Continued...
The Development of the Brain
From this evolutionary perspective, one might be led to conclude that our brain in all its striking adapted complexity is an inherited legacy of biological evolution. That once evolved it is thereafter
provided to each individual by good old natural selection, specified in all its fine detail in the genome and transmitted through the generations from parent to offspring.
This type of genetically providential thinking of course is selectionist from the viewpoint of biological evolution, but nonetheless providential at the level of the individual organism. It can be seen in the pioneering work on brain development and function of Roger Sperry for which he shared a Nobel prize in 1981. This research in the 1950s involved disturbing the normal location of nerve fibers in the developing brains of fish and rats. For example, nerve fibers that normally connect the top part of the fish's retina with the bottom part of the brain, called the optic tectum, were surgically removed and reconnected to the top part of the optic tectum. Despite this modification, the nerve grew back to its normal position in the brain. Similar experiments carried out by other researchers on rats indicated that fibers that innervate muscles also "knew" to which muscle they should be attached and made their proper connections despite surgical disturbances. This led Sperry to conclude that the connections of the nervous system are completely specified in the organism's genes. As his former student Michael Gazzaniga explains:
In the original Sperry view of the nervous system, brain and body developed under tight genetic control. The specificity was accomplished by the genes' setting up chemical gradients, which allowed for the point-to-point connections of the nervous system.
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But there is a vexing problem with the notion that the genome provides complete information for the construction of the nervous system of humans and other mammals. It is estimated that just the human neocortex alone has about 1015 (one followed by 15 zeros, or one thousand million million) synapses.
[9] Since the human genome has only about 3.5 billion (3.5 x 109) bits of information (nucleotide base pairs), with 30% to 70% of these appearing silent,
[10] some neural and molecular scientists have concluded that our genes simply do not have enough storage capacity to specify all of these connections, in addition to including information on the location and type of each neuron plus similar information for the rest of the body. The problem is not unlike trying to save a document made up of 100 million characters on a computer disk that can hold only 1.4 million characters. As Changeux noted:
Once a nerve cell has become differentiated it does not divide anymore. A single nucleus, with the same DNA, must serve an entire lifetime for the formation and maintenance of tens of thousands of synapses. It seems difficult to imagine a differential distribution of genetic material from a single nucleus to each of these tens of thousands of synapses unless we conjure up a mysterious "demon" who selectively channels this material to each synapse according to a preestablished code! The differential expression of genes cannot alone explain the extreme diversity and specificity of connections between neurons.
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Additional understanding of the relation between the genome and the nervous system can be gained by considering
Daphnia magna. Commonly referred to as the water flea or daphnid, this small fresh-water crustacean is familiar to many aquarium owners since it is relished by tropical fish. But what makes the daphnid interesting for our current purposes is that when the female is isolated from males, she can most conveniently reproduce by the asexual process of parthenogenesis, giving birth to genetically identical clones. In addition, the daphnid has a relatively simple nervous system that facilitates its study. If its genome completely controlled the development of its nervous system, it should be the case that genetically identical daphnids should have structurally identical nervous systems. However, examination of daphnid eyes using the electron microscope reveals that although genetically identical clones all have the same number of neurons, considerable variation exists in the exact number of synapses and in the configurations of connections leading to and away from the cell body of each neuron, that is, the dendritic and axonal branches. As we move to more complex organisms, the variability of their nervous systems increases. This provides clear evidence that the structure and wiring of the nervous system are not the result of following a detailed construction program provided by the genes.
How then is the brain able to achieve the very specific and adapted wiring required to function in so many remarkable ways? For example, how does a motor neuron know to which particular muscle fiber it should connect? How is a sensory neuron in the visual system able to join itself to the correct cell in the visual cortex located in the occipital lobe of the brain? If this detailed neuron-to-neuron connection information is not provided by the genes, whence does it come?
The first clues to solving this puzzle go back to 1906 when it was observed that in embryonic nerve tissue, some neurons did not stain well and appeared to be degenerating and dying.
