They took dividing progenitor cells from a host fetus of a particular age, and transplanted the cells into a donor animal of a different age. The key question was, what kinds of neurons do the transplanted progenitors produce in the host environment? In the first experiment, progenitor cells were taken from young donor animals if left in the donor these progenitors would produce neurons for layer 6 of cortex , and transplanted them into an older host whose progenitors were producing layer 2—3 neurons.
The transplanted progenitors produced layer 2—3 neurons suggesting that some kind of signaling from the host induced a change in the type of neurons being produced by the transplanted progenitors. However, when the timing was reversed and progenitors from an older host were transplanted to a younger animal, the progenitors continued to produce cells appropriate for the donor animal. It appears that early in corticogenesis progenitor cells can receive signals to produce any neural cell line, but as development proceeds and these early cell types are no longer needed, the progenitor loses the capacity to generate those cells, exhibiting what is termed fate restriction.
While there is evidence that fate restriction may be at least in part controlled by cell intrinsic signaling Shen et al. Once they have reached their target region of cortex, the young neurons need to become part of information processing networks. In order to become integrated into neural networks, the neurons need to develop neuronal processes axons and dendrites that allow them to communicate with other neurons. Axons are the principal means of sending signals from the neuron, while dendrites are major sites for receiving input from other neurons.
At the tip of each axon is a structure called a growth cone. The growth cone is the site of axon elongation and extension Brown et al.
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As the axon is extended, the growth cone samples the local environment for guidance molecules that direct the axon toward its target. Some guidance cues are attractive and signal movement toward a source, others are repulsive and guide movement away. Once the axon has reached its target, connections called synapses are formed with the target cell. Synapses allow for the transmission of electrochemical information which is the essential means of communication in the brain.
Two of the most important pathways in the brain are the ones that transmit sensorimotor information, the thalamocortical TC and corticothalamic CT pathways. The TC relays sensory and motor information from the receptors in the retina, cochlea, muscle or skin to the sensorimotor regions of the neocortex via the major subcortical sensorimotor relay, the thalamus. The CT pathway completes the feedback loop by transmitting information from cortex back to the thalamus.
These essential pathways begin to form in the later part of the second trimester in humans, and are complete by GW 26 Kostovic and Jovanov-Milosevic The cells of the transient subplate layer of the developing brain see Fig. When TC axons arrive at the developing cortex during GW22 they do not immediately make connections with neurons in the primary input layer of cortex layer 4. Rather, they initially make connections with the neurons of the subplate layer. The subplate neurons appear to provide instructive input to the TC neurons during this period.
In the absence of subplate neuron signaling, normal patterns of connectivity between TC axons and layer 4 cortical neurons do not develop. A similar pattern of instructive connectivity is seen in the development of the CT pathway. Prior to the establishment of connections between neurons from the deep layers of cortex layers 5 and 6 and the thalamus, subplate neurons extend and establish connections with thalamic neurons.
It is thought that the subplate connections may serve to guide the CT axons to their positions in the thalamus. Once the TC and CT pathways are complete, the subplate neurons retract their connections and the cells themselves gradually die off. While most neurodevelopmental events involve the proliferation of neural elements, two important processes involve substantial loss of neural elements. Both of these processes reflect nonpathological events that play an essential role in establishing the complex networks of the developing brain. The timescales of these two sets of events are different.
Most naturally occurring cell death in neuronal populations occurs prenatally, while both cell death in glia populations and the events involving exuberant production and pruning of connections are largely postnatal events. This section will consider cell death in neural populations during the prenatal period. The major postnatal regressive events will be discussed in the next section. There are two broad categories of cell death. Necrotic cell death is a pathological process that follows insult or injury to a population of cells and is a mechanism for eliminating damaged tissue from the biological system.
Apoptosis is a distinct form of cell death that reflects a highly regulated sequence of physiological events. Apoptosis is a well-understood cell-intrinsic process. It involves a cascade of gene expression that ultimately results in the breakdown of nuclear chromatin DNA and support proteins and the fragmenting of the cell. The set of genes involved in the apoptotic cascade is large, but very specific, with each molecular signal triggering the next step in the cascade. A wide variety of cell intrinsic and environmental factors can influence the apoptotic process.
Some trigger cell death, while others protect the cell by preventing the cascade. Apoptosis has been documented within all of the neuronal and neural progenitor cell compartments in the human brain Rakic and Zecevic One factor that protects against the apoptosis cascade is uptake of neurotrophic substances Levi-Montalcini ; Oppenheim Neurotrophic factors are produced by target neurons at synaptic sites, and are taken up by the afferent neurons that make effective connections with the targets Huang and Reichardt During development it is thought that neurons compete for neurotrophic resources.
According to the neurotrophic hypothesis Oppenheim , neurons that establish effective connections are able to obtain more neurotrophic factor and are more likely to survive.
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Thus one important function of cell death in brain development is its role in regulating the establishment of effective and functional neural circuits Buss et al. In addition, a number of other functions for cell death have been proposed. Although the evidence is somewhat limited, cell death may serve as a mechanism for correcting errors in neuronal production or migration Buss and Oppenheim There is substantial evidence that cell death plays an essential role in eliminating cell populations that serve only a transient function in brain development, such as cells of the MZ or SP.
Importantly there is strong evidence of high levels of cell death in the neural progenitor population de la Rosa and de Pablo ; Yeo and Gautier Rates of apoptosis in the VZ increase across the period of corticogenesis suggesting gradual elimination of this important but transient cell population. Note that the mechanism for triggering cell death in the MZ, SP or progenitor cell populations must differ from those discussed for neurons. None of these populations contain cells that enter neural networks, thus the specific effects of neurotrophin availability are not likely associated with the apoptotic pathways in these cells groups.
Though the production and migration of neurons are largely prenatal events, proliferation and migration of glial progenitors continues for an extended period after birth, and the differentiation and maturation of these cells continue throughout childhood. The full scope of neuron-glia interactions is still not fully defined, but it is clear that these interactions play an important role in functional organization of neural circuits during postnatal life.
