, but is missing in the same sites in fish, which do regenerate these central tracts.

Nogo-A, the primary antigen recognized by the IN-1 antibody, is secreted by oligodendrocytes(they are present in central nervous system), but not by Schwann cells in the peripheral nervous system. Most dramatically, the IN-1 antibody increases the extent of spinal cord regeneration when provided at the site of injury in rats with spinal cord damage. All this implies that the human central nervous system differs from that of many “lower” vertebrates in that humans and other mammals present an unfavourable molecular environment for regrowth after injury.

Why this state of affairs occurs is not known.

One speculation is that the extraordinary amount of information stored in mammalian brains puts a premium on a stable pattern of adult connectivity.

At present there is only one modestly helpful treatment for CNS injuries such as spinal cord transection. High doses of a steroid, methylprednisolone, immediately after the injury prevents some of the secondary damage to neurons resulting from the initial trauma.

Although it may never be possible to fully restore function after such injuries, enhancing axon regeneration, blocking inhibitory molecules and providing additional trophic support to surviving neurons could in principle allow sufficient recovery of motor control to give afflicted individuals a better quality of life than they now enjoy. The best “treatment,” however, is to prevent such injuries from occurring, since there is now very little that can be done after the fact.


  1. Degeneration and Regeneration in the Nervous System  edited by Norman Saunders, Katarzyna Dziegielewska; Anatomy and Physiology, The University of Tasmania, Australia©2000, OPA (Overseas Publishers Association)
  2. Neuroscience, 3rd edition. Editors: Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams. Sunderland (MA): Sinauer Associates; 2004. ISBN 0-87893-725-0

  3. BRAY, G. M., M. P. VILLEGAS-PEREZ, M. VIDALSANZ AND A. J. AGUAYO (1987) The use of peripheral nerve grafts to enhance neuronal survival, promote growth and permit terminal reconnections in the central nervous system of adult rats. J. Exp. Biol. 132: 5–19.
  4. SCHNELL, L. AND M. E. SCHWAB (1990) Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343:269–272.
  5. SO, K. F. AND A. J. AGUAYO (1985) Lengthy regrowth of cut axons from ganglion cells after peripheral nerve transplantation into the retina of adult rats. Brain Res. 359: 402–406.
  6. VIDAL-SANZ, M., G. M. BRAY, M. P. VILLEGASPEREZ, S. THANOS AND A. J. AGUAYO (1987) Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J. Neurosci. 7: 2894–2909.

Neuroplasticity And Epilepsy: The Effect of Pathological Activity on Neural Circuitry

Epilepsy is a brain disorder characterized by periodic and unpredictable seizures
mediated by the rhythmic firing of large groups of neurons. It seems likely that
abnormal activity generates plastic changes in cortical circuitry that are critical
to the pathogenesis of the disease.

Brain Plasticity: What Is It?

What is brain plasticity?

Does it mean that our brains are made of plastic?

Of course not.

Plasticity, or neuroplasticity, describes how experiences reorganize neural pathways in the brain. Long lasting functional changes in the brain occur when we learn new things or memorize new information. These changes in neural connections are what we call neuroplasticity.

To illustrate the concept of plasticity, imagine the film of a camera. Pretend that the film represents your brain. Now imagine using the camera to take a picture of a tree. When a picture is taken, the film is exposed to new information — that of the image of a tree. In order for the image to be retained, the film must react to the light and “change” to record the image of the tree. Similarly, in order for new knowledge to be retained in memory, changes in the brain representing the new knowledge must occur.

To illustrate plasticity in another way, imagine making an impression of a coin in a lump of clay. In order for the impression of the coin to appear in the clay, changes must occur in the clay — the shape of the clay changes as the coin is pressed into the clay. Similarly, the neural circuitry in the brain must reorganize in response to experience or sensory stimulation.

  • Neuroplasticity includes several different processes that take place throughout a lifetime – Neuroplasticity does not consist of a single type of morphological change, but rather includes several different processes that occur throughout an individual’s lifetime. Many types of brain cells are involved in neuroplasticity, including neurons, glia, and vascular cells.
  • Neuroplasticity has a clear age-dependent determinant – Although plasticity occurs over an individual’s lifetime, different types of plasticity dominate during certain periods of one’s life and are less prevalent during other periods.
  • Neuroplasticity occurs in the brain under two primary conditions:1. During normal brain development when the immature brain first begins to process sensory information through adulthood (developmental plasticity and plasticity of learning and memory).2. As an adaptive mechanism to compensate for lost function and/or to maximize remaining functions in the event of brain injury.
  • The environment plays a key role in influencing plasticity – In addition to genetic factors, the brain is shaped by the characteristics of a person’s environment and by the actions of that same person.

Developmental Plasticity: Synaptic Pruning

Electrical Trigger for Neurotransmission



Gopnick et al. (1999)[Gopnic, A., Meltzoff, A., Kuhl, P. (1999). The Scientist in the Crib: What Early Learning Tells Us About the Mind, New York, NY: HarperCollins Publishers.] describe neurons as growing telephone wires that communicate with one another. Following birth, the brain of a newborn is flooded with information from the baby’s sense organs. This sensory information must somehow make it back to the brain where it can be processed. To do so, nerve cells must make connections with one another, transmitting the impulses to the brain. Continuing with the telephone wire analogy, like the basic telephone trunk lines strung between cities, the newborn’s genes instruct the “pathway” to the correct area of the brain from a particular nerve cell. For example, nerve cells in the retina of the eye send impulses to the primary visual area in the occipital lobe of the brain and not to the area of language production (Wernicke’s area) in the left posterior temporal lobe. The basic trunk lines have been established, but the specific connections from one house to another require additional signals.
Over the first few years of life, the brain grows rapidly. As each neuron matures, it sends out multiple branches (axons, which send information out, and dendrites, which take in information), increasing the number of synaptic contacts and laying the specific connections from house to house, or in the case of the brain, from neuron to neuron. At birth, each neuron in the cerebral cortex has approximately 2,500 synapses. By the time an infant is two or three years old, the number of synapses is approximately 15,000 synapses per neuron (Gopnick, et al., 1999). This amount is about twice that of the average adult brain. As we age, old connections are deleted through a process called synaptic pruning.

Synaptic pruning eliminates weaker synaptic contacts while stronger connections are kept and strengthened. Experience determines which connections will be strengthened and which will be pruned; connections that have been activated most frequently are preserved. Neurons must have a purpose to survive. Without a purpose, neurons die through a process called apoptosis in which neurons that do not receive or transmit information become damaged and die. Ineffective or weak connections are “pruned” in much the same way a gardener would prune a tree or bush, giving the plant the desired shape. It is plasticity that enables the process of developing and pruning connections, allowing the brain to adapt itself to its environment.

Wiring of Brain

Plasticity of Learning and Memory

It was once believed that as we aged, the brain’s networks became fixed. In the past two decades, however, an enormous amount of research has revealed that the brain never stops changing and adjusting. 

Learning, as defined by Tortora and Grabowski (1996)[Tortora, G. and Grabowski, S. (1996). Principles of Anatomy and Physiology. (8th ed.), New York: HarperCollins College Publishers.], is the ability to acquire new knowledge or skills through instruction or experience.

Memory is the process by which that knowledge is retained over time.

The capacity of the brain to change with learning is plasticity.

So how does the brain change with learning?

According to Drubach (2000)[Drubach, D. (2000). The Brain Explained, Upper Saddle River, NJ: Prentice-Hall, Inc.], there appear to be at least two types of modifications that occur in the brain with learning:

  1. A change in the internal structure of the neurons, the most notable being in the area of synapses.
  2. An increase in the number of synapses between neurons.

Initially, newly learned data are “stored” in short-term memory, which is a temporary ability to recall a few pieces of information. Some evidence supports the concept that short-term memory depends upon electrical and chemical events in the brain as opposed to structural changes such as the formation of new synapses. One theory of short-term memory states that memories may be caused by “reverberating” neuronal circuits — that is, an incoming nerve impulse stimulates the first neuron which stimulates the second, and so on, with branches from the second neuron synapsing with the first. After a period of time, information may be moved into a more permanent type of memory, long-term memory, which is the result of anatomical or biochemical changes that occur in the brain (Tortora and Grabowski, 1996)[Tortora, G. and Grabowski, S. (1996). Principles of Anatomy and Physiology. (8th ed.), New York: HarperCollins College Publishers.]

Kindly also read Does Glial Cells Have Any Role in Creativity and Genius ? Nearly 90 % of the Brain is Composed of Glia.

Injury-induced Plasticity: Plasticity and Brain Repair

During brain repair following injury, plastic changes are geared towards maximizing function in spite of the damaged brain. In studies involving rats in which one area of the brain was damaged, brain cells surrounding the damaged area underwent changes in their function and shape that allowed them to take on the functions of the damaged cells. Although this phenomenon has not been widely studied in humans, data indicate that similar (though less effective) changes occur in human brains following injury. Kindly read Why Home Education of a Child is Very Important- Even Kindergarten is Late!

[Source: https://faculty.washington.edu/chudler/plast.html]

The importance of neuronal plasticity in epilepsy is indicated most clearly by an animal model of seizure production called kindling. To induce kindling, a stimulating electrode is implanted in the brain, often in the amygdala (a component of the limbic system that makes and receives connections with the cortex, thalamus, and other limbic structures, including the hippocampus; amygdala came from the latin-greek word, meaning almond, which describe the almond-like structure found in the brain ); Shown in research to perform a primary role in the processing of memory, decision-making, and emotional reactions, the amygdalae are considered part of the limbic system.

  • It can be found easily in mammals under the rhinal fissure and closely related to the lateral olfactory tract. This almond like structure, ranging from 1-4cm , average about 1.8cm, has extensive connection with the brain.

At the beginning of such an experiment, weak electrical stimulation, in the form of a low-amplitude train of electrical pulses, has no discernible effect on the animal’s behaviour or on the pattern of electrical activity in the brain (laboratory rats or mice have typically been used for such studies). As this weak stimulation is repeated once a day for several weeks, it begins to produce behavioural and electrical indications of seizures. By the end of the experiment, the same weak stimulus that initially had no effect now causes full-blown seizures. This phenomenon is essentially permanent; even after an interval of a year, the same weak stimulus will again trigger a seizure. Thus, repetitive weak activation produces long-lasting changes in the excitability of the brain that time cannot reverse. The word kindling is therefore quite appropriate: A single match can start a devastating fire.

The changes in the electrical patterns of brain activity detected in kindled animals resemble those in human epilepsy. The behavioural manifestations of epileptic seizures in human patients range from mild twitching of an extremity, to loss of consciousness and uncontrollable convulsions. Although many highly accomplished people have suffered from epilepsy (Alexander the Great, Julius Caesar, Napoleon, Dostoyevsky, and Van Gogh, to name a few), seizures of sufficient intensity and frequency can obviously interfere with many aspects of daily life. Moreover, uncontrolled convulsions can lead to excitotoxicity.

Up to 1% of the population is afflicted, making epilepsy one of the most common neurological problems.

Modern thinking about the causes (and possible cures) of epilepsy has focussed on where seizures originate and the mechanisms that make the affected region hyperexcitable.

Most of the evidence suggests that abnormal activity in small areas of the cerebral cortex (called foci) provide the triggers for a seizure that then spreads to other synaptically connected regions. For example, a seizure originating in the thumb area of the right motor cortex will first be evident as uncontrolled movement of the left thumb that subsequently extends to other more proximal limb muscles, whereas a seizure originating in the visual association cortex of the right hemisphere may be heralded by complex hallucinations in the left visual field. The behavioural manifestations of seizures therefore provide important clues for the neurologist seeking to pinpoint the abnormal region of cerebral cortex. Epileptic seizures can be caused by a variety of acquired or congenital factors, including cortical damage from trauma, stroke, tumors, congenital cortical dysgenesis (failure of the cortex to grow properly), and congenital vascular malformations. One rare form of epilepsy, Rasmussen’s encephalitis, is an autoimmune disease that arises when the immune system attacks the brain, using both humoral (i.e. antibodies) and cellular (lymphocytes and macrophages) agents that can destroy neurons. Some forms of epilepsy are heritable, and more than a dozen distinct genes have been demonstrated to underlie unusual types of epilepsy. However, most forms of familial epilepsy (such as juvenile myoclonic epilepsy and petit mal epilepsy) are caused by the simultaneous inheritance of more than one mutant gene.

No effective prevention or cure exists for epilepsy. Pharmacological therapies that successfully inhibit seizures are based on two general strategies.

