APPLIED NEUROPSYCHOLOGY IN PEDIATRIC NEUROLOGY
FERNANDO PIGATO – FCM – UNICAMP – 2005
NEURODEVELOPMENT
Table of Contents
1. Fertilization.
2. Implantation.
3. Gastrulation.
4. The three embryonic layers: ectoderm, mesoderm, endoderm.
5. Neurulation: the closure of the neural tube.
6. Formation of the CNS.
6.1. The three primary vesicles of the neural tube: prosencephalon, mesencephalon, and rhombencephalon.
6.2. Prosencephalon.
6.2.1. Telencephalon and diencephalon.
6.2.1.1. White and gray matter.
6.3. Mesencephalon.
6.4. Rhombencephalon.
7. Histogenesis of Neurons.
7.1. Cellular proliferation.
7.2. Cellular migration.
7.3. Cellular differentiation.
8. Genesis of Connections.
9. Cortex Layers.
10. Apoptosis.
11. Development of the CNS.
1. Fertilization.
At the moment of fertilization, when the sperm fertilizes the egg, the zygote acquires its genetic load and begins the transformations that will originate the embryo. In the woman’s fallopian tube, mitotic divisions occur, known as “cleavage or segmentation of the blastomeres,” which will transform into a solid sphere composed of many cells, the morula.
2. Implantation.
The morula reaches the uterus and at this point, at the end of the first week of pregnancy, it is called the blastocyst. It continues to divide, and soon a cavity appears inside it called the blastocyst cavity or blastocoel. The sphere now appears as a hollow ball and is called the blastula, which is firmly embedded in the uterine wall.
Between the first and second weeks, the cells of the blastula continue to divide (micromeres), but mainly proliferate at one of the poles, where the wall becomes thicker (macromeres).
The blastocyst gives rise to the embryoblast, trophoblast, and blastocyst cavity.
The embryoblast is a bilaminar embryo and gives rise to the epiblast and hypoblast. The trophoblast gives rise to the cytotrophoblast and syncytiotrophoblast.
3. Gastrulation.
In the phase of gastrulation, which occurs in the third week, the macromeres turn and adhere to the micromeres in a “shell” form, now called the gastrula. The micromeres are referred to as ectoderm and the macromeres are referred to as mesoderm.
The concave opening formed is called the archenteron, and its opening is called the blastopore.
At this point, a new cavity forms in its thickest part, that is, between the ectoderm and mesoderm cell layers, and this cavity is called the amniotic cavity, a flat structure in the shape of a ribbon.
Three important structures arise: the primitive streak, the notochord, and the neural plate.
At this stage, the three embryonic layers originate, resulting in a trilaminar embryo: ectoderm, mesoderm, and endoderm, which arise from the epiblast.
4. The Three Embryonic Layers: Ectoderm, Mesoderm, Endoderm.
These three layers will give rise to different parts of our body.
The upper blastodermic layer, the outermost, is the ectoderm, which will give rise to the epidermis and the Central Nervous System, neurons, pituitary gland, eyes, and ears.
In the transition from the second to the third week of pregnancy, at a certain point in the ectoderm, cells proliferate more intensely and migrate inward toward an opening formed in this layer. This process is called the invagination of the ectoderm, forming a third layer, the mesoderm, the middle blastodermic layer.
The mesoderm can be differentiated into dorsal or paraxial (epimer and notochord), intermediate (mesomere), and lateral (hypomere). The mesoderm will give rise to the notochord (which will form the vertebrae, bone marrow, limbs, etc.), epimer, mesomere (urinary system), and the hypomere, which will give rise to the circulatory system, skeletal and smooth musculature, peritoneum, mesenteries, and the appendicular skeleton (thoracic and lumbar limbs). The epimer, in turn, originates the dermatomes (dermis), myotomes (striated cardiac musculature), and the sclerotome—axial skeleton (spine).
The endoderm, the innermost blastodermic layer, will give rise to the respiratory system, digestive tract, and associated glands (pancreas, liver, thyroid, lungs, bladder, and urethra).
5. Neurulation: Closure of the Neural Tube
This occurs in the fourth week. The most important features are the formation of the neural plate or groove, the neural tube, and the neural crests.
The gastrula grows in length forming a plate and is then called the neurula.