Importantly, estimates of the developmental time course in humans of the postnatal processes outlined below are derived by extrapolation from data acquired in other species, often rodents, and from very limited human postmortem material. Unfortunately, the result is much remaining uncertainty about the temporal extent of proliferation, migration, differentiation, and regression during the postnatal period in humans, and about the timing of these processes relative to each other.
In vivo brain imaging of children is providing important clues about the time course of age-related biological alterations in the brain, and provides an opportunity to link these changes to evolving behavior. In the postnatal period, neurogenesis continues to only a very limited degree; however, in the subventricular zone, new neurons continue to emerge and migrate to the olfactory bulb, and neurons are also produced in the dentate gyrus of the hippocampus, where they migrate from the subgranular layer only as far as the nearby granular layer. These exceptional forms of neurogenesis appear to continue throughout adult life but produce only a small percentage of the neuronal population.
In contrast, proliferation and migration of glial progenitors, while beginning prenatally, continue for a protracted period as oligodendrocytes and astrocytes differentiate; in fact, glial progenitors particularly oligodendrocyte progenitor cells, or OPCs appear to persist indefinitely in the adult brain in a wide anatomical distribution, and can differentiate in response to injury.
Glial progenitors proliferate in the forebrain subventricular zone and migrate outward into the overlying white matter and cortex, striatum, and hippocampus, where they differentiate into oligodendrocytes and astrocytes. Unlike neural progenitors, glial progenitors continue to proliferate as they migrate Cayre et al. Upon reaching its destination, an OPC begins to differentiate by extending processes and increasing myelin protein expression.
The processes then begin to form membrane wraps around nearby axons. Eventually the oligodendrocyte forms tightly wrapped multi-layered sheaths from which most of the cytoplasm has been extruded. The dramatic increase in axonal conduction velocity associated with myelination is well known. However, recent research suggests that functional interactions between oligodendrocytes and neurons extend far beyond the effects of the electrically insulating sheath.
Oligodendrocytes synthesize a number of trophic factors that appear to contribute to the maintenance of axonal integrity and neuronal survival, and neuron-oligodendrocyte interactions have been shown to influence neuronal size and axon diameter McTigue and Tripathi An intriguing new line of evidence also suggests that a subset of the OPCs dispersed throughout the brain form excitatory and inhibitory connections with neurons, and thus may contribute actively and directly to neural signaling Lin and Bergles In summary, proliferation and migration of glial precursors and differentiation of astrocytes and oligodendrocytes are largely postnatal processes.
While there is little doubt that these processes play a critical role in the functional maturation of developing neural circuits, the full scope of their impact on neural dynamics may be much greater than was previously appreciated. Ongoing research continues to uncover additional molecular interactions between neurons, oligodendrocytes, and astrocytes.
The existence of these interactions implies that the late maturation of glial populations probably has widespread functional implications. Cell Death in Glial Populations As described above, brain development involves overproduction of neurons and glial cells, neural processes, and synapses.
Although neural apoptosis has its peak during prenatal life, apoptosis in glial cell populations has a time course corresponding to the protracted postnatal time course of differentiation from glial precursors. During the period of initial myelination, many excess oligodendrocytes undergo apoptosis a few days after differentiating, and there is evidence that this process depends on signals from nearby axons, such that the number of surviving oligodendrocytes matches the local axonal surface area see McTigue and Tripathi , for review.
Synaptic Exuberance and Pruning Although the development of neural networks requires the formation of precise connections between developing neurons and their targets, it is well documented that initial patterns of connectivity in the developing brain are exuberant in terms of both the numbers of connections formed and their topography. This exuberance can be observed on two very different time scales that appear to support different aspects of the process of emerging connectivity in the developing brain.
At a macroscopic level, exuberance and pruning can be observed within major brain areas and pathways on timescales that extend over months or even years. But at a microscopic level very rapid formation and retraction of connections can be observed at the level of individual neurons over periods of minutes or hours. At the macroscropic level, studies of both monkeys and humans have documented widespread exuberant production of connections throughout all brain regions in the early postnatal period Zecevic et al.
Across brain areas, the number of synapses plateaus at levels nearly twice as high as those observed in the adult brain, and then slowly declines to normal adult levels across the period of childhood and adolescence see Fig. But, the exuberance of connectivity extends beyond the sheer numbers of connections within a brain region. Early in development transient connections form throughout the brain, which are not observed in adults. Exuberant connectivity has been documented in pathways as diverse as the corpus callosum, thalamocortical pathways, corticospinal tract and pathways linking the temporal lobe and the limbic system Stanfield et al.
Many factors affect the retention or elimination of pathways. Competition for resources such as neurotrophic factors plays a significant role in selection of pathways. Importantly, afferent input plays a critical role in modulating the stabilization or elimination of pathways. Recent studies using real time imaging have begun to document the processes of exuberance and pruning at a more microscopic level.
These studies suggest that as axons seek their targets they very rapidly sample the surrounding space forming and retracting synaptic connections in a dynamic, ongoing and balanced fashion Hua and Smith Thus at the level of individual neurons the processes associated with exuberant production and retraction of connections provide rapid sampling of the local environment and serve to support axon guidance and target detection. Synaptic connectivity in the primate brain exhibits initial exuberant production followed by gradual pruning.
In primate brain, the number of synaptic contacts per probe was plotted along a logarithmic scale as a function of days after conception DAC. Reprinted with permission from Bourgeois and Rakic In human brains, counts of the number of synapses per constant volume of tissue were measured as a function of pre- and postnatal age.
Adapted with permission from Huttenlocher and Dabholkar Regional differences in synaptogenesis in human cerebral cortex. Journal of Comparative Neurology, , —, Fig. Since MRI is a safe technique for use in children it has now been applied widely in pediatric imaging, and it reveals dramatic changes in the tissues of the developing brain during the postnatal brain growth spurt.