One approach is to enhance the function of inhibitory synapses that use the neurotransmitter GABA;[Gamma-Aminobutyric acid(γ-Aminobutyric acid); (also called GABA for short) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays the principal role in reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.] the other is to limit action potential firing by acting on voltage-gated Na+ channels. Commonly used antiseizure medications include carbamazepine, phenobarbital, phenytoin (Dilantin®), and valproic acid.

These agents, which must be taken daily, successfully inhibit seizures in 60–70% of patients. In a small fraction of patients, the epileptogenic region can be surgically excised. In extreme cases, physicians resort to cutting the corpus callosum to prevent the spread of seizures (most of the “split-brain” subjects were patients suffering from intractable epilepsy).

One of the major reasons for controlling epileptic activity is to prevent the more permanent plastic changes that would ensue as a consequence of abnormal and excessive neural activity.

Brain-corpus collosum

    The corpus callosum (Latin for “tough body”) is by far the largest bundle of nerve fibers in the entire nervous system. Its population has been estimated at 200 million axons—the true number is probably higher, as this estimate was based on light microscopy rather than on electron microscopy—
    a number to be contrasted to 1.5 million for each optic nerve and 32,000 for the auditory nerve. Its cross-sectional area is about 700 square millimeters, compared with a few square millimeters for the optic nerve. It joins the two cerebral hemispheres, along with a relatively tiny fascicle of fibers called the anterior commissure, as shown. The word commissure signifies a set of fibers connecting two homologous neural structures on opposite sides of the brain or spinal cord; thus the corpus callosum is sometimes called the great cerebral commissure.
    Until about 1950 the function of the corpus callosum was a complete mystery. On rare occasions, the corpus callosum in humans is absent at birth, in a condition called agenesis of the corpus callosum. Occasionally it may be completely or partially cut by the neurosurgeon, either to treat epilepsy (thus preventing epileptic discharges that begin in one hemisphere from spreading to the other) or to make it possible to reach a very deep tumor, such as one in the pituitary gland, from above. In none of these cases had neurologists and psychiatrists found any deficiency; someone had even suggested (perhaps not seriously) that the sole function of the corpus callosum was to hold the two cerebral hemispheres together. Until the 1950s we knew little about the detailed connections of the corpus callosum. It clearly connected the two cerebral hemispheres, and on the basis of rather crude neurophysiology it was thought to join precisely corresponding cortical areas on the two sides. Even cells in the striate cortex were assumed to send axons into the corpus callosum to terminate in the exactly corresponding part of the striate cortex on the opposite side.
    In 1955 Ronald Myers, a graduate student studying under psychologist Roger Sperry (Roger Wolcott Sperry) at the University of Chicago, did the first experiment that revealed a function for this immense bundle of fibers. Myers trained cats in a box containing two side-by-side screens onto which he could project images, for example a circle onto one screen and a square onto the other. He taught a cat to press its nose against the screen with the circle, in preference to the one with the square, by rewarding correct responses with food and punishing mistakes mildly by sounding an unpleasantly loud buzzer and pulling the cat back from the screen gently but firmly. By this method the cat could be brought to a fairly consistent performance in a few thousand trials. (Cats learn slowly; a pigeon will learn a similar task in tens to hundreds of trials, and we humans can learn simply by being told. This seems a bit odd, given that a cat’s brain is many times the size of a pigeon’s. So much for the sizes of brains.)
    Not surprisingly, Myers’ cats could master such a task just as fast if one eye was closed by a mask. Again not surprisingly, if a task such as choosing a triangle or a square was learned with the left eye alone and then tested with the right eye alone, performance was just as good. This seems not particularly impressive, since we too can easily do such a task. The reason it is easy must be related to the anatomy. Each hemisphere receives input from both eyes, a large proportion of cells in area 17 receive input from both eyes. Myers now made things more interesting by surgically cutting the optic chiasm in half, by a fore-and-aft cut in the midline, thus severing the crossing fibers but leaving the uncrossed ones intact—a procedure that takes some surgical skill. Thus the left eye was attached only to the left hemisphere and the right eye to the right hemisphere. The idea now was to teach the cat through the left eye and test it with the right eye: if it performed correctly, the information necessarily would have crossed from the left hemisphere to the right through the only route known, the corpus callosum. Myers did the experiment: he cut the chiasm longitudinally, trained the cat through one eye, and tested it through the other—and the cat still succeeded. Finally, he repeated the experiment in an animal whose chiasm and corpus callosum had both been surgically divided. The cat now failed. Thus he established, at long last, that the callosum actually could do something—although we would hardly suppose that its sole purpose was to allow the few people or animals with divided optic chiasms to perform with one eye after learning a task with the other.[Source: David Hubel’s-Eye, Brain And Vision]

The corpus callosum is a thick, bent plate of axons near the center of this brain section, made by cutting apart the human cerebral hemispheres and looking at the cut surface. Image source

Here the brain is seen from above. On the right side an inch or so of the top has been lopped off. We can see the band of the corpus callosum fanning out after crossing, and joining every part of the two hemispheres. (The front of the brain is at the top of the picture.) Image source

The Corpus Callosum Defined

Imagine for a moment two people who think and behave in very similar ways yet perceive the world a bit differently from one another.

What if they could share their thoughts, then modify them into a single world view based on both perceptions?

This may seem weird, but our brain works this way thanks to the corpus callosum.

Located near the center of the brain, this structure is the largest bundle of nerve fibers that connects the left and right cerebral hemispheres, much like a bridge. Traffic flows in both directions, but instead of vehicles travelling over the gap, it is information.

Corpus callosum

The corpus callosum is near the center of the brain and is covered by the cerebral hemispheres. Image source

Split Brain Patients

Until the early 1950s, the function of the corpus callosum had alluded scientists. No one knew what it did, except to connect the two cerebral hemispheres. By the 1960s, scientists at least knew that nerve fibers within the callosum connected corresponding areas in the two hemispheres but did not yet understand the complexity involved. However, this limited knowledge was used in an attempt to help patients who suffered from severe and constant seizures.

Normally, electrical activity in the brain flows down specific pathways. This is not so during seizures. The electrical charges could end up anywhere in the brain and stimulate the uncoordinated muscular activity that many people associate with a seizure. Roger Sperry was the scientist who developed a surgical procedure to cut the corpus callosum and stop the spread of this activity from one hemisphere to the other. This procedure was a last ditch effort to normalize the lives of seizure patients, and it was very effective. However, there were a few unexpected results.

After surgery, some patients exhibited contrary behaviours, such as pulling their pants on with one arm while simultaneously pulling them off with the other. Another patient began to shake his wife aggressively with his left hand as his right hand intervened to stop the attack. These results began a plethora of investigations which eventually lead to the understanding that each hemisphere tends to specialize in certain activities, i.e., speech (left side) or emotional reactivity (right side).

After the patient’s callosum was cut, the attack on his wife was instigated by the right hemisphere (via his left hand) because the left hemisphere (right hand) didn’t realize what was happening soon enough to prevent it. Such a conflict ordinarily would have been resolved in the patient’s brain before the external behaviour was produced.

To a greater or lesser degree, both hemispheres contribute to the initiation of a particular behaviour. It is the corpus callosum that provides the communication pathway to coordinate these activities and helps to incorporate them into daily life. Without this brain structure, we literally have two separate personalities in your head, each with its own agenda. [Source: Jay Mallonee – Jay is a wildlife biologist, college professor and writer. His master’s degree is in neurobiology and he has studied animal behaviour since 1976.]


  1. SCHEFFER, I. E. AND S. F. BERKOVIC (2003) The genetics of human epilepsy. Trends Pharm. Sci. 24: 428–433.
  2. ENGEL, J. JR. AND T. A. PEDLEY (1997) Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven Publishers.
  3. McNamara, J. O. (1999) Emerging insights into the genesis of epilepsy. Nature 399:

Neuroscience, 3rd edition

Editors: Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams.

Sunderland (MA): Sinauer Associates; 2004.
ISBN 0-87893-725-0

Epilepsy: Still an Enigma For Common People

“It starts with the sensation of a light switch being pulled violently behind my eyes. I lose cognitive control quickly. I can’t focus on even a simple task, and I forget what I’m doing while I’m in the middle of doing it. I could pick up a pen, then forget why I’m holding it. As the weight behind my eyes intensifies, my eyes roll into my head and start to flutter so rapidly it feels like they are going to pop out. This can last for a split second, a few hours, a few days, or a week.

I have epilepsy, a neurological disorder characterised by recurring, unprovoked seizures. The episodes I described are seizures — they are simply misfiring neurones. Sometimes, these seizures are affected by the season. Other times, they are more easily triggered by stress.

I had my first Tonic-Clonic Seizure in December 1996, my Grade Six year. I fell unconscious into a snow bank in the parking lot of my elementary school. Many people are more familiar with this seizure’s older name, Grand Mal.

I was diagnosed with Generalized Seizures that same year. This news left my family and teachers confused. I had never shown any signs of what they thought of as epilepsy, the violent shaking on the ground portrayed in movies and on TV. No one realised I had been having seizures for many years. Instead, they misread my childhood behaviour as misbehaving.

I frequently blacked out for split seconds in elementary school. The blackouts were likely Absence Seizures, a type of seizure that looks like daydreaming. Even though the blackouts happened on a regular basis, they were almost impossible to spot with an untrained eye.

In a Grade Three art class, I blacked out and knocked over a cup of water that contained a few paint brushes. At the time, no one realised it was a Partial Seizure. When I came to, my teacher asked me why I had done that. She told me it was a disturbance to the class and I needed to watch my behaviour.

I had never even heard the word “seizure” before the age of 11. Without a reference point, these incidents in school seemed normal to me. As far as I was concerned, I didn’t have seizures; I just needed to control my behaviour so I would stop getting in trouble at school.

There was no information about raising a child with Generalized Seizures available to families living with epilepsy in the late-’90s. My family and my teachers didn’t know anyone with epilepsy who could help them figure it out. There were no community epilepsy agencies in our area at the time. Without available resources, we felt left in the dark.

Without a clear understanding of epilepsy as I grew up, it became difficult for me to talk about it with others in my life. As a young adult, I would often avoid discussing it with boyfriends, new employers, and new friends.” [Source: Undiagnosed Epilepsy Made People Think I Was Acting Out

Globally, one in 100 people are diagnosed with epilepsy. It is one of the most common neurological conditions worldwide, yet public knowledge is extremely limited. Many people with epilepsy never talk publicly about their diagnosis fearing discrimination. Seizures and seizure first aid on television are often inaccurate. Myths and misconceptions about epilepsy persist.

Epilepsy is a chronic disorder characterised by recurrent seizures, which may vary from a brief lapse of attention or muscle jerks to severe and prolonged convulsions. The seizures are caused by sudden, usually brief, excessive electrical discharges in a group of brain cells (neurones). In most cases, epilepsy can be successfully treated with anti-epileptic drugs. [Source: http://www.who.int/topics/epilepsy/en/


File:Opisthotonus in a patient suffering from tetanus - Painting by Sir Charles Bell - 1809.jpg

Painting by Sir Charles Bell (1809) showing opisthotonos (in a patient suffering from tetanus.  Opisthotonus (धनुर्वात), Tetanus (धनुस्तम्भ)

Imitators of Epilepsy

  • Fainting (syncope)
  • Mini-strokes (transient ischemic attacks or TIAs)
  • Hypoglycemia (low blood sugar)
  • Migraine with confusion
  • Sleep disorders, such as narcolepsy and others
  • Movement disorders: tics, tremors, dystonia
  • Fluctuating problems with body metabolism
  • Panic attacks
  • Nonepileptic (psychogenic) seizures


What is a Seizure?

A seizure is a brief disruption in normal brain activity that interferes with brain function.

The brain is made up of billions of cells called neurones which communicate by sending electrical messages. Brain activity is a rhythmic process characterised by groups of neurones communicating with other groups of neurones. During a seizure, large groups of brain cells send messages simultaneously (known as “hypersynchrony”) which temporarily disrupts normal brain function in the regions where the seizure activity is occurring.

Seizures can cause temporary changes or impairments in a wide range of functions. Any function that the brain has can potentially be affected by a seizure, such as behaviour, sensory perception (vision, hearing, taste, touch, smell), attention, movement, emotion, language function, posture, memory, alertness, and/or consciousness. Not all seizures are the same. Some seizures may only affect one or two discrete functions, other seizures affect a wide range of brain functions.