The mesoderm strongly influences the ectoderm covering it, now called neuroectoderm, because almost the entire nervous system will form from it. Through the interaction between mesoderm and neuroectoderm, cells proliferate and elongate, becoming cylindrical. The region thickens and becomes known as the neural plate. The cells continue to divide, causing the folding of the neural plate around a groove. The plate gradually closes upon itself, forming the neural tube. The process through which the neural plate transforms into the neural tube is called neurulation and occurs around the third or fourth week of pregnancy.
The neural plate, located above the notochord, begins to fold onto itself, forming the neural folds, and the groove that forms is called the neural groove. The neural folds continue to come closer together. At this point, the neural tube closes, starting from the first somite at the center of the plate and advancing cephalically and caudally until the complete closure of the tube.
When the neural crests fuse, they form tissue that will give rise to the epidermis (neural ectoderm). The closed neural tube is then located between the notochord and the epidermis (neural ectoderm).
The diameter of the neural tube is not uniform. In the cranial part, in the fourth week, three dilatations are initially observed; these are the so-called primordial encephalic vesicles: prosencephalon, mesencephalon, and rhombencephalon, followed by the spinal cord.
6. Formation of the CNS.
Between the prosencephalon and the mesencephalon is the cephalic flexure, while between the rhombencephalon and the spinal cord is the cervical flexure.
In the fifth week, the prosencephalon will give rise to the telencephalon and the diencephalon. The mesencephalon will not undergo changes. Finally, the rhombencephalon will give rise to the metencephalon and the myelencephalon, separated by the pontine flexure. The metencephalon will give rise to the pons and cerebellum, while the myelencephalon will give rise to the medulla oblongata (bulb).
The medulla oblongata, pons, and mesencephalon form the brainstem, a structure responsible for connecting the brain to the spinal cord.
The entire CNS develops from the walls of the neural tube. When the neural folds come together, the neural ectoderm detaches and relocates laterally to the neural tube. This tissue is the neural crest. All neurons and neuronal cell bodies in the peripheral nervous system are derived from the neural crest.
The process by which structures become more elaborate during development is called differentiation. The first step in the differentiation of the brain is the development of three dilations known as primary vesicles. The brain derives entirely from the three primary vesicles of the neural tube: prosencephalon, mesencephalon, and rhombencephalon.
The lateral ventricles arise from the cavity of the telencephalon, the third ventricle arises from the cavity of the diencephalon, the Sylvian aqueduct arises in the mesencephalon, the fourth ventricle arises from the cavity of the rhombencephalon, and the central canal arises from the lumen of the spinal cord.
The meninges also arise during this period, with the dura mater deriving from the mesoderm surrounding the neural tube, the arachnoid from the cells of the neural crest, and the pia mater, also originating from the cells of the neural crest, separated by the subarachnoid space.
6.1. The three primary vesicles of the neural tube: prosencephalon, mesencephalon, and rhombencephalon.
In addition to the mesencephalon, secondary vesicles arise on both sides of the prosencephalon. At this stage, the prosencephalon consists of two telencephalic vesicles (cerebral cortex and basal nuclei) and the diencephalon.
From the rhombencephalon, two secondary vesicles also arise: the metencephalon (cerebellum and pons) and the myelencephalon (medulla).
6.2. Prosencephalon.
The prosencephalon is the location for conscious perceptions, cognition, and voluntary action. All of this depends on extensive interconnections with sensory and motor neurons of the brainstem and spinal cord. Undoubtedly, the most important structure of the prosencephalon is the cerebral cortex, which is the telencephalic structure that has most expanded in human evolution.
6.2.1. Telencephalon and Diencephalon.
The cells of the telencephalon wall divide and differentiate into various structures. The walls of the telencephalic vesicles appear dilated due to neuronal proliferation. These neurons form two types of gray matter in the telencephalon: the cerebral cortex and the basal telencephalon.
Likewise, the diencephalon differentiates into two structures: the thalamus and hypothalamus.
The developing neurons of the brain extend their axons to communicate with other parts of the nervous system. These axonal bundles join to form the main white matter system: the cortical white matter, corpus callosum, and internal capsule.
6.2.1.1. White and Gray Matter.
In a cross-section of the brain, it is easy to see the gray and white areas. The cortex and other nerve cells are gray, while the regions between them are white.
The grayish color is produced by the aggregation of thousands of cell bodies (neurons), while the white color is the color of myelin (glial cells or glia).
In white matter, there are no neuron cell bodies, only axons and glial cells. Among these, oligodendrocytes are the most numerous and often show a clear perinuclear halo.
Glia is considered a group of cells performing secondary functions such as support, nutrient supply, and insulation for neurons.