These MRI signal changes reflect alterations in tissue chemistry that are presumed to mark the proliferation of oligodendrocytes and deposition of myelin, and they reveal much about the timing and anatomical distribution of these processes Barkovich ; Barkovich However the changes in gross brain structure that continue past this age are subtler, and were not well described until after quantitative morphometry techniques were applied.
Early MR morphometry studies comparing brain morphology in children and adults showed that gray matter volumes, both in the cerebral cortex and in subcortical nuclei, were considerably larger in school-aged children than in young adults Jernigan and Tallal ; Jernigan et al. This suggested that tissue alterations related to brain maturation might be much more protracted during childhood than was generally supposed, and that some of these alterations might be regressive; that is, they might involve tissue loss.
These findings were confirmed and extended by later studies see Toga et al. The size of the cranial vault increases dramatically after birth but very little after the first decade. These observations are consistent with ample histological evidence for ongoing myelination across this period Yakovlev and Lecours , and more limited, but persuasive, evidence for reduction of synaptic density in cortex during childhood Huttenlocher and Dabholkar , but it remains unclear to what extent these factors, and perhaps others, contribute to the changing morphology observed with MRI.
Data shown in Fig. The plots illustrate results from an extended age-range for volumes of particular brain structures modified from Jernigan and Gamst Shown are continuous age-related decreases in volume of frontal cortex, thalamus, and nucleus accumbens across the lifespan, and increases in cerebral white matter volume during childhood and early adulthood that give way to decreases later in life. All volumes are normalized for cranial volume—which does not change appreciably over this age range. Estimated volumes of brain structures in normal volunteers are plotted against age.
The volumes in the figures are presented as standardized residuals removing variability associated with volume of the supratentorial cranial vault. They are, from left, volumes of frontal cortex, thalamus, nucleus accumbens, and cerebral white matter. Note the rapid age-related change and striking individual differences in the childhood and adolescent age-range. More recent MR morphometry studies have provided more anatomical detail by employing mapping methods for visualizing the pattern of age-related change Giedd, Snell and et al.
The most detailed studies, employing both high-resolution mapping techniques and longitudinal assessments Gogtay et al. On average, cortical thinning appears to occur first in primary sensory-motor cortex and then to progress into secondary, then multimodal, and then supramodal cortical areas throughout childhood and adolescence. A recent study [Ostby et al. This is an important contribution since studies of cortical volume conflate these factors, and no previous studies had addressed whether the changes in cortical thickness are accompanied by alterations of surface area as well.
An important issue germane to the interpretation of these effects is their relationship to myelination. This is clearly a part of what is measured as cortical thinning with morphometry, especially in younger children. This can be inferred from the fact that the progressive changes that would be expected to result from continuing myelination do not seem to increase cranial volume in late childhood as though they were opposed by some regressive factor ; and from the fact that there are modest but significant CSF volume increases adjacent to the cortical surface and in the ventricular system over this age-range, as might be expected, ex vacuo , in the wake of the loss of neural elements in the adjacent tissues Jernigan et al.
Using mapping methods, Sowell et al. It is possible that functional changes resulting from maturation of fiber tracts stimulate cortical thinning or thickening , or, conversely, that increasing activity due to intrinsic cortical maturation stimulates myelination of the axons in the maturing network. Neuron-glia signaling mechanisms mediating effects of action potentials on oligodendrocyte differentiation and myelination have been reported see Fields and Burnstock for review ; therefore it is plausible that increasing activity in neural circuits plays a role both in myelination and in stimulating intracortical structural alterations..
However, the interactions among these factors in developing brain tissues are still poorly understood. In summary, MR morphometry studies reveal a complex pattern of development in brain structure during childhood and hint that ongoing maturation of fiber tracts probably plays a key role. Only recently, however, has it been possible to examine the maturation of fiber tracts directly, using diffusion tensor imaging DTI Basser et al.
Diffusion imaging measures the diffusion of water molecules through the tissue. A common use of diffusion imaging involves fitting, for each voxel, a mathematical function called a tensor, that estimates proton diffusion motion along each of 3 orthogonal spatial axes. Tensors from voxels in the brain with high water content, such as in ventricles, exhibit high levels of proton diffusion that has no preferred direction; i. Diffusion in gray matter voxels is lower but also relatively isotropic.
However, in voxels that contain fiber bundles, the diffusion is higher along the long axis of the fibers. This directionality of the diffusion is usually measured as an index of anisotropy , usually as fractional anisotropy FA. It has been shown that proton diffusion in the cerebral white matter of human newborns is high, and exhibits low anisotropy Hermoye et al. As the fiber tracts mature, and myelination proceeds, diffusion declines, and anisotropy or FA increases.
By examining the change in detail, i. The interpretation Suzuki et al. The denser packing of axons that results from myelination and increases in axonal diameter are likely to reduce diffusion by decreasing extra-axonal water. How alterations of fiber morphology or intra-axonal diffusion contribute to changing tensor values is less well understood.
Nevertheless, there is growing evidence that alterations reflected in and measurable with diffusion imaging continue throughout childhood and adolescence Schneider et al. The pattern of FA increases, for example, suggests that FA reaches asymptote earliest in long projection, then commissural, and finally association fibers, the latter continuing to exhibit age-related FA increases well into adulthood see Huppi and Dubois ; Mukherjee and McKinstry for reviews; Cascio et al.
These plots reveal the rapid change in FA in young school-aged children and also demonstrate that different tracts vary in the pace with which adult values of FA are approached. This group recently reported individual trajectories of tract FA obtained with repeated imaging of school-aged children. Some of the results are shown in Fig.
Cross sectional data from Lebel et al. Reprinted with permission from Lebel et al. Individual trajectories for sequential measurements of FA in the genu of the corpus callosum left and the superior longitudinal fasciculus SLF right , redrawn from Lebel et al. In summary, in vivo brain imaging is opening a window on continuing brain development during infancy and childhood.