Most people associate a seizure with a loss of consciousness and rhythmic jerking movements. Some seizures do cause convulsive body movements and a loss of consciousness, but not all. There are many different kinds of seizures. A temporary uncontrollable twitching of a body part could be due to a seizure. A sudden, brief change in feeling or a strange sensation could be due to a seizure.

Most seizures are brief events that last from several seconds to a couple of minutes and normal brain function will return after the seizure ends. Recovery time following a seizure will vary. Sometimes recovery is immediate as soon as the seizure is over. Other types of seizures are associated with an initial period of confusion afterwards. Following some types of seizures, there may be a more prolonged period of fatigue and/or mood changes.

What is the Difference Between a Seizure and Epilepsy?

A seizure is a brief episode caused by a transient disruption in brain activity that interferes with one or more brain functions.

Epilepsy is a brain disorder associated with an increased susceptibility to seizures.

When a person experiences a seizure it does not necessarily indicate that they have epilepsy, there are many possible reasons that a seizure could happen. When someone has been diagnosed with epilepsy it indicates that they have had a seizure (usually 2 or more) and they are considered to have an increased risk of future seizures due to a brain-related cause.

Causes of Epilepsy

Just as there are many different types of epilepsy there are many different causes too, which include:

  • a brain injury or damage to the brain – Anything that can injure the brain is a potential cause of epilepsy including head trauma; stroke; brain injury during birth; neurodegenerative diseases; brain tumours; and many others. Epilepsy may begin weeks, months or years after an injury to the brain.
  • structural abnormalities that arise during brain development – Sometimes these structural changes in the brain are visible on a brain scan (such as an MRI), other times there could be subtle changes in brain structure that are not easy to detect with current imaging techniques. Epilepsy due to a structural abnormality may begin early in life, during adolescence or in adulthood.
  • genetic factors
    Some genetic causes of epilepsy are inherited and there may be other family members with epilepsy, while other genetic factors that cause epilepsy occur at random.
  • a combination of two or more of the above factors
  • Infections, including brain abscess, meningitis, encephalitis, and HIV/AIDS

For many people with epilepsy, the cause of their seizures is unknown. It is hoped that research and new developments in diagnostic testing will provide more answers for people with epilepsy and their families.

Epilepsy that does not get better after two or three anti-seizure drugs have been tried is called “medically refractory epilepsy.” In this case, the doctor may recommend surgery to:

  • Remove the abnormal brain cells causing the seizures.
  • Place a vagal nerve stimulator (VNS). This device is similar to a heart pacemaker. It can help reduce the number of seizures.

Neural Stem Cells – Promise and Perils

One of the most highly publicized issues in biology over the past several years has been the use of stem cells as a possible way of treating a variety of neurodegenerative conditions, including Parkinson’s, Huntington’s, and Alzheimer’s diseases.

Amidst the social, political, and ethical debate set off by the promise of stem cell therapies, an issue that tends to get lost is…

What, exactly, is a stem cell?

Neural stem cells are an example of a broader class of stem cells called somatic stem cells. These cells are found in various tissues, either during development or in the adult.

All somatic stem cells share two fundamental characteristics:

  1. they are self-renewing, and
  2. upon terminal division and differentiation they can give rise to the full range of cell classes within the relevant tissue.

Thus, a neural stem cell can give rise to another neural stem cell or to any of the main cell classes found in the central and peripheral nervous system (inhibitory and excitatory neurons, astrocytes, and oligodendrocytes; Figure A).

A neural stem cell is therefore distinct from a progenitor cell, which is incapable of continuing self-renewal and usually has the capacity to give rise to only one class of differentiated progeny.

  • An oligodendroglial progenitor, for example, continues to give rise to oligodendrocytes until it’s mitotic capacity is exhausted;
  • a neural stem cell, in contrast, can generate more stem cells as well as a full range of differentiated neural cell classes, presumably indefinitely.

Neural stem cells, and indeed all classes of somatic stem cells, are distinct from embryonic stem cells.

Embryonic stem cells (also known as ES cells) are derived from pre-gastrula embryos. ES cells also have the potential for infinite self-renewal and can give rise to all tissue and cell types throughout the organism including germ cells that can generate gametes (recall that somatic stem cells can only generate tissue specific cell types). Stem cells

There is some debate about the capacity of somatic stem cells to assume embryonic stem cell properties.

Some experiments with hematopoetic and neural stem cells indicate that these cells can give rise to appropriately differentiated cells in other tissues; however, some of these experiments have not been replicated.

The ultimate therapeutic promise of stem cells—neural or other types—is their ability to generate newly differentiated cell classes to replace those that may have been lost due to disease or injury.

Such therapies have been imagined for some forms of diabetes (replacement of islet cells that secrete insulin) and some hematopoetic diseases. In the nervous system, stem cell therapies have been suggested for replacement of dopaminergic cells lost to Parkinson’s disease and replacing lost neurons in other degenerative disorders.

While intriguing, this projected use of stem cell technology raises some significant perils.

  • These include insuring the controlled division of stem cells when introduced into mature tissue, and
  • identifying the appropriate molecular instructions to achieve differentiation of the desired cell class.

Clearly, the latter challenge will need to be met with a fuller understanding of the signalling and transcriptional regulatory steps used during development to guide differentiation of relevant neuron classes in the embryo.

At present, there is no clinically validated use of stem cells for human therapeutic applications in the nervous system. Nevertheless, some promising work in mice and other experimental animals indicates that both somatic and ES cells can acquire distinct identities if given appropriate instructions in vitro (i.e., prior to introduction into the host), and if delivered into a supportive host environment.

For example, ES cells grown in the presence of platelet-derived growth factor, which biases progenitors toward glial fates, can generate oligodendroglial cells that can myelinate axons in myelindeficient rats. Similarly, ES cells pretreated with retinoic acid matured into motor neurons when introduced into the developing spinal cord (Figure below).

While such experiments suggest that a combination of proper instruction and correct placement can lead to appropriate differentiation, there are still many issues to be resolved before the promise of stem cells for nervous system repair becomes a reality.

Schematic of the injection of fluorescently labeled embryonic stem (ES) cells into the spinal cord of a host chicken embryo.

ES cells integrate into the host spinal cord and apparently extendaxons.

the progeny of the grafted ES cells are seen in the ventral horn of the spinal cord. They have motor neuron-like morphologies, and their axons extend into the ventral root. (From Wichterle et al., 2002.)

Source: Neuroscience, 3rd edition
Editors: Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams.
Sunderland (MA): Sinauer Associates; 2004.
ISBN 0-87893-725-0

Microglia – Trying to Set a New Paradigm in the Realm of Brain’s Development, Homeostasis & Diseases

Microglia Cells Accelerate Damage from Retinitis Pigmentosa, Other Blinding Eye Diseases; Finding May Suggest Entirely New Therapeutic Strategies; Targeting Microglia May Complement Gene Therapy for RP http://www.bioquicknews.com/node/2770

The traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression.

Recent evidence extends their role to healthy brain homoeostasis, including the regulation of cell death, synapse elimination, neurogenesis and neuronal surveillance. These actions contribute to the maturation and plasticity of neural circuits that ultimately shape behaviour.

Gardeners know that some trees require regular pruning: some of their branches have to be cut so that others can grow stronger.

The same is true of the developing brain: cells called microglia prune the connections between neurones, shaping how the brain is wired.[https://www.embl.de/aboutus/communication_outreach/media_relations/2011/110721_Monterotondo/]

Electron micrograph showing the interaction of microglia (immunolabeled with and antibody to Iba1) and synaptic elements. Blue: axon terminal; Purple: dendrite and dendritic spine; Pink: microglia; Green: astrocyte. Scale bar: 250nm. http://www.urmc.rochester.edu/labs/majewska-lab/projects/microglial_function_in_the_healthy_brain

Microglia, the immune cells of the brain, have long been the underdogs of the glia world, passed over for other, flashier cousins, such as astrocytes. Although microglia are best known for being the brain’s primary defenders, scientists now realise that they play a role in the developing brain and may also be implicated in developmental and neurodegenerative disorders.

The change in attitude is clear, as evidenced by the buzz around this topic at this year’s Society for Neuroscience (SfN) conference, which took place from October 17 to 21 in Chicago (2015), where scientists discussed their role in both health and disease.

Activated in the diseased brain, microglia finds injured neurones and strip away the synapses, the connections between them. These cells make up around 10 percent of all the cells in the brain and appear during early development.

For decades scientists focussed on them as immune cells and thought that they were quiet and passive in the absence of an outside invader. That all changed in 2005 when experimenters found that microglia were actually the fastest-moving structures in a healthy adult brain. Later discoveries revealed that their branches were reaching out to surrounding neurones and contacting synapses. These findings suggested that these cellular scavengers were involved in functions beyond disease.

Microglial dynamics           https://www.youtube.com/watch?v=XPsGiTVNVnU

(In vivo imaging of microglial dynamics in Cx3CR1-GFP mice. Images were taken 5 minutes apart. Notice that dynamic microglial processes constantly explore the brain environment.)


Types of Synapses Image source


The Brain’s Sculptors

The discovery that microglia were active in the healthy brain jump-started the exploration into their underlying mechanisms:

Why do these cells hang around synapses?

And what are they doing?

For reasons scientists don’t yet understand, the brain begins with more synapses than it needs. “As the brain is making it’s [connections], it’s also eliminating them,” says Cornelius Gross, a neuroscientist at the European Molecular Biology Laboratory. Microglia a critical to this process, called pruning: they gobble up synapses, thus helping to sculpt the brain by eliminating unwanted connections.

But how do microglia know which synapses to get rid of and which to leave alone?

New evidence suggests that a protective tag that keeps healthy cells from being eaten by the body’s immune system may also shield against microglial activity in the brain. Emily Lehrman, a doctoral candidate in neuroscientist Beth Stevens’s laboratory at Boston’s Children’s Hospital, presented these unpublished findings at this year’s SfN (Society for Neuroscience (SfN) conference).

“The [protective tag]’s receptor is highly expressed in microglia during peak pruning,” Lehrman says. Without an abundance of this receptor, the tag is unable to protect the cells, leading to excess engulfment by microglia and overpruning of neuronal connections.

 But pruning is not always a bad thing. Other molecules work to ensure that microglia removes weak connections, which can be detrimental to brain function.

Cornelius Gross, a neuroscientist at the European Molecular Biology Laboratory, and his research group have been investigating the activity of fractalkine, a key molecule in neuron-microglia signalling whose receptors are found exclusively on microglia. “Microglia mature in a way that matches synaptogenesis, which sets up the hypothesis that neurones are calling out to microglia during this period,” Gross says.

His lab found that removing the receptor for fractalkine created an overabundance of weak synaptic contacts caused by deficient synaptic pruning during development in the hippocampus, a brain area involved in learning and memory. These pruning problems led to decreased functional connectivity in the brain, impaired social interactions and increased repetitive behaviour—all telltale signs of autism. Published last year in Nature Neuroscience, this work was also presented at the conference.

When Pruning Goes Awry

Studies have also found evidence for increased microglial activation in individuals with schizophrenia and autism; however, whether increased microglial activity is a cause or effect of these diseases is unclear. “We still need to understand whether pruning defects are contributing to these developmental disorders,” Stevens says.

Some findings are emerging from studies on Rett syndrome, a rare form of autism that affects only girls. Dorothy Schafer, now at the University of Massachusetts Medical School, studied microglia’s role in Rett syndrome while she was a postdoctoral researcher in Stevens’s lab. Using mice with mutations in MECP2, the predominant cause of the disease, she found that while microglia were not engulfing synapses during early development, the phagocytic capacity (or the gobbling ability) of these cells increased during the late stages of the disease. These unpublished results suggest that microglia were responding secondarily to a sick environment and partially resolve a debate going on about what microglia do in Rett syndrome—in recent years some studies have shown that microglia can arrest the pathology of disease, whereas others have indicated that they cannot. “Microglia are doing something, but in our research, it seems to be a secondary effect,” Shafer says. “What’s going on is still a huge mystery.”

Activated microglial cells (red) among a GFP-expressing neurone and astrocyte (green) in a rat hippocampal tissue slice. http://keck.bioimaging.wisc.edu/lecture-series-2006-2007.html

Return of the Pruning Shears

As the resident immune cells, microglia act as sentinels, sensing and removing disturbances in the brain. When the brain is exposed to injury or disease, microglia surrounds the damaged areas and eat up the remains of dying cells. In Alzheimer’s disease, for example, microglia are often found near the sites of beta-amyloid deposits, the toxic clumps of misfolded proteins that appear in the brain of affected people. On one hand, microglia may delay the progression of the disease by clearing cellular debris. But it is also possible that they are contributing to disease.