Glia also surrounds synapses, the communication points between neurons where they exchange substances such as glutamate. At these sites, its function is to quickly absorb any excess glutamate that overflows from the synapse.
The white color reveals the presence of axonal bundles passing through the brain, more so than in other areas where connections are being made. At the end of the axon, there are terminal filaments, which are close to other neurons. These can be near the dendrites of other neurons, in special structures called dendritic spines, or close to the cell body.
6.3. Mesencephalon.
Unlike the prosencephalon, the mesencephalon undergoes little differentiation during the subsequent development of the brain. The cerebral aqueduct is a reference point for identifying the mesencephalon.
It conducts information from the spinal cord to the prosencephalon and vice versa. It contains neurons involved with the sensory system in movement control and various other functions.
The mesencephalon contains axons that descend from the cerebral cortex to the brainstem and spinal cord.
6.4. Rhombencephalon.
The rhombencephalon differentiates into three important structures: the cerebellum, pons (metencephalon), and medulla (myelencephalon). It is also here that the fourth ventricle originates.
Like the mesencephalon, the rhombencephalon is an important conduit for information that passes from the prosencephalon to the spinal cord and then back to the prosencephalon. The neurons of the rhombencephalon contribute to processing sensory information, controlling voluntary movements, and regulating the autonomic nervous system.
7. Histogenesis of Neurons.
The organization and development of the neural tube occur in layers or zones: in the ventricular layer (germinative) through mitosis of neuroepithelial cells (neuroblasts, glioblasts, radial glia, and ependymal cells); in the intermediate layer (mantle) through cell bodies; and in the marginal layer through axons and dendrites.
A neuron has three distinct parts: the cell body, dendrites, and axon.
In the cell body, the largest part of the nerve cell, is the nucleus and most of the cytoplasmic structures.
The dendrites are thin, usually branched extensions that conduct stimuli from the environment or other cells toward the cell body.
The axon is a thin extension, usually longer than the dendrites, whose function is to transmit nerve impulses from the cell body to other cells.
The cell bodies of neurons are concentrated in the central nervous system and in small globular structures scattered throughout the body, called ganglia. The dendrites and axon, known as nerve fibers, extend throughout the body, connecting the cell bodies of neurons to each other and to sensory, muscular, and glandular cells.
Neuronal structures develop in three main stages: cellular proliferation, cellular migration, and cellular differentiation.
7.1. Cellular Proliferation.
This process begins between the 2nd and 4th month of gestation.
The brain develops from the walls of five fluid-filled vesicles. The walls of these vesicles will be made up of two layers: the ventricular zone and the marginal zone. Within these layers, all neurons and glial cells will originate.
Each newly formed daughter cell will have a different fate. After cleavage in the vertical plane, the two daughter cells remain in the ventricular zone to divide again. After cleavage in the horizontal plane, the daughter cell farther from the ventricle stops dividing and migrates.
The precursor cells of the ventricular zone repeat this pattern until all the neurons of the cortex are formed.
7.2. Cellular Migration.
This process starts between the 4th and 9th months of gestation.
The first cells to migrate away from the ventricular zone will reside in layers called the subplate, which eventually disappears as development proceeds. The next cells divide and will form layer VI, followed by layers V, IV, III, and II.
The daughter cells migrate by sliding along fine fibers that radiate from the ventricular zone. These fibers are derived from specialized radial glial cells, providing the foundation upon which the cortex will be built. Immature neurons, called neuroblasts, follow this radial path from the ventricular zone to the brain surface. Once the cortical set is complete, the radial glial cells remove their radial processes. However, not all migratory cells follow the path provided by the radial glial cells. About one-third of the neurons “wander” horizontally on their way to the cortex. Neuroblasts destined to become the subplate are among the first to migrate out of the ventricular zone. Neuroblasts destined to become the adult cortex migrate next. They cross the subplate and form another cellular layer called the cortical plate. The first cells to arrive in the cortical plate will be those of layer V, followed by layer IV, and so on. Each new wave of migrating neuroblasts passes beyond the previous one in the cortical plate, so the cortex forms from the inside out.
In summary, neuronal migration is the process by which neurons move from their origin site to their permanent location in the developing brain.
7.3. Cellular Differentiation.
This is the process by which a cell takes on the appearance and characteristics of a neuron. Further neuronal differentiation occurs when the neuroblasts reach the cortical plate. Thus, neurons of layer V differentiate into pyramidal cells before the cells of layer II migrate to the cortical plate.
