Development of the Nervous System

Transcription

1 Development of the Nervous System OBJECTIVES 1. Describe the formation and fate of the neural tube and neural crest. 2. Name and describe the formation of the primary and secondary embryological compartments of the CNS. Describe what they represent in the adult CNS. 3. Understand the role of growth factors and other molecular signals during development. 4. Understand the concept of cortical layering. Describe how cortical layers develop. Describe syndromes associated with defects in cortical proliferation and migration. 5. Understand postnatal mechanisms that result in maturation of the CNS (myelination, synaptogenesis, dendritic pruning, critical period). Development is a critical time for the nervous system. Insults that alter CNS development have great impact on the structure and function of the postnatal brain. These changes can lead to abnormal brain function involving cognition, intelligence, personality, behavior, seizures, function of sensory and motor systems and other properties. 1) During 3rd week of embryonic development: Ectoderm on the dorsal surface of the embryo thickens to become the neural plate. This invaginates to form the neural groove, which continues to deepen. The dorsal edges (neural folds) eventually fuse and the cylinder separates from the surface ectoderm to form the neural tube and neural crest. Neural crest gives rise to most of the spinal, cranial nerve, and autonomic ganglia including neurons and supporting cells (schwann cells, meninges). The neural tube becomes the central nervous system: cranial portion becomes the brain caudal portion becomes the spinal cord cavity becomes the ventricles and central canal of spinal cord Neural plate Day 15 Neural groove Neural folds Cross-section through embryo at each stage neural tube Closure of neural tube From: Neuroscience: Exploring the Brain, M.F.Bear, B.W.Connors, M.A.Paradiso, Lippincott, Developmental disorders result from failure of the neural tube to close or separate from surface ectoderm; rostral defects cause anencephaly, caudal defects cause spina bifida. 1

2 Defects vary in severity from a few defective vertebral arches (10% of population) to the CNS being an open pit continuous with the body surface. Dr Ostrow will discuss in more detail. From: Netter Spina bifida anencephaly 2

3 2) Overview of Changes in Neural Tube during Development weeks 4-36 The neural tube expands in size and undergoes bending near its anterior end in the region of the brainstem. The bending is important for the development of the cerebellum, shaping of the midbrain, pons, and medulla, and for repositioning the ventricular system toward the anterior surface Cerebral hemispheres show the greatest expansion and eventually over-grow the brainstem. Actual sizes compared to other figs. 25 days 5 months 8months 35 days 40 days 50 days 6 months 100 days 7 months 9 months From: Principles of Neural Development, Purves and Lichtman, Sinauer,

4 3) Early Changes in the Neural Tube Weeks 4-8 the neural tube develops three primary compartments (vesicles) and bends by week 4. These further develop into 5 secondary compartments by week 6, which will form the 5 major brain divisions. From: Dr. P.Phelps, Physiological Sci., UCLA Week 4 Week 4 Week 6 Dorsal View 4 weeks 6 weeks Side View Modified from Neuroanatomy by JD Fix, Williams&Wilkins, 1992 Cell proliferation and migration causes complex shape changes in the neural tube. 4

5 Fate of the embryonic compartments Prosencephalon Telencephalon Diencephalon Cerebral Hemispheres and Lateral Ventricle Dorsal Thalamus + Epi, Hypo, Sub Thalamus, Visual System, Pituitary, 3rd Ventricle Mesencephalon Mesencephalon Midbrain and Cerebral Aqueduct Rhombencephalon Metencephalon Myelencephalon Pons, Cerebellum, rostral half of 4th Ventricle Medulla, caudal half of 4th Ventricle Early Development of the Spinal Cord and Brainstem During the 5 th week, proliferating neurons in the dorsal half of the neural tube form the Alar Plate, where sensory neurons develop. This becomes the dorsal horn. The ventral half forms the Basal Plate, that will give rise to motor neurons of the ventral horn. In the spinal cord, these regions produce the characteristic butterfly appearance,. However, in the brainstem, the alar plate migrates laterally and the basal plate migrates dorsally so that sensory and motor nuclei lie lateral-medial to each other. alar plate Spinal Cord sensory areas basal plate motor areas Brainstem/Medulla Fourth ventricle Graphics from Marvin Sodicoff, Ph.D. Temple University School of Medicine 5