As the imaging techniques mature, and the biological significance of the signals they record are more firmly established, these techniques promise to reveal much more about the dynamic interactions within human brain tissues that attend the molecular and microstructural events described in this review. The events of the prenatal period serve to establish the core compartments of the developing nervous system from the spinal cord and hindbrain to the cortical structures of the telencephalon.
These early events also provide initial patterning within each of the major subdivisions of the brain, but this early patterning, particularly in the neocortex, is both underspecified and malleable. The mature organization of the neocortex emerges over a protracted time during the postnatal period, and it requires diverse forms of input.
Some of this input arises from within the organism in the form of molecular signaling and cross-regional activity. But the specific experience of the individual organism also plays an essential role in establishing the mature organization of the neocortex. The development of normal brain organization requires input via all of the major sensory systems. When specific aspects of input are lacking, alternative patterns of brain organization can and do emerge.
These alternative patterns of organization reflect the effects of altered profiles of neural competition and capture a fundamental property of mammalian brain development, the capacity for plastic adaptation. Although cortical patterning begins in the embryonic period it remains malleable for an extended period of time.
Typical, expected, postnatal experience is necessary for the emergence of normal patterns of neocortical organization. When that input is lacking brain areas develop differently, and the specific pattern of development reflects the kinds of input that the organism actually received. At later ages, the developing—and even the mature—nervous system continues to require input to acquire new knowledge and to develop functional neural systems.
These two important constructs suggest that throughout development experience plays an essential role in establishing and refining neural organization in ways that allow the organism to adapt to the contingences of the world in which it lives. Studies that systematically manipulate the specific experience of the young organism provide insight into the dynamic and adaptive nature of brain development. Two simple ways to alter input are enrichment and deprivation. Both have dramatic effects on the structural and functional organization of the developing brain.
Greenough has shown that simply rearing animals in either impoverished standard laboratory cage or enriched environments large enclosures with interesting and changing landmarks and multiple littermates affects the development of a wide range of brain structures and functions Black et al. Animals reared in complex environments show enhancement in density of cortical synapses, increases in the number of brain support cells, and even augmentation of the complexity of the brain vascular system. Further, many of the effects of rearing in the complex environment persist even when the animal is returned to more impoverished conditions.
Sensory deprivation has more selective effects that target particular cortical sensory systems. Within the typical primary visual pathway, inputs from the two eyes remain segregated from the retina to the thalamus to PVC. When patterned input to one eye is blocked by suturing the eyelid closed the effect of this altered experience on ODC organization is striking see Fig.
The bands representing the active eye widen and expand into the territory of the deprived eye; while the bands representing the deprived eye shrink to thin stripes. The monocular reduction in activity introduced by the suturing procedure alters the competitive balance of the input from the two eyes. The inputs from the active eye invade and subsume territory that would normally have received input from the deprived eye.
Autoradiographs of the ocular dominance columns ODC in two young monkeys. A radioactive transneuronal dye was injected into one eye and taken up by neurons in the input layer of primary visual cortex PVC. The normal patterning of the ODC in a 6-week old monkey. ODCs from each eye are equal and adultlike. ODC for the nondeprived eye light bands expand and while those of the deprived eye dark bands shrink showing clear dominance of the nondeprived eye in PVC.
Adapted from LeVay et al. Journal of Comparative Neurology, , 1—51, Figs. The enrichment and deprivation studies provide powerful evidence of the role of experience on brain development. The enrichment studies suggest widespread effects of experience on the complexity and function of the developing system, while the deprivation studies document the capacity for neural reorganization within particular sensory systems But experimental studies can be more invasive, introducing procedures that directly affect or eliminate specific brain areas.
These studies provide evidence that plasticity in developing neural systems can extend to the capacity to develop fundamentally different patterns of organization and function in the face of injury. For example, Sur and colleagues Sur et al. In the normal course of early development the visual pathway from the retina extends what are typically transient connections to PAC, in addition to the normal connections to PVC. The retina-PAC connections are typically pruned as part of the normal competitive processes. However, in the absence of competition, the inputs from the retina stabilize and form a functional visual pathway to PAC.
Thus the altered early experience of the organism results in fundamental functional and structural reorganization of a primary sensory area, providing robust evidence for the role of neural plasticity in early brain development. Over the past three decades there has been tremendous progress in our understanding of the basic principles of neural development. This progress has changed our fundamental models of how brains develop. Strongly deterministic models have given way to more dynamic and interactive models anchored in the process of development, itself.
As suggested by the examples presented in this paper, the processes that underlie and guide brain development involve the ongoing interplay of genetic and environmental factors. Brains do not develop normally in the absence of critical genetic signaling and they do not develop normally in the absence of essential environmental input.
Rather, at each point in development, organism intrinsic and environmental factors interact to support the increasingly complex and elaborate structures and functions of the brain. During the embryologic period the interactive processes are most prominent at the level of cell-cell interactions where gene expression in one population of cells generates molecular signals that alter the developmental course of another population of cells. However, even during this earliest period, interactions involving factors in the external environment also play essential roles in the development of the embryonic brain.
During the fetal and postnatal periods, organism intrinsic factors continue to play a critical role in development, but across this extended period a wide array of factors in the external world influence the course of brain development in increasingly prominent ways.
The regularity of developmental process arises from constraints imposed by both genetic and environmental factors. Genes provide the templates for creating particular proteins that are essential to the developmental process; the environment provides essential input that shapes and influences the direction of the emerging neural networks. A third essential constraint arises from the fact that the developmental process unfolds over time.
The integrity of the developmental process depends absolutely upon the availability of the right neural elements appearing at the appropriate moment in developmental time. Often the emergence of a new element depends upon developmental events that immediately precede its appearance. For example, the differentiation of the neural progenitor cells along the axial midline of the neural plate during gastrulation sets the stage for the formation of the ventricular zone during neurulation. Furthermore, at each point in developmental time the organism has both a state and a history that limit which factors can influence its development.