Early synapse loss is a hallmark of many neurodegenerative disorders. Growing evidence points to the possibility that microglial pruning pathways seen in early development may be reactivated later in life, leading to disease. Unpublished data from Stevens’s lab presented at the conference suggest that microglia are involved in the early stages of Alzheimer’s and that blocking microglia’s effects could reduce the synapse loss seen in Huntington’s disease.

As a newly burgeoning field, there are still more questions than answers. Next year’s conference is likely to bring us closer to understanding what these dynamic cells are doing in the brain.

Once the underdogs, microglia may be the key to future therapeutics for a wide variety of psychiatric and neurodegenerative disorders.

Source: Rise of the Microglia By Diana Kwon | October 23, 2015


Microglia represent the endogenous brain defence and immune system, which is responsible for CNS protection against various types of pathogenic factors. Microglial cells derive from progenitors that have migrated from the periphery and are from the mesodermal/ mesenchymal origin. During postnatal development, they immigrate into the brain commonly until postnatal day 10 in rodents. After invading the CNS, microglial precursors disseminate relatively homogeneously throughout the neural tissue and acquire a specific phenotype, which clearly distinguishes them from their precursors, the blood-derived monocytes.

The ´resting´ microglia are the fastest moving cells in the brain.

Under physiological conditions microglia in the CNS exist in the ramified or what was generally termed the ‘resting’ state. The resting microglial cell is characterised by a small cell body and much elaborated thin processes, which send multiple branches and extend in all directions. Similar to astrocytes, every microglial cell has its own territory, about 15 –  30 µm wide; there is very little overlap between neighbouring territories. The processes of resting microglial cells are constantly moving through its territory; this is a relatively rapid movement with a speed of about 1.5 µm/min and thus microglial processes represent the fastest moving structures in the brain. At the same time microglial processes also constantly send out and retract small protrusions, which can grow and shrink by 2–3 µm/min. The microglia seems to be randomly scanning through their domains. Recent studies, however, have demonstrated that these processes rest for periods of minutes at sites of synaptic contacts. Considering the velocity of this movement, the brain parenchyma can be completely scanned by microglial processes every several hours.

The motility of the processes is not affected by neuronal firing, but it is sensitive to activators (ATP and its analogues) and inhibitors of purinoceptors.

Focal neuronal damage induces a rapid and concerted movement of many microglial processes towards the site of lesion, and within less than an hour the latter can be completely surrounded by these processes. This injury-induced motility is also governed, at least in part, by activation of purinoceptors; it is also sensitive to the inhibition of gap junctions, which are present in astrocytes, but not in microglia; inhibition of gap junctions also affects the physiological motility of astroglial processes. Therefore, it appears that astrocytes signal to the microglia by releasing ATP (and possibly some other molecules) through connexin hemichannels.

All in all, microglial processes act as a very sophisticated and fast scanning system. This system can, by virtue of receptors residing in the microglial cell plasmalemma (plasma membrane), immediately detect injury and initiate the process of active response, which eventually triggers the full blown microglial activation.

Activation of microglia

When a brain insult is detected by microglial cells, they launch a specific program that results in the gradual transformation of resting, ramified microglia into an ameboid form; this process is generally referred to as ‘microglial activation’ and proceeds through several steps.

During the first stage of microglial activation resting microglia retract their processes, which become fewer and much thicker, increase the size of their cell bodies, change the expression of various enzymes and receptors, and begin to produce immune response molecules. Some microglial cells return into a proliferative mode, and microglial numbers around the lesion site start to multiply. Microglial cells become motile and using amoeboid-like movements they gather around sites of insult. If the damage persists and CNS cells begin to die, microglial cells undergo further transformation and become phagocytes. This is, naturally, a rather sketchy account of the complex and highly coordinated changes which occur in microglial cells; the process of activation is gradual and most likely many sub-states exist on the way from resting to phagocytic microglia. Furthermore, activated microglial cells may display quite heterogeneous properties in different types of pathologies and in different parts of the brain.

The precise nature of the initial signal that triggers the process of microglial activation is not fully understood; it may be associated either with the withdrawal of some molecules (the ‘off-signal’) released during normal CNS activity or by the appearance of abnormal molecules or abnormal concentrations of otherwise physiologically present molecules (on-signal). Both types of signalling can provide microglia with relevant information about the status of brain parenchyma within their territorial domain.

The ‘off-signals’ that may indicate deterioration in neural networks are not yet fully characterised. A good example of this type of communication are neurotransmitters. Microglial cells express a variety of the classical neurotransmitter receptors such as receptors for GABA, glutamate, dopamine, noradrenaline. In most cases, activation of the receptors counteracts the activation of microglial cells with respect to acquiring a pro-inflammatory phenotype. One might speculate that depression of neuronal activity could affect neighbouring microglia, turning them into an ‘alerted’ state. In fact, these ‘off-signals’ allow microglia to sense disturbance even if the nature of the damaging factor cannot be identified.

The ‘on-signalling’ is conveyed by a wide array of molecules, either associated with cell damage or with foreign matter invading the brain. In particular, damaged neurones can release high amounts of ATP, cytokines, neuropeptides, growth factors. Many of these factors can be sensed by microglia and trigger activation. It might well be that different molecules can activate various subprogrammes of this routine, regulate therefore the speed and degree of microglial activation. Some of these molecules can carry both ‘off’ and ‘on’ signals:


for example, low concentrations of ATP may be indicative of normal ongoing synaptic activity, whereas high concentrations signal cell damage.


Microglia are also capable of sensing disturbances in brain metabolism: for example, accumulation of ammonia, which follows grave metabolic failures (e.g. during hepatic encephalopathy) can activate microglial cells either directly or via intermediates such as NO (Nitric oxide) or ATP.

Spidery microglia, in red. From Kettenmann et al., Neuron 2013 http://phenomena.nationalgeographic.com/2013/01/11/best-cells-ever/


Migration and motility

Microglial migration is essential for many pathophysiological processes, including immune defence and wound healing.

Microglial cells exhibit two types of movement activity:

in the ramified (“resting”) form, they actively move their processes without translocation of the cell body as was already described above.

In the amoeboid form, microglial cells not only move their processes but in addition, the entire cell can migrate through the brain tissue. Microglial migration occurs in development when invading monocytes disseminate through the brain.

Another type of migration is triggered by a pathologic insult when ramified microglia undergoes activation, transform into the amoeboid form and migrate to the site of injury. There are many candidate molecules which may serve as pathological signals and initiate microglial migration and act as chemoattractant molecules. These molecules include ATP, cannabinoids, chemokines, lysophosphatidic acid and bradykinin. The actual movement of microglial cells involves redistribution of salt and water and various ion channels and transporters important for this process. In particular, K+ channels, Cl channels, Na+/H+ exchanger, Cl/HCO3 exchanger, and Na+/HCO3 co-transporter contribute to microglial motility and migration.


The influence of gold surface texture on microglia morphology and activation Microglia seeded on glass, ultra-flat gold (UF-Au), ultra-thin (UT) nanoporous gold (np-Au) np-Au and np-Au monolith were adherent to all surfaces and their viability was not compromised as assessed by multiple toxicity assays. http://pubs.rsc.org/en/Content/ArticleLanding/2014/BM/C3BM60096C#!divAbstract


Microglial cells are the professional innate phagocytes of the CNS tissue.

This function is important for the normal brain, during brain development; in pathology and regeneration.

In the CNS development, microglial phagocytosis is instrumental in removing apoptotic cells and may be involved in synapse removal during development and potentially in pruning synapses in the postnatal brain. Microglial phagocytosis is intimately involved in many neurological diseases. In response to the lesion, microglial cells accumulate at the damaged site and remove cellular debris or even parts of damaged cells.

Through phagocytosis, microglial cells can also accumulate various pathological factors such as for example beta-amyloid in Alzheimer’s disease or myelin fragments in demyelinating diseases. Multiple factors, receptors and signalling cascades can regulate the phagocytic activity. In particular, microglial phagocytosis is controlled by purinoceptors; the metabotropic P2Y6 receptors stimulate whereas ionotropic P2X7 receptors inhibit phagocytotic activity. Microglial phagocytosis is also controlled by the glial-derived neurotrophic factor, by the ciliary neurotrophic factor, by TOLL receptors, by prostanoid receptor etc.


Age-primed microglia hypothesis of Parkinson’s disease. Microglia functions differentially in the young (left) and aged (right) brain. Left: when facing pathogenic stimuli (large black dots), the healthy microglia in the young brain respond by releasing neurotrophic factors (small yellow dots) to support the endangered dopaminergic neurones and limit neuronal damages. Right: in the aged brain oxidative stress and inflammatory factors (small black dots), which damage the vulnerable dopaminergic neurones and eventually lead to neurodegeneration. (From Luo et al.,2010 with permission). Image source

Antigen presentation

Microglial cells are the dominant antigen presenting cells in the central nervous system. Under resting conditions the expression of the molecular complex for presenting antigen, the major histocompatibility complex II (MHCII) and co-stimulatory molecules such as CD80, CD86 and CD40 is below detection. Upon injury, the molecules are highly upregulated and the expression of this complex is essential for interacting with T lymphocytes. This up-regulation has been described in a number of pathologies and is well studied in Multiple Sclerosis. Microglial cells phagocytose myelin, degrade it and present peptides of the myelin proteins as antigens. By releasing cytokines such as CCl2 microglial cells are important for recruiting leukocytes into the CNS. Microglia interacts with infiltrating T lymphocytes, and thus, mediate the immune response in the brain. They have the capacity to stimulate proliferation of both TH1- and TH2-CD4 positive T cells.

Source: http://www.networkglia.eu/en/microglia

microglial and mo-MΦ functions – cascade of events. (a) Resident microglia originates from yolk sac macrophages that repopulate CNS parenchyma during early development and are self-renewed locally, independent from bone marrow-derived monocytes, by the proliferation of primitive progenitors. (b) In the steady state, microglia are constantly scanning their environment through their highly motile processes. These cells facilitate the maintenance of synapses (c) and neurogenesis (d), as well as secrete growth factors essential for normal CNS performance (e). Upon recognition of a danger signal, microglia retracts their branches, become round and ameboid, and convert into an activated mode (f). A short or moderate signal directs microglia toward a neuroprotective phenotype; these cells clear debris by phagocytosis (g), secrete growth factors associated with remyelination (h) and support regeneration (i). Intensive acute or chronic activation renders microglia neurotoxic; under such conditions, microglia fails to acquire a neuroprotective phenotype. Instead, these cells produce reactive oxygen species (ROS), nitric oxide (NO), proteases, and pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, all of which endanger neuronal activity (j). Microglial malfunction results in the recruitment of mo-MΦ to the damage site (k). mo-MΦ secrete anti-inflammatory cytokines such as IL-10 and TGF-β, express factors associated with an immune resolution such as mannose receptor and arginase 1 (ARG1), and promote neuroprotection and cell renewal (l), all of which are functions that cannot be provided, under these conditions, by the resident microglia. http://journal.frontiersin.org/article/10.3389/fncel.2013.00034/full

Signalling pathways implicated in the phagocytosis of neurons and neuronal structures.

Signalling pathways implicated in the phagocytosis of neurones and neuronal structures. Microglial phagocytosis of neurones is regulated by the neuronal presentation and microglial recognition of ‘eat-me’ (left) and ‘don’t eat-me’ (right) signals. However, note that the utilisation of different signals, opsonins and receptors is dependent on the specific (patho)physiological context. Neuronal eat-me signals are recognised by microglial phagocytic receptors either directly or following their binding by opsonins, which are in turn recognised by microglial receptors. Phosphatidylserine that is exposed on neurons can be bound by the opsonins milk fat globule-EGF factor 8 (MFG-E8), growth arrest-specific protein 6 (GAS6) or protein S, which can induce phagocytosis by binding to and activating a vitronectin receptor (VNR) (in the case of MFG-E8) or MER receptor tyrosine kinase (MERTK) (in the case of GAS6 or protein S). Note that stimulation of MERTK can also occur downstream of VNR activation (dashed arrow). Alternatively, neuron-exposed phosphatidylserine may directly bind to brain-specific angiogenesis inhibitor 1 (BAI1) on microglia, and neuron-exposed calreticulin or neuron-bound C1q can induce phagocytosis by activating the microglial low-density lipoprotein receptor-related protein (LRP). C1q can also bind to glycoproteins from which sialic acid residues have been removed by the enzyme neuraminidase. C1q deposition on desialylated glycoproteins, in turn, leads to the conversion of C3 to the opsonin C3b, which activates neuronal phagocytosis via the microglial complement receptor 3 (CR3) and its signalling partner DNAX-activation protein 12 (DAP12). By contrast, neuronal don’t eat-me signals inhibit phagocytosis and can in some instances also suppress inflammation. Neuronal CD47 and sialylated glycoproteins inhibit phagocytosis of neurones by binding to the microglial receptors signal regulatory protein 1α (SIRP1α) and sialic acid binding immunoglobulin-like lectins (SIGLECs), respectively.