The differentiation of neuroblasts into neurons begins with the appearance of neurites budding from the cell body. Initially, all these neurites look alike, but soon some will resemble axons and others will resemble dendrites. Differentiation occurs even if the neuroblast is removed from the brain and placed in a tissue culture medium. This means that differentiation is programmed even before the neuroblasts reach the site where they will settle. The complexity of dendritic trees, however, also depends on environmental factors.
This process is also known as maturation or myelination, and it begins from the 4th month of gestation.
8. Genesis of Connections.
As neurons differentiate, they extend their axons, which must find their appropriate targets, forming synapses. These connections are long-range.
Since neurons form a network of electrical activities, they must somehow be interconnected. When a nerve signal, or impulse, reaches the end of its axon, it means it has traveled as an action potential or electrical pulse. However, there is no cellular continuity between one neuron and the next; there is a space or gap called the synapse. The membranes of the sending and receiving cells are separated by the synaptic space, filled with fluid. The signal cannot electrically cross this space. Thus, special chemicals, called neurotransmitters, perform this role. They are released by the presynaptic membrane and diffuse through the space to the receptors on the postsynaptic membrane of the receiving neuron. The binding of neurotransmitters to these receptors allows ions (charged particles) to flow in and out of the receiving cell.
The normal direction of information flow is from the terminal axon to the target neuron, so the terminal axon is called the presynaptic (conducing information to the synapse) and the target neuron is called the postsynaptic (conducing information away from the synapse).
9. Cortical Layers.
The cerebral cortex has 6 layers. The most superficial, in direct contact with the pia mater, is called the molecular layer. It has a loose texture, and there are no neuron cell bodies in it, only many synapses. In the other layers, neurons are characterized by round and vesicular nuclei and a prominent nucleolus. The cytoplasm is clear, well-defined, and basophilic (purplish), due to the abundant ribosomes (RNA). The larger neurons group together to form Nissl bodies. The clear space, often seen around neurons, is called artifact.
Normal glial cells do not show cytoplasm in H&E staining. The nuclei of astrocytes are slightly larger and looser than those of oligodendrocytes, and both are round, while microglia nuclei are elongated and have dense chromatin. The capillaries in the cortex are abundant and contain red blood cells, but they do not stand out much due to the thin walls and the spacing between the nuclei of endothelial cells.
10. Apoptosis.
Entire populations of neurons are eliminated during the formation of pathways in a process called programmed cell death or apoptosis. After the axons reach their targets and synapse formation begins, there is a progressive decline in the number of presynaptic axons and neurons. Cell death reflects competition for trophic factors, essential substances provided in limited quantities by the target cell.
The description of cell death during development as something “programmed” reflects the fact that it is, indeed, a consequence of genetic instructions for self-destruction. This process is called apoptosis.
11. Development of the CNS.
Around the 2nd week, the cerebral cortex increases differentially in each part.
The cerebral cortex in the fetus becomes identifiable at around eight weeks. From then on, it gradually increases in thickness, first uniformly. According to the development of different parts of the brain, we can outline some periods of evolution, with the first period in the fetus until the 2nd month of gestation, remaining almost immobile. In the second period, from the 5th to the 8th week of gestation, spontaneous movements appear.
From the 2nd to the 4th month of intrauterine life, the first neural movements appear, i.e., those controlled by the nervous system, which are more active, rapid, coordinated, and widespread. They are triggered by various excitations and can still be considered reflexes. They appear in the back and mucous membranes, including oral and anal reflexes, with the oral reflex being the most precocious and constant, involving mouth closure, sucking, and swallowing movements. There are also short movements of the extremities, such as the flexion reflex, extension reflex, hand grasp reflex, and plantar reflex. Tonic-cervical reflexes, triggered by changes in head position relative to the body, and postural reflexes, triggered by changes in body position in space, also emerge. These reflexes are a consequence of the differentiation of the peripheral motor neuron from the matrix plate of peripheral receptors and sensory cells. There is a connection between external sensory neurons and motor neurons, as well as developing proprioceptive sensitivity.
By around the 26th week, most of the cortex shows the typical structure of six layers, somewhat indeterminate, of nerve cells with a fiber layer in the center.
References.
BEAR, M.F.; CONNORS, B.W.; PARADISO, M.A. Neurosciences; Unveiling the Nervous System. Porto Alegre: Artes Médicas, 1996.
KANDELL, E.; SCHWAARTZ, J.H.; JESSEL, T.M. Fundamentals of Neuroscience and Behavior. Rio de Janeiro: Prentice-Hall do Brasil, 2000.