Visual and auditory signals have little effect on the gastrulating embryo, but both are essential for the typical development of vision and audition in the newborn. At all levels of the neural system, progressive differentiation of specific elements and structures coupled with progressive commitment of those elements to functional systems appear to be the governing principles of brain development.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author s and source are credited. National Center for Biotechnology Information , U. Published online Nov 3. Joan Stiles 1 and Terry L. Jernigan 1, 2, 3. Author information Article notes Copyright and License information Disclaimer. Received Aug 7; Accepted Oct This article has been cited by other articles in PMC.
Abstract Over the past several decades, significant advances have been made in our understanding of the basic stages and mechanisms of mammalian brain development. Brain development; maturation, Magnetic resonance imaging, Diffusion weighted imaging, Genetic patterning of brain, Neurogenesis, Myelination, Effects of experience on connectivity. Open in a separate window. Brain Development in the Embryonic and Early Fetal Periods This section considers some of the major foundational changes that occur during the embryonic period and early fetal period.
The First Step in Brain Development: Differentiation of the Neural Progenitor Cells At the end of the second week after conception, the embryo is a simple, oval-shaped, two-layered structure. The Formation of the Neural Tube: The First Brain Structure The next major step in brain development involves the formation of the first well-defined neural structure, the neural tube.
Neural Patterning in the Embryonic Period The transformations in the overall shape of the embryo reflect more specific change in neural patterning within all regions of the embryonic nervous system. Brain Development in the Fetal Period The fetal period of human development extends from the ninth gestational week through the end of gestation. For example, common prenatal infections, such as influenza, and less common ones, such as rubella, toxoplasmosis, and cytomegalovirus, can increase the risk of developing mental retardation, schizophrenia, and autism Fruntes and Limosin, ; Jones, Lopez, and Wilson, ; Meyer, Yee, and Feldon, ; Pearce, ; Penner and Brown, Prenatal exposure to various environmental toxins, including certain insecticides used in homes and for agricultural purposes Rauh, Garfinkel, et al.
Premature birth and low birth weight can also predispose to a wide variety of disorders Peterson, a , including schizophrenia Kunugi, Nanko, and Murray, , autism Kolevzon, Gross, and Reichenberg, , and learning disabilities and educational difficulties Peterson, a. Between weeks 5 and 25 of human fetal gestation, undifferentiated precursor cells divide repeatedly, rapidly giving rise to large numbers of cells that will become neurons. Glial cells, the supporting cells of the nervous system, are also generated, but somewhat later than neurons, between weeks 20 and 40 de Graaf-Peters and Hadders-Algra, Once cells are generated, two different processes overlap in time.
Second, neurons must travel from the site of their origin to their appropriate final location in the brain to provide the function they will ultimately serve, a process called neuronal migration de Graaf-Peters and Hadders-Algra, ; Levitt, ; Rakic, The number of migrating neurons in the human fetus peaks by about week 20 of gestation, and migration stops by about week 30 de Graaf-Peters and Hadders-Algra, Disturbances in neuronal migration have emerged as a key area of interest in understanding the developmental basis of MEB disorders.
Failures in neuronal migration produce an accumulation of neurons in the wrong areas of the brain and, consequently, can lead to disorganized brain structure and function. This can be seen in major malformations of the brain, such as lissencephaly a brain that lacks the usual, complex folded surface Guerrini and Filippi, More subtle disturbances of neuronal migration can create isolated islands of neurons or disruptions of normal circuit function, leading to seizures Guerrini and Filippi, Genetic and environmental influences on neuronal migration can produce even more subtle disturbances in the locations of cells that may not be visible at the gross anatomical level but may nevertheless affect functional circuits.
Once cells are properly differentiated and as they are migrating to their final locations in the brain, they grow extensions, called axons and dendrites, that allow them to connect to and communicate with other neurons. Axons are primarily responsible for sending signals to other cells, and dendrites are processes that primarily receive signals from other cells. Axons use the guidance of external molecular signals to find their way to the right target cells with which they will connect and communicate. A combination of growth-promoting and growth-inhibiting signals provides the growing tip of the axon with a map of connectivity to get to the right location and connect with the right target cell Chilton, ; Tessier-Lavigne and Goodman, Dendritic growth and branching begins early in development, initially proceeding slowly but then accelerating rapidly starting in the third trimester de Graaf-Peters and Hadders-Algra, , producing a thickening of the cortex the complex, multilayered collection of cells composing the entire outer surface of the brain Huisman, Martin, et al.
The timing of dendritic growth differs by brain region and by layer of the cortex. For example, dendritic elaboration is slower in frontal than in visual cortex, and it begins in the deeper layers earlier than in more superficial ones Becker, Armstrong, et al. Overall, dendritic development is highly active from the third trimester of gestation through the first postnatal year, continuing at lower rates through age 5 years de Graaf-Peters and Hadders-Algra, Differing neuronal cell types have diverse shapes and sizes. Some have relatively simple shapes. Others have many axonal branches, allowing them to innervate and influence more target cells.
Some have complex dendritic trees that provide a greater range of input from other cells. This diversity of form and structure provides for a range of computational functions across different kinds of neurons, from a limited signal input and response to a complex integration of multiple signals. Connections are established with cells that are nearby and cells that are much more distant, eventually linking and integrating information from different regions of the brain.
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The basis of this communication between neurons is their physical connection, called a synapse. The formation of synapses requires the development of specialized cellular machinery on both the presynaptic side of the synapse where neurotransmitters are prepared and released from the terminals of axons and at the postsynaptic target where receptors for those neurotransmitters receive and process the signal Waites, Craig, and Garner, The rate of synapse formation increases rapidly after about weeks 24—28 and peaks, at the rate of almost 40, new synapses per second, between 3 and 15 months after birth in the primary sensory and prefrontal cortices, respectively de Graaf-Peters and Hadders-Algra, ; Levitt, The synapse is the primary site of information transfer in the nervous system, and it is also likely to be the primary site of learning and memory.