Microglial phagocytosis of live cells and neuronal structures.

Microglial phagocytosis of live cells and neuronal structures. The figure illustrates situations in which phagocytic recognition leads to the removal of neuronal structures (synapses and neurites) or live cells (glioma cells, neutrophils, neuronal precursors and stressed-but-viable neurones) in the CNS. The shown pathways have been implicated in mediating phagocytic recognition of each target, but other signals may contribute to these processes. a | During development as well as in the adult animal, weak synapses are removed through a process that is dependent on the complement components C1q and C3 and the microglial complement receptor 3 (CR3). b | During development, microglia phagocytose live neuronal progenitors, and this involves the local release of reactive oxygen and nitrogen species (RONS) by microglia. RONS may induce caspase 3 activation in the targeted neuronal progenitor, which may be phagocytosed via the CR3-subunit CD11b and the adaptor protein DNAX-activation protein 12 (DAP12). c | During brain pathology, sub-toxic neuronal insults (such as inflammation, oxidative stress, excessive levels of glutamate or energy depletion) can induce the reversible exposure of the neuronal eat-me signal phosphatidylserine. Phosphatidylserine is recognised by the opsonin milk fat globule-EGF factor 8 (MFG-E8), which induces phagocytosis through activation of the microglial vitronectin receptor (VNR). In addition, MER receptor tyrosine kinase (MERTK)9 also contributes to phagocytic signalling under these circumstances, either through its activation downstream of VNR or through the recognition of unidentified opsonins or eat-me signals. d,e | In addition to the removal of neurones, neuronal precursors and neuronal structures, microglia can phagocytose live neutrophils through activation of the microglial VNR and lectins, or live glioma cells19 through microglial sialic acid binding immunoglobulin-like lectin-H (SIGLEC-H) and DAP12.

Mechanisms mediating microglial phagocytosis of stressed-but-viable neurons during inflammation.

Mechanisms mediating microglial phagocytosis of stressed-but-viable neurones during inflammation. Activation of microglial Toll-like receptor 2 (TLR2) and TLR4 by damage- or pathogen-associated molecules or by amyloid-β results in the release of reactive oxygen and nitrogen species (RONS) derived from inducible nitric oxide synthase (iNOS) and NADPH oxidase (PHOX). RONS can cause nearby neurones to expose phosphatidylserine in a reversible manner on their surface5 through the stimulation of a phosphatidylserine scramblase (probably a TMEM16 protein26) and/or the inhibition of a phosphatidylserine translocase (probably type 4 P-type ATPases (P4-ATPases) ATP8A1 or ATP8A2 ). Neuronal stress induced by activated microglia or by other means may also cause exposure of phosphatidylserine on stressed-but-viable neurons via calcium- or RONS-mediated activation of a scramblase or inhibition of a translocase, via ATP depletion-induced inhibition of translocase or, in some circumstances, via caspase-mediated activation of a distinct scramblase (probably XK-related protein 8 (XKR8)). Exposed phosphatidylserine is bound by milk fat globule-EGF factor 8 (MFG-E8), which is released by activated microglia and astrocytes and which promotes phagocytosis of the phosphatidylserine-tagged neurone through the vitronectin receptor (VNR). The VNR may drive phagocytosis by triggering actin polymerization in synergy with MER receptor tyrosine kinase (MERTK). MERTK is upregulated by microglia activation and may also bind to neurones via opsonins that bind exposed phosphatidylserine or other eat-me signals.

—Summary Of Evidence —

That Molecular Pathways Characterised In Pathology Are Also Utilised By MICROGLIA —-

In The Normal And Developing Brain To Influence Synaptic Development And Connectivity,

And Therefore Should Become Targets Of Future Research

Microglia: New Roles for the Synaptic Stripper

Neurone: Volume 77, Issue 1, 9 January 2013, Pages 10–18

Helmut Kettenmann(1), Frank Kirchhoff(2), Alexei Verkhratsky(3, 4)

  • 1 Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
  • 2 Department of Molecular Physiology, University of Saarland, 66424 Homburg, Germany
  • 3 Faculty of Life Sciences, The University of Manchester, Manchester M13 9PL, UK
  • 4 Achucarro Center for Neuroscience, Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Spain

For more details

Physiology of Microglia

Helmut Kettenmann, Uwe-Karsten Hanisch, Mami Noda, Alexei Verkhratsky
  1. Matthew R. Ritter, Eyal Banin, Stacey K., Moreno, Edith Aguilar, Michael I, Dorrell, and Martin Friedlander.  Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy: J Clin Invest. 2006 Dec 1; 116(12): 3266–3276. Vision loss associated with ischemic diseases such as retinopathy of prematurity and diabetic retinopathy are often due to retinal neovascularization. While significant progress has been made in the development of compounds useful for the treatment of abnormal vascular permeability and proliferation, such therapies do not address the underlying hypoxia that stimulates the observed vascular growth. Using a model of oxygen-induced retinopathy, we demonstrate that a population of adult BM–derived myeloid progenitor cells migrated to avascular regions of the retina, differentiated into microglia, and facilitated normalisation of the vasculature. Myeloid-specific hypoxia-inducible factor 1α (HIF-1α) expression was required for this function, and we also demonstrate that endogenous microglia participated in retinal vascularization. These findings suggest what we believe to be a novel therapeutic approach for the treatment of ischemic retinopathies that promotes vascular repair rather than destruction.
  2. Judy Choi, Qingdong Zheng, Howard E. Katz, Tomás R., Guilarte. Silica-Based Nanoparticle Uptake and Cellular Response by Primary Microglia: Environ Health Perspect 118:589-595 (2010). http://dx.doi.org/10.1289/ehp.0901534 [online 21 December 2009]    Silica nanoparticles (SiNPs) are being formulated for cellular imaging and for nonviral gene delivery in the central nervous system (CNS), but it is unclear what potential effects SiNPs can elicit once they enter the CNS. As the resident macrophages of the CNS, microglia are the cells most likely to respond to SiNP entry into the brain. Upon activation, they are capable of undergoing morphological and functional changes.  This is the first study demonstrating the in vitro effects of SiNPs in primary microglia. Our findings suggest that very low levels of SiNPs are capable of altering microglial function. Increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, changes in proinflammatory genes, and cytokine release may not only adversely affect microglial function but also affect surrounding neurones.
  3. Yang Zhan, Rosa C Paolicelli, Francesco Sforazzini et al. Deficient neuron-microglia signalling results in impaired functional brain connectivity and social behaviour: Nature Neuroscience; March 2104; vol. 17; number 3; pg 400-406. In summary, our findings reveal a role for microglia in promoting the maturation of circuit connectivity during development, with synapse elimination going hand in hand with enhanced synaptic multiplicity. Our data support the hypothesis that microglia-mediated synaptic pruning during development has a critical role in sculpting neural circuit function, which may contribute to the physiological and behavioural features of a range of neurodevelopmental disorders. Our data also opens the possibilty that genetic and environmental risk factors for such disorders may exert their effect by modulating synapse elimination. Further studies are warranted to test the hypothesis that variation in synaptic pruning may underlie individual differences in human brain wiring.
  4. Juan I. Rodriguez, Janet K. Kern. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol. 2011 May; 7(2-4): 205–213. Evidence indicates that children with autism spectrum disorder (ASD) suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation. When microglia remain activated for an extended period, the production of mediators is sustained longer than usual and this increase in mediators contributes to loss of synaptic connections and neuronal cell death. Microglial activation can then result in a loss of connections or underconnectivity. Underconnectivity is reported in many studies in autism. One way to control neuroinflammation is to reduce or inhibit microglial activation. It is plausible that by reducing brain inflammation and microglial activation, the neurodestructive effects of chronic inflammation could be reduced and allow for improved developmental outcomes. Future studies that examine treatments that may reduce microglial activation and neuroinflammation, and ultimately help to mitigate symptoms in ASD, are warranted.

    An external file that holds a picture, illustration, etc.Object name is S1740925X12000142_fig1.jpg

    This diagram shows the relationships and interplay between microglial activation and the neuropathology, medical issues and symptoms in ASD. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523548/figure/fig01

  5. Anat London, Merav Cohen and Michal Schwartz. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair.  Front. Cell. Neurosci., 08 April 2013 | http://dx.doi.org/10.3389/fncel.2013.00034
  6. Carmelina Gemma and Adam D. Bachstetter. The role of microglia in adult hippocampal neurogenesis. Front. Cell. Neurosci., 22 November 2013 | http://dx.doi.org/10.3389/fncel.2013.00229
  7. Sabine Hellwig, Annette Heinrich and Knut Biber. The brain’s best friend: microglial neurotoxicity revisited. Front. Cell. Neurosci., 16 May 2013 | http://dx.doi.org/10.3389/fncel.2013.00071
  8. Peter Thériault, Ayman ElAli and Serge Rivest. The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimer’s Research & Therapy 2015, 7:41 doi:10.1186/s13195-015-0125-2      The present review summarises current knowledge on the role of monocytes and microglia in AD and how these cells can be mobilised to prevent and treat the disease.
  9. Guy C. Brown & Jonas J. Neher. Microglial phagocytosis of live neurones. Nature Reviews Neuroscience 15, 209–216 (2014) doi:10.1038/nrn3710
    Published online 20 March 2014.
  10. Neuropathology. APPLIED NEUROCYTOLOGY AND BASIC REACTIONS. Dimitri P. Agamanolis, M.D. 
  11. Rosa C. Paolicelli, Giulia Bolasco, Francesca Pagani et al. Synaptic Pruning by Microglia Is Necessary for Normal Brain Development. Published Online July 21, 2011. Science 9 September 2011: Vol. 333 no. 6048 pp. 1456-1458
    DOI: 10.1126/science.1202529
  12. Axel Nimmerjahn, Frank Kirchhoff, Fritjof Helmchen. Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo. Published Online April 14, 2005. Science 27 May 2005: Vol. 308 no. 5726 pp. 1314-1318. DOI: 10.1126/science.1110647
  13. Hiroaki Wake, Andrew J. Moorhouse, Shozo Jinno, Shinichi Kohsaka, and Junichi Nabekura. Resting Microglia Directly Monitor the Functional State of Synapses In Vivo and Determine the Fate of Ischemic Terminals. The Journal of Neuroscience, 1 April 2009, 29(13): 3974-3980; doi: 10.1523/JNEUROSCI.4363-08.2009. In summary, we report direct, activity-dependent connections between microglia and synapses and have quantified the kinetics of this interaction. These interactions are very consistent in the control brain but markedly prolonged in the ischemic brain. We propose that microglia detects the functional state of the synapses, responding with prolonged contact under pathological conditions. Such prolonged contact is followed on some occasions by synapse elimination, suggesting that microglia are perhaps either attempting to restore synapse function or initiating their subsequent removal (as illustrated schematically in supplemental Fig. 3, available at www.jneurosci.org as supplemental material). Such microglial diagnosis of synapse function is likely to be important in any subsequent remodelling of neuronal circuits after brain injury and provides a novel target for the development of new therapies to improve the recovery of neuronal function after brain damage.
  14. Sarah E. Schipul, Timothy A. Keller, and Marcel Adam Just. Inter-Regional Brain Communication and It’s Disturbance in Autism. Front Syst Neurosci. 2011; 5: 10.
    Published online 2011 Feb 22. doi: 10.3389/fnsys.2011.00010     Recent findings of atypical patterns in both functional and anatomical connectivity in autism have established that autism is a not a localised neurological disorder, but one that affects many parts of the brain in many types of thinking tasks. fMRI studies repeatedly find evidence of decreased coordination between frontal and posterior brain regions in autism, as measured by functional connectivity. Furthermore, neuroimaging studies have also shown evidence of an atypical pattern of frontal white matter development in autism. These findings indicate that limitations of brain connectivity give rise to the varied behavioural deficits found in autism. As research continues to explore these biological mechanisms, new intervention methods may be developed to help improve brain connectivity and overcome the behavioural impairments of autism.
  15. Noël C. Derecki, James C. Cronk, Zhenjie Lu, Eric Xu, Stephen B. G. Abbott, Patrice G. Guyenet & Jonathan Kipnis. Wild-type microglia arrests pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (05 April 2012) doi:10.1038/nature10907
  16. Jieqi Wang, Jan-Eike Wegener, Teng-Wei Huang, Smitha Sripathy, Hector De Jesus-Cortes, Pin Xu, Stephanie Tran, Whitney Knobbe, Vid Leko, Jeremiah Britt, Ruth Starwalt, Latisha McDaniel, Chris S. Ward, Diana Parra, Benjamin Newcomb, Uyen Lao, Cynthia Nourigat, David A. Flowers, Sean Cullen, Nikolas L. Jorstad, Yue Yang, Lena Glaskova, Sébastien Vigneau, Julia Kozlitina, Michael J. Yetman et al. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521, E1–E4 (21 May 2015) doi:10.1038/nature14444

Does Glial Cells Have Any Role in Generating & Propagating Creative Thought ? Nearly 80 – 90 % of the Brain is Composed of Glia.