[12] Since it had been assumed that in a developing embryo, nerve cells should be
increasing in number and not dying off, this finding was somewhat surprising. But nerve cell death in the developing nervous system has since been observed repeatedly. The extent to which it occurs was dramatically demonstrated by Viktor Hamburger. He found that in a certain area of the spinal cord of the chicken embryo over 20,000 neurons were present, but that in the adult chicken only about 12,000, or 60%, of these cells remained.
[13] Much of this neuronal death occurs during the early days of the embryo's existence. Nerve cells continue to expire thereafter, albeit at a slower pace.
A particularly striking example of neuronal elimination in development involves the death of an entire group of brain cells:
Most frequently, neuron death affects only some of the neurons in a given category. However, in one case . . . a whole category of cells dies. These particular neurons of layer I, the most superficial layer of the cerebral cortex, characteristically have axons and dendrites oriented parallel to the cortical surface rather than perpendicular to it, like the pyramidal cells. These cells were first observed in the human fetus but have since been found in other mammals. Purely and simply, they disappear in the adult.Changeux (1985, p. 217).
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But the death of obviously useless brain cells cannot account for the specific connections that are achieved by the remaining neurons. For example, the visual cortex of cats and monkeys has what are called
ocular dominance columns within a specific region known as cortical layer 4. In any one column of this brain area in the adult animal we find only axons that are connected to the right eye, while in the neighboring column are located only axons with signals originating from the left eye. So not only must the axons find their way to a specific region of the brain, which can be quite far from where their cell bodies are located, they must also find a specific address within a certain neighborhood.
The ability of axons to connect to the appropriate regions of the brain during development has been studied in careful detail since the beginning of this century. Axons grow in the brain like the stem of a plant. At the end of the growing axon is found a growth cone which was described by Spanish neuroscientist Ramón y Cajal in 1909 as "a sort of club or battering ram, possessing an exquisite chemical sensitivity, rapid amoeboid movements, and a certain driving force that permits it to push aside, or cross, obstacles in its way . . . until it reaches its destination."
[15] Although the exact mechanisms by which this is accomplished are still unknown, it appears that the growth cone is sensitive to certain chemicals along its path that are released by its target region. In this way visual system axons originating in the lateral geniculate nucleus find their way to cortical layer 4 in the occipital lobe of the brain in much the same way that a police bloodhound is able to sniff out the escaped prisoner hiding in an Illinois cornfield.
But although these growth cones lead their axons to the proper region of the brain (or muscle in the case of motor neurons), they cannot lead them to the precise target addresses. For a particular growth cone, it appears that any cell of a particular type will serve as a target. Indeed, in the newborn cat, ocular columns receive axons from both eyes, not just from one or the other, as in the adult brain. For this final and important fine-tuning to be achieved (on which stereoscopic vision depends), many of the original terminal connections of the axon must be eliminated. In the case of vision, all axonal connections from the wrong eye are eliminated, and those from the correct eye are retained. In the case of motor systems that initially have many-to-many connections between motor neurons of the spinal column and muscle fibers (that is, many motor neuron axons connected to same muscle fiber, and many muscle fibers connected to the same axon), the mature animal possesses a much more finely ordered system with each muscle fiber enervated by one and only one motor neuron. The mammalian nervous system changes from birth to maturity from a degenerate system having many redundant and diffuse connections, to a much more finely tuned system that makes both adaptedly complex behaviors and perceptions (such as stereoscopic vision) possible.
So now the question naturally arises, how does the nervous system know which connections to retain and which to eliminate? The work of David Hubel and Torsten Wiesel in the 1970s (both of whom shared a Nobel prize with Sperry in 1981) provided the first clue. They conducted their ground-breaking experiments by closing the lid of one eye of newborn cats, and found that even one week without sight altered the connections of the eyes to layer 4 of the occipital cortex. Axons carrying nervous signals from the closed eye made fewer connections with the cortex, whereas axons from the open eye made many more connections than was normal. This suggested that visual system axons
compete for space in the visual cortex, with the result of the competition dependent on the amount and type of sensory stimulation carried by the axons. Subsequent research by others using drugs to block the firing of visual system neurons, as well as artificial stimulation of these neurons, showed that it is not neural activity per se that results in the selective elimination of synapses, but rather that only certain types of neural activity result in the retention of certain synapses, while all others are eventually eliminated.