Several disorders that begin early in life and are associated with profound intellectual and emotional disability can be considered disturbances of learning and memory. These include fragile X and other causes of mental retardation, Rett syndrome, and autistic spectrum disorders.
Genes that have been identified as either causing or increasing the risk for developing these disorders can be conceived as having in common the disruption of normal development and function of synapses Chao, Zoghbi, and Rosenmund, ; Dierssen and Ramakers, ; Willemsen, Oostra, et al. Neurons and the connections between them are produced in an over-abundance during fetal life relative to their levels at birth and in adulthood. The number of neurons in the human brain, for example, peaks around midgestation. Thereafter, overproduction is reduced through a process of molecularly programmed cell death, called apoptosis de Graaf-Peters and Hadders-Algra, ; Levitt, For continued survival, neurons require a successful interaction with a target cell, and neurons that do not achieve this interaction will die.
Neuronal survival is mediated in part by the limited availability of neurotrophic factors, a class of molecules that are derived from the target cells Monk, Webb, and Nelson, The process of brain development also produces an initial surplus of connections between neurons. Early in postnatal life, the density of synapses in the brain increases dramatically, reaching its peak during infancy de Graaf-Peters and Hadders-Algra, ; Huttenlocher, ; Huttenlocher and Dabholkar, ; Levitt, The process of forming synapses, or synaptogenesis, is paired with the complementary process of synaptic pruning, in which some synaptic connections are eliminated.
Primates are widely believed to have evolved synaptic pruning as a means for removing synaptic connections that are unused and therefore not needed in the environmental context in which the animal finds itself, while conserving and increasing the efficiency of connections that are useful in that context. Thus, survival of most of the synaptic connections that subserve human behavior is influenced by patterns of neural activity, which in turn are the product of environmental influences and experience Kandel, Schwartz, and Jessell, Studies in humans during childhood are limited but, in combination with data from studies in monkeys, indicate that after the peak of synaptogenesis in infancy, synapse formation and synaptic pruning plateau during childhood and then reach a regressive phase between puberty and adulthood.
At that point, a massive, activity-dependent pruning eliminates more than 40 percent of synapses de Graaf-Peters and Hadders-Algra, ; Huttenlocher and Dabholkar, ; Levitt, ; Rakic, ; Rakic, Bourgeois, and Goldman-Rakic, Another important process in developing and refining appropriate connectivity in the brain is the wrapping of neuronal axons in an insulating sheath of myelin, which promotes the rapid and efficient conduction of electrical impulses. In humans, myelination progresses rapidly from 1 to 2 months prior to birth through the first 1 to 2 years of life, but it also continues through adolescence and into adulthood Levitt, ; Paus, Collins, et al.
This timing is similar to the developmental timing of dendritic elaboration and synapse formation. The survival of cells and synapses requires their ongoing neural activity, suggesting that external stimuli and environmental conditions, including relative deprivation, can have important long-term influences on brain development. These influences have been demonstrated in animal models, from rodents to nonhuman primates Sanchez, Ladd, and Plotsky, Their demonstration in humans has been more indirect.
It includes evidence that differences in cognitive and psychosocial stimulation are associated with modest differences in cognitive development Gottlieb and Blair, ; Santos, Assis, et al. Pathological synaptic pruning in particular may contribute to the genesis of at least some MEB disorders, although in the absence of direct longitudinal data, this hypothesis has not yet been confirmed Levitt, ; Rakic, Disturbances in synaptic pruning that occur during adolescence are hypothesized to underlie many of the anatomical and functional disturbances seen in brain imaging of persons with schizophrenia Lewis and Levitt, ; McGlashan and Hoffman, Longitudinal studies have reported exaggerated rates of cortical thinning in the dorsal prefrontal, parietal, and temporal cortices compared with healthy developing controls Mathalon, Sullivan, et al.
Nevertheless, the cellular bases for this cortical thinning, as well as the mechanism whereby exaggerated cortical thinning would produce psychotic symptoms, are unknown. As noted, many developmental processes in the brain continue into childhood, adolescence, and young adulthood. This appears to be true of the frontal lobe in particular. In fact, several large human imaging studies have reported a progressive reduction in the thickness or volume of gray matter regions containing neuronal cell bodies in the cerebral cortex that begins in childhood and continues through young adulthood, particularly in areas of the frontal and parietal cortices Giedd, Blumenthal, et al.
These are higher cortical areas that contribute to attentional processes and the regulation of thought and behavior. The decline in cortical gray matter may represent a synaptic pruning in adolescence and young adulthood that could produce more efficient processing in the neural pathways that support improvements in these cognitive processes, which constitute a vitally important feature of adolescent development. The brain is subject to continual change even after its fundamental architecture and functional circuitry have been established, as evidenced by the capacity to learn new skills and establish new memories throughout life.
Changes in brain structure in response to experience, learning, various physiological processes, and pharmacological or environmental agents are known as neural plasticity. Although the molecular mechanisms underlying neural plasticity are not fully understood, experience is known to induce anatomical changes across all levels of the nervous system, from molecular and cellular processes to entire neural pathways. Such changes in brain structure begin with changes in the architecture of the synapse.
Experience in the short term produces transient changes in the strength of communication across synaptic connections primarily by changing the availability of neurotransmitters and other signaling molecules. Experience in the longer term produces changes in synaptic activity, which can influence signaling pathways to regulate the function of receptors and other proteins or to change the number of receptors at the synapse.
In addition, ongoing synaptic activity induces changes in gene expression that alter the production of proteins either to build up new synapses or to break down existing ones Purves, Augustine, et al. The molecular pathways that alter gene expression and modify synaptic architecture have been studied most extensively in brain regions that subserve learning and memory, especially the hippocampus and the cerebellum.
Whether and how these molecular pathways produce changes in the strength of synapses that encode other complex behaviors are not yet known. In addition to these neuroplastic changes at the level of individual synapses, the brain is plastic at the level of cortical organization. Studies in monkeys have demonstrated that when a digit is amputated, the amount of tissue in the brain that controls movement and sensation changes over a period of weeks, so that the areas representing the remaining digits, which continue to receive sensory input, expand to take over the regions previously occupied by the missing digit Merzenich, Nelson, et al.