Until recently, neuroscientists thought glial cells did little more than hold your brain together. But in the past few years, they’ve discovered that glial cells are extraordinarily important. In fact, they may hold the key to understanding intelligence, treating psychiatric disorders and brain injuries and perhaps even curing fatal conditions like Alzheimer’s, Parkinson’s, and Lou Gehrig’s Disease.

In The Root of Thought, leading neuroscientist Dr. Andrew Koob reveals what we’ve learned about these remarkable cells, from their unexpected role in information storage to their function as adult stem cells that can keep your brain growing and adapting longer than scientists ever imagined possible.

Ranging from fruit flies to Einstein, Koob reveals the surprising correlation between intelligence and the brain’s percentage of glial cells – and why these cells’ unique wavelike communications may be especially conducive to the fluid information processing human beings depend upon.

Here’s an introductory teaser to five types of glia researchers have discovered so far:

Astrocytes: The star-shaped astrocyte uses thousands of arms to take up neurotransmitters, cleaning up after neuronal activity. Scientists suspect that they’re the most common type of glial cell in the brain, and some believe that the calcium waves astrocytes generate may underlie creative thought.

Oligodendrocytes: The octopus-like oligodendrocyte wraps the tips of its tentacles around axons in a fatty white coating called myelin. Studying such ‘white matter’ may provide insights into intelligence and learning and problems with myelin are at the heart of diseases such as multiple sclerosis.

Schwann cells: Much like an oligodendrocyte’s protective tentacles, Schwann cells form a snug layer of myelin around the axon like the bread around a corn dog. As the only glial cell in the peripheral nervous system—the nerves outside the brain and spinal cord—Schwann cells adopt a range of different roles, including astrocyte-like chemical clean ups.

Microglia: While the previous three cells belong to a category called macroglia, there are also smaller microglia. These wee cells are the brain’s rapid response team. Since the immune system’s molecular machines can’t cross the blood-brain barrier, the versatile microglia defends the brain from invaders.

NG2 Cells: Their name may not be that memorable, but NG2s—or the cell previously known as “oligodendrocyte precursor cells“—are big news in the world of glia research and may even constitute a whole new category of macroglia. These cells transform not only into different kinds of glia, such as oligodendrocytes and astrocytes but also into neurones, further blurring the lines that distinguish the two types of cells.


Astrocytes are shown in red, OPCs in green, and neurones in blue. The cells are taken from rat hippocampus and grown in culture. Credit:  Dr. Jonathan Cohen, NICHD. R. Douglas Fields, Ph. D. is the Chief of the Nervous System Development and Plasticity Section at the National Institute of Child Health and Human Development and Adjunct Professor at the University of Maryland, College Park. Fields, who conducted postdoctoral research at Stanford University, Yale University, and the NIH, is Editor-in-Chief of the journal Neuron Glia Biology and a member of the editorial board of several other journals in the field of neuroscience.

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Káradóttir et al report that some NG2+ glia can be induced to fire action potentials by excitatory synaptic input (highlighted by red starbursts) formed by myelinated (top) or unmyelinated (bottom) axons. The physiological role of NG2+ cell excitability is not yet clear, but, as suggested by the authors, may influence the transition of NG2+ cells into myelinating oligodendrocytes. These NG2+ cells have processes that wrap nodes of Ranvier, and they might, therefore, be well positioned for a role in optimising nodal spacing or stability. Image source

One learns how crucial glial cells grow and develop

why almost all brain tumours are comprised of glial cells and

the potential implications for treatment

even the apparent role of glial cells in our every thought and dream!



The structures within the brain are made up of about 100 billion neurons, as well as trillions of support cells called glia. Neurons may be the more important cells in the brain that relay messages about what you’re thinking, feeling, or doing. But they couldn’t do it without a little help from their friends, the glial cells.  There are a few different types of glia in the brain: oligodendrocytes, microglia, and astrocytes. Each is needed to optimize brain function. Oligodendrocytes are specialized cells that wrap tightly around axons to form the myelin sheath. These cells speed up the electrical signals (action potentials) that travel down an axon. Without oligodendrocytes, an action potential would travel down an axon 30 times slower! http://learn.genetics.utah.edu/content/neuroscience/braincells/



Microglia are mesodermal in origin.



Astrocytes are star-shaped glia that hold neurons in place, supply nutrients, and digest parts of dead neurons. But because astrocytes cannot generate action potentials, they haven’t gotten much attention, until recently. http://learn.genetics.utah.edu/content/neuroscience/braincells/ Astrocytes can actually communicate with neurons and modify the signals they send and receive. That means astrocytes are much more involved than we once thought in both the processing of information, and the signaling at the synapse.



Astrocytes appear to be involved in almost all aspects of brain function. Scientists want to know more about how gliotransmitters can inhibit, stimulate, or fine-tune the action potentials fired by neurons. But astrocytes may even do more. There is growing evidence that astrocytes can alter how a neuron is built by directing where to make synapses or dendritic spines. They can also attract new cells (like immune cells and perhaps even adult neural stem cells) to repair damage. The Future of Gliotransmission Knowing more about astrocytes will also shed light on diseases in which communication between astrocytes and neurons is altered, including Alzheimer’s disease, AIDS, brain cancer, and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease). http://learn.genetics.utah.edu/content/neuroscience/braincells/


Why glia have been overlooked for centuries, and how new experiments with glial cells shed light on some of the most mysterious aspects of the mind?

Originally, scientists didn’t think they did anything.  Until the last 20 years, brain scientists believed neurones communicated to each other, represented our thoughts, and that glia were kind of like stucco (A plaster now made mostly from Portland cement and sand and lime; applied while soft to cover exterior walls or surfaces) and mortar holding the house together.  They were considered simple insulators for neurone communication.

There are a few types of glial cells, but recently scientists have begun to focus on a particular type of glial cell called the ‘astrocyte’, as they are abundant in the cortex.

Interestingly, as you go up the evolutionary ladder, astrocytes in the cortex increase in size and number, with humans having the most astrocytes and also the biggest

Scientists have also discovered that astrocytes communicate to themselves in the cortex and are also capable of sending information to neurones.

Finally, ‘astrocytes’ are also the

adult stem cell in the brain [Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain.]

  • There is another study which identifies Ependymal cells as neural stem cells.[Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System]. New neurons are continuously generated in specific regions of the adult mammalian brain. These neurons are derived from multipotent stem cells, the identity of which has been enigmatic. We show here that ependymal cells are neural stem cells and that they generate olfactory bulb neurons. Ependymal cells divide rarely, but after an injury the proliferation rate increases and their progeny migrates to the site of the lesion, where they differentiate to astrocytes.

and astrocytes control blood flow to regions of brain activity. Because of all these important properties, and since the cortex is believed responsible for higher thought, scientists have started to realize that astrocytes must contribute to thought.

Why have glia been neglected for so long?

To understand this, you have to take a tour of the history of brain science.

Glia were mainly a sidebar for 200 years in the struggle over the idea of the neurone.

A few highlights were: In the late 18th century, scientists discovered the electrical properties of the neurone in the spine of frogs. Neurones have long tethers that are easy to study called ‘axons’ that extend from the cell body from the brain into the spine and the spine out to the limbs and body. Similarly, neurones in the senses were linked to the neurones in the brain. This is where the notion of neurones as the base of our thoughts took root. In the mid-19th century, glia were just being discovered, and researchers figured the glial cells simply held the neurones together (glia is greek for glue).

What I find sort of hilarious is that scientists stumbled upon a very numerous cell in the brain, an organ responsible for our thoughts and personality, but they were so focused on neurones that they concluded the new cell was worthless. In the late 19th century a staining method was developed to look at cells more effectively in the brain.

A brilliant researcher from Spain, Santiago Ramon y Cajal, took it upon himself to study the brain from the perspective of neurons. He meticulously mapped out a scheme for how they process information and are connected, which led to “The Neuron Doctrine.”  (“The Neuron Doctrine” is a belief that neurons are responsible for our thoughts.)

However, Cajal seemed inconvenienced by glial cells. They were very numerous and obviously hanging out all over the cortex.  Meanwhile, his brother Pedro, who was also a scientist, developed the theory that glial cells were ‘support cells’ that insulated neuron electrical propertiesCajal decided to back his brother’s theory.  And since 1906 when he won the Nobel prize, this has been the dogma. (A doctrine or code of beliefs accepted as authoritative)

Some of the early experiments that first led scientists to reconsider the role of glial cells?

Glial experiments didn’t get going until the 1960s. All scientists knew about glia was that if you put neurones in a petri dish, you had to have glia, or neurones would die. Then, Stephen W. Kuffler at Harvard, for reasons unknown, decided to test Pedro’s accepted theory of insulation. This was around same time that cell counts in the brain revealed glial cells to be nearly 90% of the brain (this is where the neurone based idea that we only use 10% of our brain comes from). Kuffler is notable because he ironically established the Harvard ‘neuro’ biology department while he was performing these groundbreaking glial experiments.

Anyway, Kuffler took astrocytes from the leech and mud puppy and added potassium, something that is known to flow out of neurons after they are stimulated. He thought this would confirm Pedro’s theory that glial cells were insulators. What he found instead was that the electrical potential of glial cells responded to potassium. Kuffler and colleagues found that astrocytes exhibited an electrical potential, much like neurons. They also discovered in the frog and the leech that astrocytes were influenced by neuronal ion exchange, a process long held to be the chemical counterpart to thought. Since then many researchers have completed experiments on the communicatory ability of glial cells with neurons, including in the late 80s and early 90s when it was discovered glial cells respond to and release ‘neuro’ transmitters.

Why are calcium waves important?

In short, calcium waves are how astrocytes communicate to themselves. Astrocytes have hundreds of ‘endfeet’ spreading out from their body. They look like mini octopi, and they link these endfeet with blood vessels, other astrocytes and neuronal synapses. Calcium is released from internal stores in astrocytes as they are stimulated, then calcium travels through their endfeet to other astrocytes. The term ‘calcium waves’ describes the calcium release and exchange between astrocytes, and between, astrocytes and neurons. Scientists at Yale, most notably Ann H. Cornell-Bell and Steven Finkbeiner, have shown that calcium waves can spread from the point of stimulation of one astrocyte to all other astrocytes in an area hundreds of times the size of the original astrocyte.

Furthermore, calcium waves can also cause neurones to fire.

And calcium waves in the cortex are leading scientists to infer that this style of communication may be conducive to the processing of certain thoughts.

If that isn’t convincing, it was recently shown that a molecule that stimulates the same receptors as Tetrahydrocannabinol (THC) can ignite astrocyte calcium release.

Glia and their calcium waves might play a role in creativity.

This idea stems from dreams, sensory deprivation and day dreaming.

Without input from our senses through neurones, how is it that we have such vivid thoughts?

How is it that when we are deep in thought we seemingly shut off everything in the environment around us?

In this theory, neurones are tied to our muscular action and external senses. We know astrocytes monitor neurones for this information. Similarly, they can induce neurones to fire. Therefore, astrocytes modulate neurone behaviour.

This could mean that calcium waves in astrocytes are our thinking mind.

Neuronal activity without astrocyte processing is a simple reflex; anything more complicated might require astrocyte processing.