In a sense, then, cells that fire together wire together. The timing of the action-potential activity is critical in determining which synaptic connections are strengthened and which are weakened and eliminated. Under normal circumstances, vision itself acts to correlate the activity of neighboring retinal ganglion cells, because the cells receive inputs from the same parts of the visual world.
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The dependence of the development of the visual system on sensory stimulation would seem to indicate that the fine-tuning of its connections would have to wait until the birth of the animal when it is delivered from the comforting warm darkness of the womb to the cold light of day. However, recent evidence suggests that this fine-tuning actually begins to take place in utero. Prenatal development appears to depend on spontaneous firing of retinal cells that do not depend on light stimulation from the external world. Similar endogenous patterns of activity may also exist in the spinal cord, and may refine the synaptic connections of motor systems as well.
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Nonetheless, interactive postnatal experience of the external world
is required for normal development of senses and nervous systems in mammals. Cats who have one eye sewn shut at birth lose all ability to see with this eye when it is opened several months later. The same applies to humans. Before the widespread use of antibiotics, eye infections left many newborn infants with cloudy lenses and corneas that caused functional blindness, even though their retinas and visual nervous systems were normal at the time of birth. Years later a number of these individuals underwent operations to replace their cloudy lenses and corneas with clear ones, but it was too late. Contrary to initial expectations, none of these people was able to see after the transplant.
[18]It was simply not known at the time that early visual experience was essential to the normal maturation of the brain's visual circuitry. Similarly, some children are born with a wandering eye that does not fixate the same part of the visual field as the normal eye, and other children have one eye that is seriously nearsighted or farsighted; in both cases, the retina of the abnormal eye must be provided with clear visual stimulation, usually by age four years, or it will become functionally blind since its connections to the brain's vision centers will be eliminated in favor of the normal eye.
We thus see that the normal development of the brain depends on a critical interaction between genetic inheritance and environmental experience. The genome provides the general structure of the central nervous system, and nervous system activity and sensory stimulation provide the means by which the system is fine-tuned and made operational. But this fine-tuning does not depend on adding new components and connections in the way that a radio is assembled in a factory, but rather it is achieved by
eliminating much of what was originally present. It is as if the radio arrived on the assembly line with twice as many electrical components and connections as necessary to work. If such an overconnected radio were plugged in and turned on, nothing but silence, static, or a hum would be heard from its speaker. However, careful removal of unnecessary components and judicious snipping of redundant wires would leave just those components and connections that result in a functioning radio. This snipping is analogous to the elimination of synapses in the human brain as part of its normal development.
The process by which brain connections change over time as maturing animals interact with their environments has been studied in detail by psychologist William Greenough of the University of Illinois at Urbana-Champaign. Using sophisticated techniques for determining the numbers and densities of neurons and synapses in specific regions of the rat's brain, he and his associates found that during the first months of the rat's life a rapid spurt in the growth of synapses occurs regardless of the amount or type of sensory experience.
[19] This period of synaptic "blooming" is followed by a sharp decline in the number of synapses. That is, an elimination or "pruning" of synapses then takes place based on the activity and sensory stimulation of the brain, and ultimately results in the configuration of connections characteristic of the mature rat's brain. Greenough refers to this initial blooming and pruning of synapses as "experience-expectant" learning, since the initial synaptic overproduction appears to be relatively independent of the animal's experiences. It is as though the brain is expecting important things to be happening during the first weeks and months of life, and is prepared for these experiences with an overabundance of synapses, only a fraction of which, however, will be selectively retained.
The work of Greenough and his associates is limited to rats and monkeys, but their findings have much in common with those of Peter Huttenlocher of the University of Chicago who counted the synapses in specific regions of the brains of humans who died at various ages. Huttenlocher found that:
The increase in synaptic density plus expansion of total cortical volume leave no doubt that the postnatal period is one of very rapid synaptogenesis in human frontal cortex. By age 2 years, synaptic density is at its maximum, at about the same time when other components of cerebral cortex also cease growing and when total brain weight approaches that of the adult. Synaptic density declines subsequently, reaching by adolescence an adult value that is only about 60% of the maximum.
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