Similarly, if a monkey is trained to use a digit disproportionately to accomplish a task, the representation of that digit in the motor cortex expands to take over areas previously mapped to neighboring digits Jenkins, Merzenich, et al. In addition, new connections in the cortex are generated when monkeys learn a new skill, such as using a tool, or after localized brain damage Dancause, Barbay, et al.
Similarly, the learning of new skills in humans leads to changes in the cortical regions that subserve that task Doyon and Benali, ; Ungerleider, Doyon, and Karni, One emerging question in the study of neural plasticity is the role that newly generated neurons may have in the postnatal brain. Mature, differentiated neurons have generally lost the capacity to divide to produce new cells, and a central dogma in neuroscience for most of the past century has been that all proliferation of new neurons ends during fetal life. However, many studies have recently provided indisputable evidence that postnatal production of new neurons, or neurogenesis, does in fact occur, even in adult life, in a small number of brain regions and in a large range of species Gould, These neurons are generated from a population of neural stem cells that are retained in the brain.
Although the full range of triggers for neurogenesis has yet to be identified, it appears to include a broad array of stimuli from experience and the environment, including physical activity and even antidepressant medications Lledo, Alonso, and Grubb, The birth of new neurons in postnatal life is one of many means through which experience can modify anatomical circuitry and functional activity in the brain.
The number of new neurons generated is small, however, and whether and to what extent these neurons are able to integrate into synaptic circuits and exert a significant functional influence in the brain are at present unclear Ghashghaei, Lai, and Anton, ; Gould, ; Lledo, Alonso, and Grubb, The ongoing capacity for change in the brain underlies potential mechanisms through which brain function can compensate for, or even recover from, a disorder, whether that disorder derives primarily from adverse genetic or environmental influences or a combination of both.
In a broad sense, then, virtually all responses in the brain that help compensate for the presence of a disorder can be considered neuroplastic responses, and they are likely to have their structural basis in the remodeling of synaptic connections and neural systems in the brain. This is thought to be a prominent feature of the pathogenesis of addictive disorders, for example, in which substances of abuse pharmacologically induce plasticity in brain circuits that are involved in reward and associative learning. Environmental influences that affect specific developmental processes have maximal effects during the developmental stages when those processes are under way.
Perhaps the paradigmatic example of this point is the effect of monocular occlusion, in which one eye is sutured closed and prevented from receiving any sensory input. In adult animals, monocular occlusion produces no effect on vision or on brain structure and function. When imposed early in development, however, it permanently alters both: It impairs vision in that eye, it reduces cortical representation of the sutured eye, and it expands cortical representation of the open eye.
Binocular occlusion produces perhaps even more extraordinary reorganization of the brain during an early critical period, as neurons in the would-be visual area respond not to light or visual stimuli, but to auditory and somatosensory stimuli instead Purves, Augustine, et al. Sensitive periods in humans are most clearly identified for disturbances in development of gross sensory and motor functions. For example, problems that create an imbalance in the activity of the two eyes early in life can have a permanent effect on the function of the cortical visual system.
Failure to correct congenital cataracts by about age 4 months in human infants produces irreversible impairments in the visual system Purves, Augustine, et al. Similarly, correction of strabismus, a misalignment of eye orientation, by age 7 produces optimal prevention of permanent visual impairment Flynn, Schiffman, et al. Evidence in humans for the existence of sensitive periods when exposure to specific environmental and experiential influences confers enhanced vulnerability to the development of MEB disorders is thus far modest and largely circumstantial. The effects on cognitive development of environmental deprivation and separation from human caregivers may be more severe during early development Nelson, Zeanah, et al.
Furthermore, traumatic experiences in childhood and adolescence appear to predispose to the development of severe character pathologies in adulthood; these effects are distinct from the effects of trauma experienced later in life Bierer, Yehuda, et al. These effects of childhood maltreatment in humans are consistent with animal models of child abuse and neglect that suggest that early maltreatment alters emotional responses and behaviors in adulthood while supporting learned preferences that are necessary for attachment to abusive caregivers Moriceau and Sullivan, ; Roth and Sullivan, ; Sevelinges, Moriceau, et al.
Additional evidence for sensitive periods in humans comes from studies reporting that prenatal but not postnatal exposure to tobacco smoke increases the risk of attention disorders in school-age children Braun, Kahn, et al. The neural bases for the effects of early experience on higher-order neurodevelopmental outcomes in humans and in animal models are thus far largely unknown. Developmental processes early in brain development establish fundamental brain structure and circuitry. To achieve the complex functions of the brain, signaling circuits that serve similar functions are grouped and integrated in networks both within the cortex and between the cortex and other regions of the brain.
These neural systems subserve complex processes, such as learning and memory, attachment, social relatedness, and self-regulatory control. These behaviors underlie the cognitive and social competence that is an essential part of healthy emotional and behavioral development, and deficits in these systems play a role in many MEB disorders. Multiple systems for learning and memory exist in the brain. Declarative memory, in contrast, is the conscious recall of facts, prior experiences, and semantic knowledge that is rapidly acquired and then consolidated for storage as long-term memory Kandel, ; Purves, Augustine, et al.
The hippocampus, working within networks with cortical regions, is important for remembering spatial and temporal relationships and for associative learning processes. It is centrally important for conscious learning and memory, contributing significantly to overall intellectual capacity Amat, Bansal, et al. S-R learning relies on a neural system that is distinct anatomically and functionally from the hippocampus-based declarative memory system and includes the striatum, a portion of the basal ganglia deep within the brain Packard and Knowlton, Changes in activity of dopaminergic neurons within the striatum also support learning in response to reward.