The fact that humans have the most abundant and largest astrocytes of any animal and we are capable of creativity and imagination also lends credence to this speculation.

Calcium is also released randomly and without stimulation from astrocytes’ internal stores in small bursts called ‘puffs.’ These random puffs can lead to waves. It is possible that the seemingly random thoughts during dreams and sensory deprivation experience could be calcium puffs becoming waves in our astrocytes.

Basically, it is obvious that astrocytes are involved in brain processing in the cortex, but the main questions are,

Do our thoughts and imagination stem from astrocytes working together with neurones, or are our thoughts and imagination solely the domain of astrocytes?

Maybe the role of neurones is to support astrocytes.


Adapted from

Andrew Koob

The Root of Thought: What Do Glial Cells Do? 

Andrew Koob received his PhD in neuroscience from Purdue University in 2005 and has held research positions at Dartmouth College, the University of California, San Diego, and the University of Munich, Germany. He’s also the author of The Root of Thought, which explores the purpose and function of glial cells, the most abundant cell type in the brain

A Brief Historical Perspective

Source: www.oxfordscholarship.com

 The Concept of Neuroglia: A Historical Perspective

Image Credit

Virchow’s illustration of neuroglia.

A. Ependyma and neuroglia in the floor of the fourth ventricle. Between the ependyma and the nerve fibres is “the free portion of the neuroglia with numerous connective tissue corpuscles and nuclei.” Numerous corpora amylacea are also visible, shown enlarged below the main illustration (ca).

E: ependymal epithelium;

N: nerve fibres;

v-w: blood vessel.

B: Elements of neuroglia from white matter of the human cerebral hemispheres.

a. free nuclei with nucleoli;

b. nuclei with partially destroyed cell bodies;

c: complete cells. (From Virchow, 1858.)

We may conclude, therefore (although it is not emphasised in most historical accounts), that Virchow in 1856 used the term neuroglia to refer to the interstitial substance, not to the cellular elements within it. Time has blurred this distinction.

What then is Virchow’s interstitial substance or tissue in today’s terms?

It is undoubtedly the complex, space-filling processes of macroglial cells, especially astrocytes (Nedergaard et al., 2003). So, in retrospect, the meaning of Virchow’s term neuroglia morphed to accommodate the reality that neuroglial cells are the material between neurones. In other words, the two terms, neuroglia and neuroglial cells, soon became synonymous.


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Retinal neuroglial cells.

A. Cross section of frog retina. Note the radial (i.e., Müller) cells with their characteristic endfeet in the layer numbered “8.”

B. Isolated radial fibres from the frog retina.

C. Müller fibres of the sheep retina. Brush-like processes extend from the Müller fibre in the outer granular layer (labelled y); b. very delicate network of fenestrated membranes similar to those in the ganglion cell layer; c. network in the molecular layer; d. nuclei shown as part of the Müller fibres; e. cavity in which the nuclei or the cells of the internal granular layer are located.

A and B from Müller (1856). C from Schultze (1859).


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Deiters’ illustrations of connective tissue cells.

A. Connective tissue cell from white matter.

B. Connective tissue cell from grey matter (hypoglossal nucleus). (From Deiters, 1865.)

C. The section from the spinal cord of the ox stained by carmine after chromic acid preparation. 1. grey matter; 2. white matter with exposed axons; multipolar connective tissue cells (magnification 400×). (From Henle and Merkel, 1869.)


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Neuroglial cells depicted in Golgi’s early work.

A. a. Neuroglial cell from the superficial layer of the cerebral cortex; b. neuroglial cell from the deeper cortical layer of the

cerebrum from a 2-month-old child. The cell bodies and proximal processes contain fat droplets.

B. Slice of the cerebral cortex hardened in osmium; a. blood vessel; b. neuroglial cells with multiple thread-like processes;

c. processes from neuroglial cells terminating on the vessel wall.

C. Section through deep white matter tracts. Between the axons and directly attached are several flattened neuroglial cells.

Neuroglial processes project in all directions among the axons and attach to their ensheathments.

D. Neuroglial cells in white matter. Longitudinal view of neuroglial cells showing their relationship to axons. All panels from Golgi (1894).

Golgi’s greatest contribution, some would argue, was his famous ‘La reaziona nera’, or ‘the black reaction’, that permitted entire neurones and glial cells to be stained. While this method (potassium dichromate-silver) did not distinguish between neurones and neuroglia, it allowed them to be visualised better than ever before and in their entirety. Only later would specific stains for neuroglia appear (Cajal, 1913; Rio-Hortega, 1919).

So impressive were the gains in knowledge that by 1909 Cajal could say (Cajal, 1995): “We have emphasised that two special elements, which are really abstractions derived from many examples, form all neural tissue: the neurone with its various processes and the glial cell.”

Image Credit

Vertical slice from the human cerebellum showing the glial cells in this structure, including the Golgi epithelial cells (also known as Bergmann glial cells). (From Golgi (1894).


In 1893 Michael von Lenhossek (1863–1937) from Würzburg introduced the term astrocyte to refer to star-shaped neuroglial cells. Because Virchow thought that neuroglia constituted connective tissue, it was assumed that these cells must arise from mesoderm. This idea died slowly. The failure of connective tissue stains, increasingly specific for mesoderm, to stain these cells was one line of evidence refuting the idea that they were mesodermal, but it left open the defence that negative results might only mean that neuroglial cells were a special type of connective tissue. Wilhelm His (1831–1904) studied early development and recognized that neuroblasts and spongioblasts, which formed radial glia, are both of ectodermal origin (His, 1889). Lenhossek (1893) showed that the radially aligned spongioblasts transformed into astrocytes (Fig. 1.6 B) (later confirmed by Cajal [1913]). These findings were finally accepted as definitive proof that astrocytes were of ectodermal origin.

Another long-standing misimpression was that neuroglial cells formed a physical syncytium, often called the neurospongium (His, 1889). In retrospect, this mistake was mainly a consequence of limited microscopic resolution and misleading staining techniques. It was seriously questioned by many, including Lenhossek and Cajal, whose studies using the Golgi technique showed separate glial cells that transitioned from radial glial cells to typical astrocytes during development. The syncytium theory also came under attack when it became apparent that a normal glial cell could exist immediately adjacent to a glial cell showing marked pathological change; this did not make sense if the cells were continuous with one another. Unassailable evidence, however, was not provided until the 1950s, when the newly developed electron microscope showed that glial cells are always separated from each other by a thin layer of extracellular space.

Image Credit

Astrocytes and radial glia in material prepared by Lenhossek in 1893.

A: Supportive cells (i.e. astrocytes) from the spinal cord of a 9-month-old child; Golgi impregnation.

B. The spinal cord of a 14 cm human embryo; Golgi impregnation of the supportive cells. Left: ependymal (i.e., radial glial) scaffold. Right: precursors of spider cells (astroblasts). (From Lenhossek, 1893.)


The term Schwann cell appears to have been first used by Louis-Antoine Ranvier (1835–1922) in 1871, but it may not have come into common usage until Cajal’s treatise was published in 1909.

Virchow enters the picture again in the story about peripheral glia. He introduced the term myelin in 1858 to refer to the fatty sheath surrounding some axons: “It is this substance, for which I have proposed the name of medullary matter (Markstoff), or myeline, that in extremely large quantity fills up the interval between the axis-cylinder and the sheath in primitive nerve fibers” (Virchow, 1978). He, like many of his contemporaries, felt that myelin was secreted by the axon, not made by the Schwann cell. For example, in 1909 Cajal states: “Also, many writers, including ourselves, view myelin itself as nothing more than a secretory product of axons, rather than the contents of a cell that the axon passes through.” This concept endured as long as it did, in part, because central nervous system (CNS) myelin appeared not to be associated with nuclei; in the apparent absence of a cell to make myelin, it seemed logical that the axon must make it. Ranvier was not the first to see interruptions in the myelin covering axons, but he was the first to realize that these interruptions were not artifacts. He correctly perceived that the axon was passing through a series of independent myelin segments and that each segment was associated with a single Schwann cell (Ranvier, 1872).


In Histology of the Nervous System, Cajal (1995) summarised what was known about the functions of glia. He did not consider Schwann cells glia and, microglia and oligodendrocytes were not yet discovered, so his discussion was exclusively about astrocytes. He begins with these prescient (perceiving the significance of events before they occur) remarks: “What is the function of glial cells in neural centres? The answer is still not known, and the problem is even more serious because it may remain unsolved for many years to come until physiologists find direct methods to attack it.”

He first addressed the suggestion by Golgi and his students that glial cells carry important nutritional fluids from capillaries to neuronal cell bodies.This idea was spawned by Golgi’s observation that most astrocytes contact capillaries with their processes.

Cajal raised objections to this hypothesis:

(1) Glial cells that surround neurones often lack processes that contact capillaries. He may have been referring, without realising it, to perineuronal oligodendrocytes. However, he illustrates protoplasmic astrocytes from adult human grey matter with processes “never appearing to end near capillaries.” In retrospect, limitations imposed by available staining methods and microscopes probably caused him to overestimate this population.

(2) Amphibian and fish white matter does not contain glia. Subsequent studies have at least partially refuted this statement. Nevertheless, Cajal’s disregard for this theory was echoed nearly 60 years later in Kuffler and Nicholl’s review (1966). Only in the past 15 years has the nutritional theory of Golgi experienced an evidence-based renaissance.

Cajal carefully considered the filling theory of Weigert: “According to the celebrated neurologist, Weigert, glia serves an entirely passive role, filling spaces not occupied by neurones.” Cajal strongly denigrated (cause to seem less serious; play down) this notion based on careful reasoning. Despite his disdain, however, similar ideas have persisted and are sometimes encountered even today (Ransom et al., 2003).

The isolation theory developed by his brother, P. Ramon y Cajal, received strong support. The premise was that astrocytes act as physical insulation against the passage of neuronal impulses. “These processes are always arranged so as to prevent contact between either unmyelinated axons or dendrites, or between axons and dendrites, but only at points where these two different kinds of neuronal process should not lie immediately adjacent to one another” (Cajal, 1995). In white matter, he and others of this period intuitively assigned insulating function to myelin, which posed a nasty riddle: Why are there astrocytes in white matter? Cajal had no answer.

Ironically, he failed to appreciate the glial origin of myelin and so was denied the key insight that makes the isolation theory credible today, at least in regard to the oligodendrocyte.


Cajal’s understudy, Pio del Rio-Hortega (1882–1945), took up the problem of glial cells and developed his own stain (silver carbonate) that selectively stained the third element cells (Rio-Hortega, 1921). Two distinct cell populations emerged, which he named oligodendroglia (and later called oligodendrocytes to make the nomenclature consistent for the two forms of macroglia) and microglia. Oligodendrocytes, so named because they exhibited fewer and smaller branches than astrocytes, were felt to be true classical neuroglial cells of ectodermal origin (Rio-Hortega, 1928).

Image Credit

Early photomicrographs of oligodendrocytes and microglia.

Left panel: interfascicular oligodendrocytes form a sheath about the myelin segments. Right panels, A–I. Evolution of microglial cells during phagocytic activity.

A. Cell with thick, rough processes;

B. cells with short processes and an enlarged cell body;

C. hypertrophic cell with pseudopodia;

E. ameboid form;

F. cell with phagocytosed leukocyte;

G. cell with numerous phagocytosed red cells;

H. fat granule cell:

I. cell in mitotic divisions. Left panel from Rio-Hortega (1928). A-I from Rio-Hortega (1932).

Rio-Hortega recognised that oligodendrocytes were most common in white matter. He considered the oligodendroglia to be a member of the macroglial or classical neuroglial family. Because these cells had a relationship to myelin sheaths that bore a striking resemblance to the relationship between Schwann cells and the myelin sheaths of peripheral fibres, he proposed that oligodendrocytes made and sustained CNS myelin.

Microglia were viewed by Rio-Hortega as distinct from all other neuroglial cells because his studies showed them to be of mesodermal origin and to have migratory and phagocytic capabilities. Rio-Hortega summed up his position on the microglial cell as follows: “Since it is of different ancestry and its characteristics differ from those of the nerve cells (first element) and the neuroglial astrocytes (second element*), the microglia constitutes the true third element of the central nervous system” (Rio-Hortega, 1932). He acknowledged that microglia were the same cells, or closely related cells, as seen earlier by pathologists such as Nissl (1899; i.e., rod cells). In fact, Nissl and Alzheimer had argued that the glial cells seen under pathological conditions were of mesodermal origin.