Reward is an essential component of many learning processes, and it is thought to be involved in both declarative and S-R learning Adcock, Thangavel, et al. Emotional experiences have powerful influences on memory, particularly on the accuracy and emotional tone of recalled memories in the declarative memory system. Emotional learning depends heavily on the interactions of the amygdala with the physically adjacent hippocampus, as well as with more remote structures that include the striatum and the frontal cortex.
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The interaction of the amygdala with memory systems imbues memories with the emotional tone experienced during and following the recalled event McGaugh, Experimental emulation and manipulation of various emotions in animal models have shown that the interactions between the amygdala and the hippocampus are influenced heavily by the actions of various neurotransmitters and hormones that mediate the effects of emotional experience on the recall of arousing, rewarding, and stressful life events McGaugh, ; Roozendaal, Okuda, et al.
In addition to declarative, S-R, and working memory systems, the brain supports associative or conditioned learning, as originally described by Pavlov. Conditioned learning involves numerous brain regions, including the hippocampus and the cerebellum Thompson, ; Daum, Schugens, et al. The obverse of conditioned learning is extinction, in which the unconditioned response to the CS is modulated downward over time. Extinction involves exposing an animal repeatedly to a stimulus that has been previously conditioned to elicit fear, but now in the absence of any aversive event.
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This will extinguish the fearful, conditioned response. Extinction is therefore an active process and not simply a passive, dissipating process of forgetting Myers and Davis, ; Quirk and Mueller, Extinction is cue-specific, in that extinction to one CS does not induce or accompany extinction to another CS Myers and Davis, When extinction fails, as it can during times of stress, the conditioned behavior can reappear Akirav and Maroun, The neural basis of fear extinction is thought to include the amygdala, the hippocampus, and the medial prefrontal cortex Myers and Davis, ; Quirk and Mueller, Disturbances in one or more of these various learning and memory systems have been implicated in the pathogenesis of a wide range of disorders.
This may not be surprising if the brain is viewed as having been constructed quintessentially for the processes of learning and remembering in order to enhance adaptation and survival efficacy. The diverse and spatially distributed neural systems subserving a great variety of learning and memory systems can give rise to equally numerous and diverse illnesses.
For example, attention deficit hyperactivity disorder ADHD has been conceptualized as a disturbance in emotional and reward-based learning, given the difficulty that children with ADHD have learning from prior mistakes, as well as their poor performance on delay aversion tasks, their preferences for smaller immediate rewards over larger delayed ones, and their more frequent risk-taking behaviors Farmer and Peterson, ; Oosterlaan and Sergeant, ; Sonuga-Barke, Taylor, et al. Localized reductions in volumes of the amygdala have been reported in ADHD, primarily over the basolateral nuclear complex Plessen et al.
Structural disturbances in the basolateral complex may disrupt emotional learning and the affective drive to sustain attention to otherwise mundane sensory stimuli Cardinal, Parkinson, et al.
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The basolateral complex is densely connected with the inferior pre-frontal cortex Baxter and Murray, , another region in which reduced volumes have been reported in youth with ADHD Sowell, Thompson, et al. Limbic-prefrontal circuits support the ability to tolerate delayed rewards and to suppress unwanted behaviors Elliott, Dolan, and Frith, , areas of difficulty that are defining hallmarks of ADHD Barkley, Cook, et al. Disturbances in the extinction of conditioned fear responses have been postulated in the pathogenesis of a wide range of anxiety disorders.
For example, fear is a normative response following exposure to trauma, and in most individuals it soon extinguishes completely.
In a minority of individuals, however, fear will fail to extinguish, and they subsequently manifest symptoms of posttraumatic stress disorder PTSD Yehuda, Flory, et al. Consequently, PTSD has been conceptualized as a disturbance of insufficient inhibitory control over conditioned fear responses Liberzon and Sripada, ; Yehuda et al. Human imaging studies of PTSD patients have reported 1 exaggerated amygdala responses to a variety of emotional stimuli, presumably representing exaggerated fear responses; 2 deficient activation of frontal cortices, which is thought to mediate disordered fear extinction and impaired suppression of attention to trauma-related stimuli; and 3 reduced volumes and deficient activation of the hippocampus, which may mediate deficits in recognizing safe contexts Bremner, Elzinga, et al.
Similar circuit-based disturbances have been postulated in other pediatric anxiety disorders, and they are thought to account for the minority of children whose anxiety disorders do not remit by adulthood Pine, Preclinical and clinical studies have suggested that cognition-enhancing medications and repetitive exposure-based interventions, either alone or in combination, may offer a paradigm shift in anxiety disorders. Instead of treating the symptoms of anxiety pharmacologically, this strategy attempts to improve the extinction learning that occurs during cognitive-behavioral therapy Myers and Davis, ; Quirk and Mueller, Early bonding to a primary caregiver is an innate predisposition for children.
It is an important feature of infant development that contributes to social and emotional learning, as well as to resilience and risk for psychopathology Bakermans-Kranenburg and van Ijzendoorn, ; Corbin, ; Swain, Lorberbaum, et al. The classic model for early attachment is visual imprinting in newly hatched chicks. During a specific sensitive period, they develop an enduring selectivity for following either their mother or a replacement object.
This imprinting consists of three independent behavioral processes: Specific cortical brain regions and synaptic changes are involved in the memory of and response to the imprinted object in chicks Insel and Young, Mammalian animal models of the attachment of an infant to a care-giver, as well as the behavioral and neuroendocrine responses to separation from that caregiver, have revealed physiological mediators of attachment and separation responses that have specific and long-term regulatory effects on the hormonal, physiological, and behavioral reactivity of the infant Hofer, The cry of the infant upon separation, for example, is released by loss of the warmth, specific odors, and passive tactile cues of the mother Shair, Brunelli, et al.
Nutritional and tactile factors also regulate hormone release and thereby cause abnormal levels of stress-response hormones during separation. Loss of the maternal nutrient supply affects hormone production by the adrenal gland, whereas loss of the tactile interaction between mother and infant affects hormone release by the pituitary gland Hofer, These physiological regulators constitute the building blocks from which attachment develops.
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