Rio-Hortega’s accomplishments in rigorously defining the final two members of the CNS glial family and in deducing their functions are impressive. He was the first to describe the two types of microglia: ameboid and ramified. He recognised that the ameboid form was mobile and phagocytic ??? and was similar to a blood macrophage. In fact, he believed, as is believed today, that microglial cells originate from peripheral macrophages. He understood that the microglial cell can transform from its relatively inactive ramified form into the phagocytic ameboid form in response to a threat like the infection. “In historical perspective, we see that what Cajal is to the neurone, Rio-Hortega is to the neuroglia” (Jacobsen, 1993).

Image Credit

Illustration of cells stained with the platinum method of Robertson.

Composite diagram showing (1) “large pyramidal nerve cell of the cerebral cortex of sheep” and (2) “Three branching cells in the cerebral cortex of dog.” The cells labelled 2 were either microglia or oligodendrocytes. (From Robertson, (1899.)


Image Credit

Neuroglial cells in pathological situations.

A, B. Different types of glial cells found in multiple sclerosis plaques of the human cortex.   C. Glial cell close to a 14-day-old haemorrhage in the human white matter. Axons pass through the network of the cell. D. Rod cells stained with toluidine blue. E. Gitter cells stained with toluidine blue. A and B from Frommann (1878). C from Alzheimer (1910). D and E from Alzheimer (1904).

Image Credit

Relationship between (Alzheimer) plaque and glial cells; gaz: neuron; glz: glial cell; P 1: central part of the plaque; P 2: peripheral part of the plaque. (From Alzheimer, 1911.)

In studying brains from deceased multiple sclerosis patients, Carl Frommann (1831–1892) noted that glial cells underwent changes in the demyelinated plaques (Frommann, 1864). He believed that the cells in the areas of fiber degeneration were glial cells that had undergone morphological changes. He stated that the cells became larger and had fewer processes compared to normal glia. It was also clear to him that glial cells were still present in the degenerated areas despite the fiber loss (Fig. 1.10 A,B). He also claimed that some of the glial cells lacked a nucleus. In retrospect, it is likely that he observed activated microglia in these areas of fiber degeneration.

Franz Nissl (1860–1919) noted two new cell types that appeared in the pathological brain. One form was elongated and bipolar in shape, and he called such cells Stäbchenzellen (rod cells). He described this cell type in brains of demented patients but found them also in animals. He originally described these cells as glial elements (Nissl, 1899) but later considered the possibility that they were of mesodermal origin (Nissl, 1904). A second cell type was found mainly in pathological tissue associated with disruption of the blood–brain barrier. These cells were round, without processes, and he termed them Körnerzellen (granule cells) or Gitterzellen (lattice cells). Nissl speculated that they were infiltrating blood cells.

In 1910, Alois Alzheimer (1864–1915) published a book chapter summarizing the responses of neuroglia to different pathologies. It was clear to him and his contemporaries that any type of pathology is accompanied by a glial response. He described ameboid glial cells, or ameboid change, in response to both acute and chronic diseases of the nervous system. The ameboid glial cell was believed to be a transformed astrocyte (swollen, with granular cytoplasm and fragmented processes). Unfortunately, these cells were often, and easily, confused with Gitterzellen, as alluded to above. Alzheimer’s discussion about these cells is a good example of how static microscopic images were used to draw conclusions about function. “The ameboid glial cells do not share the task of glia to provide structural support. They do not form fibers and networks, but they appear at areas of neuronal degeneration. They develop probably in response to a stimulus from the degradation products. Since we did not observe that they take up neuronal structures, we have to assume that they help to liquefy them. This we conclude from our observations on ganglion cells. Over time they grow in size and replace the ganglion cells which will completely disappear and they can be found everywhere in the (degenerating) tissue. This leads to the conclusion that they assimilate the products generated by the degradation of the ganglion cell and neuronal structures. After reaching the peak of their development, they undergo regressive changes while producing various granula and deteriorate rapidly. Their degradation products move to the lymphatic and perivascular space as fluid phase and are there taken up by mesodermal cells to be converted to lipoid matter. Thus, they clean the nervous tissue from waste, transform it to a substance harmless to ectodermal tissue and deliver it to the mesodermal tissue” (Alzheimer, 1910).

In addition to relating the occurrence of ameboid glia to neuronal degeneration, as in the case of acute postmortem change, Alzheimer realised that they could be present in chronic diseases such as epilepsy and syphilis. He also confirmed their presence in the disease that bears his name. His histopathological analysis of the first dementia patient illustrated activated glial cells surrounding the plaques. His insights promoted glial cells to the status of important cellular elements in brain pathology. It was, however, Rio-Hortega who defined these pathological cell types and distinguished between astrocytes and microglia.


The early historical path to understanding neuroglia was circuitous (marked by obliqueness or indirection in speech or conduct) . Penfield’s general comment about the journey is telling: “Knowledge of the form and function of neuroglia is the result of progressive improvement in histological technique in the hands of careful workers. … Insight into the principles involved has been made difficult by numerous uncritical publications of men who, although doubtless sincere, are opportunists rather than cytologists” (Penfield, 1932). The essence of his sentiments continues to be valid today. The history of discoveries about neuroglia highlights a major obstacle to rapid scientific progress. Scientists become so attached to their theories that contradictory evidence fails to modify their viewpoint. When conflicting data appear, new arguments are concocted to preserve the attacked notion. When evidence emerged that myelin was formed by cells, and not by axons, these contrary findings failed to convince the faithful committed to the older idea. It is provocative to ask ourselves what evidence would be necessary for us to abandon our own pet theories. Historians of our own era will, undoubtedly, have many examples to choose from to illustrate this point.

Rio-Hortega considered the oligodendroglia to be a member of the macroglial or classical neuroglial family.

Why Home Education of a Child is Very Important- Even Kindergarten is Late!

Wiring of Brain

An individual animal’s history of interaction with the environment—its “experience”—helps to shape neural circuitry and thus determines subsequent response.

In some cases, experience functions primarily as a switch to activate innate behaviours. More often, however, experience during a specific time in early life (referred to as a “critical period”) helps shape the adult behavioural repertoire.

Critical periods influence behaviours as diverse as maternal bonding and the acquisition of language.

Over the first few years of life, the brain grows rapidly. As each neurone matures, it sends out multiple branches (axons, which send information out, and dendrites, which take in information), increasing the number of synaptic contacts and laying the specific connections from house to house, or in the case of the brain, from neurone to neurone. At birth, each neurone in the cerebral cortex has approximately 2,500 synapses. By the time an infant is two or three years old, the number of synapses is approximately 15,000 synapses per neurone (Gopnick, et al., 1999)[Gopnic, A., Meltzoff, A., Kuhl, P. (1999). The Scientist in the Crib: What Early Learning Tells Us About the Mind, New York, NY: HarperCollins Publishers.]. This amount is about twice that of the average adult brain. As we age, old connections are deleted through a process called synaptic pruning.

Synaptic pruning eliminates weaker synaptic contacts while stronger connections are kept and strengthened.

Experience determines which connections will be strengthened and which will be pruned; connections that have been activated most frequently are preserved. Neurones must have a purpose to survive. Without a purpose, neurones die through a process called apoptosis in which neurones that do not receive or transmit information become damaged and die.

Ineffective or weak connections are “pruned” in much the same way a gardener would prune a tree or bush, giving the plant the desired shape. It is plasticity that enables the process of developing and pruning connections, allowing the brain to adapt itself to its environment. Source: https://faculty.washington.edu/chudler/plast.html 

Although it is possible to define the behavioural consequences of critical periods for these complex functions, their biological basis has been more difficult to understand. The most accessible and thoroughly studied example of a critical period is the one pertinent to the establishment of normal vision.

  • These studies show that experience is translated into patterns of neuronal activity that influence the function and connectivity of the relevant neurones. In the visual system, and other systems as well, competition between inputs with different patterns of activity is an important determinant of adult connectivity. Correlated patterns of activity in afferent axons tend to stabilise connections and conversely a lack of correlated activity can weaken or eliminate connections.
  • When normal patterns of activity are disturbed during a critical period in early life (experimentally in animals or by pathology in humans), the connectivity in the visual cortex is altered, as is the visual function. If not reversed before the end of the critical period, these structural and functional alterations of brain circuitry are difficult or impossible to change.
  • In normal development, the influence of activity on neural connectivity presumably enables the maturing brain to store the vast amounts of information that reflect the specific experience of the individual.

The capacity of the nervous system to change—generally referred to as neural plasticityis obvious during the development of neural circuits.

The adult nervous system exhibits a plastic change in a variety of circumstances. Studies of behavioural plasticity in several invertebrates and of the neuromuscular junction suggest that modification of synaptic strength is responsible for much of the ongoing change in synaptic function in adults.

  • Synapses exhibit many forms of plasticity that occur over a broad temporal range. At the shortest times (seconds to minutes), facilitation, post-tetanic potentiation, and depression provide rapid but transient modifications based on alterations in Ca2+ signalling and synaptic vesicle pools at recently active synapses.
  • Some patterns of synaptic activity in the CNS produce a long-lasting increase in synaptic strength known as long-term potentiation (LTP), whereas other patterns of activity produce a long-lasting decrease in synaptic strength, known as long-term depression (LTD). LTP and LTD are broad terms that describe only the direction of change in synaptic efficacy; in fact, different cellular and molecular mechanisms can be involved in producing LTP or LTD at different synapses. In general, these different forms of synaptic plasticity are produced by different histories of activity and are mediated by different complements of intracellular signal transduction pathways in the nerve cells involved.


Functional changes in the somatic sensory cortex of an owl monkey following amputation of a digit.

(A) Diagram of the somatic sensory cortex in the owl monkey, showing the approximate location of the hand representation.

(B) The hand representation in the animal before amputation; the numbers correspond to different digits.

(C) The cortical map determined in the same animal two months after amputation of digit 3. The map has changed substantially; neurones in the area formerly responding to stimulation of digit 3 now respond to stimulation of digits 2 and 4. (After Merzenich et al., 1984.)

Longer-lasting forms of synaptic plasticity such as LTP and LTD are also based on Ca2+ and other intracellular second messengers. In these more enduring forms of plasticity, protein phosphorylation and changes in gene expression greatly outlast the period of synaptic activity and can yield persistent changes in synaptic strength (hours to days or longer). Different brain regions evidently use one or more of these strategies to learn new behaviours and acquire new memories.



Functional expansion of a cortical representation by a repetitive behavioural task. An owl monkey was trained in a task that required heavy usage of digits 2, 3, and occasionally 4. The map of the digits in the primary somatic sensory cortex prior to training is shown. After several months of “practice,” a larger region of the cortex contained neurones activated by the digits used in the task. Note that the specific arrangements of the digit representations are somewhat different from the monkey shown in Figure 24.14, indicating the variability of the cortical representation of particular animals.     (After Jenkins et al., 1990.)




Different responses to injury in the peripheral (A) and central (B) nervous systems. Damage to a peripheral nerve leads to series of cellular responses, collectively called Wallerian degeneration (after Augustus Waller, the nineteenth century English physician who first described these phenomena). Distal to the site of injury, axons disconnected from their cell bodies degenerate, and invading macrophages remove the cellular debris. Schwann cells that formerly ensheathed the axons proliferate, align to form longitudinal arrays and increase their production of neurotrophic factors that can promote axon regeneration. Schwann cell surfaces and the extracellular matrix also provide a favourable substratum for the extension of regenerating axons. In the CNS, the removal of myelin debris is relatively slow, and the myelin membranes produce inhibitory molecules that can block axon growth. Astrocytes at the site of injury also interfere with regenerationProximal to the injury, neurone cell bodies react to peripheral nerve injury by inducing expression of growth-related genes, including those for major components of axonal growth cones. Following CNS injury, however, neurones typically fail to activate these growth-associated genes. As a result, axonal damage in the retina, spinal cord, or the rest of the brain leads to permanent blindness, paralysis, and other disabilities.


Neuronal damage can also induce plastic changes. Peripheral neurones can regenerate axons following the damage, though the capacity of CNS axons to regenerate is severely limited. In addition, neural stem cells are present in certain regions of the adult brain, allowing the production of some new neurones in a few brain regions. These various forms of adult plasticity can modify the function of the mature brain and provide some hope for improving the limited ability of the CNS to recover successfully from trauma and neurological disease.

Source:  Neuroscience, 3rd edition

Editors: Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams.

Sunderland (MA): Sinauer Associates; 2004.
ISBN 0-87893-725-0