6 4) Nerve cells depend on molecular signals for survival and growth Nerve cell growth involves extension of axons and dendrites from the cell body, pathfinding to targets, and subsequent synaptogenesis with targets. These events are essential for development of normal structure and connectivity. To a large degree these depend on molecular signals provided by their targets. Growth Factors Nerve cells depend on growth factors for their survival; Without factor, neurons undergo apoptosis. Growth factors are synthesized and released by target tissues and they interact dynamically with nerve terminals by binding to them and modulating both survival and growth. Growth factors are limited in supply and they are available only to neurons that form synapses with targets. A key feature of neurodevelopment is that there is an initial overproduction of neurons that send axons toward their target. Since neurons depend on growth factors for their survival, only those neurons that form synapses with the target cells will be maintained. This is a fundamental way by which the nervous system allows the size of target tissues to control the number of neurons that supply them based on a competition to form a synapse with the target. Growth factors are released by many types of cells including neurons, muscle, glands and organs, and many non-neural cells (fibroblasts, macrophages, etc). Each population of nerve cells depends on a specific type of growth factor. Examples: Neurotrophins (Nerve Growth Factor family: NGF, BDNF-brain derived neurotrophic factor, NT-3, NT-4), CNTF-ciliary neurotrophic factor, GDNF-glial derived neurotrophic factor Growth factors continue to be synthesized in the ADULT brain and also regulate other important properties such as synaptic function and axon and dendrite branching. Major Questions: Are neurodegenerative diseases caused by decreased secretion of growth factors; Can growth factors be used therapeutically to rescue dying nerve cells. Growth of axons and dendrites occurs at their tips, where specialized, motile structures known as growth cones occur. Growth cones are guided to their targets by a variety of environmental signals. Extra Cellular Matrix (ECM) molecules provide an adhesive substrate for growing nerve fibers examples: collagens, fibronectin, laminins Cell Adhesion Molecules (CAMs) on cell membranes cause adhesion and fasciculation examples: NCAM, L1, cadherins (Ca ++ dependent) Secreted molecules and molecules expressed on cell membranes can attract or repel growing nerve tips. The signals that guide outgrowing nerve fibers are now recognized also to be important in guiding the growth of blood vessels to establish the vascular pattern for the body! 6

7 5) Development of the Cerebral Hemispheres and Cortex weeks 8-36 Adult cerebral hemispheres: 1. Cell bodies are located in a thin region of outer cortex (gray matter), axons are located deeper in a thick fiber layer (white matter), and some nuclei (cell bodies) are buried deep in the fiber layer. 2. Cortex is layered based on the types and positions of nerve cell bodies with regional differences; Neocortex has 6 layers, archicortex and paleocortex have 3 layers. The organization of cortical layers is critical to how the brain receives, processes, and transmits information. Failure to form layers results in deficits such as seizures and mental retardation. Cell bodies/grey matter axons/white matter Coronal section of adult brain stained (nissl) to show locations of cell bodies, which lie in a thin, external cortex. Magnified view of adult cortex showing cell bodies arranged in cortical layers 7

8 Embryonic brain is composed of thin telencephalic compartments containing scattered cells surrounding the internal space that will become the ventricles. How does the complex structure of the adult brain (1. large mass, 2. cortex/cell bodies on the external surface, and 3. cortex layered) develop from the simple embryonic form? ventricles Thin region of scattered cells Embryonic brain Answer: The hemispheres develop by proliferation and migration of neuroblasts in the wall of the embryonic telencephalic vesicles. This process 1) increases the mass of the telencephalic compartments, 2) allows neurons to migrate towards the pial surface where they form the cortex, and 3) results in the formation of cortical layers for information processing. How this happens: Neuroepithelial cells proliferate in a zone (subventricular zone) adjacent to the lateral ventricle of the telencephalic vesicle. Cell bodies of differentiating neurons migrate toward the pial surface either on their own or along fibers of radial glial cells that span the width between ventricle and pial surface. Note: the subventricular zone remains an important area in some regions of the adult brain where neuronal stem cells continue to form neurons even in adults. These areas have potential for harvesting stem cells for use in repairing damaged areas of the brain. Modified from Nadarajah et al, Nature Rev Neuro. 3:

9 Becomes cortex Becomes white matter sub(retains stem cells in adult in some brain areas.) Embryonic telencephalon Neuronal proliferation and migration results in thickening of telencephalic compartment, outer cortex of cell bodies, and inner fiber layer. As proliferation and migration proceed, telencephalic vesicles grow forward, upward and backward in a C shaped path covering subcortical structures. In the adult, many structures conform to this C-shape (e.g. lateral ventricles) Local differences in rate of proliferation cause gyri, sulci, and fissures between weeks 14 and 32. You should recognize that CNS development is characterized by: proliferation, migration, differentiation, synaptogenesis, myelination (mostly postnatal) Defects in proliferation and migration cause abnormalities such as: microcephaly - decreased brain size polymicrogyria or macrogyria - abnormally small or large gyri lissencephaly smooth cortex lacking gyri and sulci heterotopias misplaced gray matter schizencephaly clefts in hemisphere abnormal development of the corpus callosum (communication between hemispheres) Defects may affect specific areas of the brain and not others. They may cause a range of syndromes differing in degree including epilepsy, mental retardation, and death. 6) Threats to Normal Prenatal Development Teratogens are environmental substances that can impair fetal development. The timing, amount of exposure, and sensitivity of organs to these substances determines the magnitude of defects. Compounds such as alcohol, thalidomide (sedative), anti-seizure drugs, retinoic 9

10 acid (accutane) and other substances are known to alter early CNS development. These substances can result in disorders that permanently impair postnatal brain function. Normal CNS development also depends on maternal thyroid hormone and iodine, which cross the placenta. Maternal hypothyroidism or iodine deficiency result in Cretinism (mental retardation and other physical defects). 7) POSTNATAL Development What Changes Occur Pre and post -natal development are characterized by the cephalocaudal principle, i.e growth follows a pattern that starts with the head and upper body and proceeds down the rest of the body. Thus, an infant s head is disproportionately larger than it s body. Postnatal CNS development occurs over a long time course, at least until the end of the teen years. In fact, development more appropriately can be considered over the span of a lifetime. The brain triples in weight and reaches 3/4 adult size during the first 2 years!! This brain growth and the subsequent acquisition of new functional capabilities are due primarily to 3 types of postnatal changes within the CNS: 1. Myelination required by larger axons to conduct action potentials. The infant CNS is not fully functional until myelination of pathways has occurred by end of year Dendritic growth and pruning provide the opportunity for adjustments in input and connections from other neurons. The growth and retraction of dendrites as well as changes in number of spines are dynamic processes that are influenced by levels of activity in neural circuits. 3. Synapse Formation communication between neurons. This is a dynamic process in which connections between neurons are strengthened or weakened based on activity. Synapses peak in number postnatally! Environmental stimulation has a major impact on all 3 of the above processes. The growth/pruning of dendrites and the subsequent formation/loss of synaptic connections are controlled to a large extent by the use/disuse of circuits in the brain. Dendritic growth and synapse formation peak postnatally and then these are subsequently refined based on how circuits are used. This provides a fantastic capacity for adjusting communication between nerve cells, allowing brain function to be shaped by use. The formation and normal function of these circuits are not specified genetically (they are too great in number) so the brain relies on experience the way an infant is stimulated by and interacts with its environment. Thus, experience provides the mechanism for establishing the basic circuitry of the brain. These capabilities still persist throughout life to enable the CNS to continue to change in response 10

11 to experience (plasticity). However, the capacity to remodel the CNS is greatest early in life so that early experience has great implications for later functional capabilities of the CNS. Dangers of Lead: The earlier years are particularly sensitive to some toxic substances that can alter CNS function permanently. Heavy metal compounds such as lead can cause irreversible CNS damage and it is a constant threat to children who may ingest lead or breathe lead-based fuel byproducts from their environment. Critical Periods: Neural circuits are shaped in large part by an individual s experiences during sensitive periods of plasticity. Experiments with sensory systems have shown that normal sensory function in adults requires appropriate sensory stimulation at certain critical times during postnatal development. These critical periods are times when neuronal circuits are especially capable of dendritic and synaptic reorganization that establishes their capacity to process information. The early formation of functional circuits is required for normal function in the mature brain. For example, appropriate visual and auditory stimulation are required early in the postnatal period for subsequent normal development of vision and language capabilities. Absence of stimulation or abnormal stimulation during the critical period can permanently impair brain function. In a lesser way, sensitive periods also are recognized as opportune times in postnatal development that can influence, but not completely determine, functional capabilities in the mature brain. The concept of critical/sensitive periods probably applies to many CNS systems (sensory, motor, cognitive, emotional) because of the role of experience in the postnatal processes that control CNS maturation. The timing of sensitive periods may vary and some may extend over many years because brain structures mature at different rates and some (frontal lobes) do not complete maturation until the late teen years. Effects of Stress on Brain Development Prenatal Stress stress hormones (glucocorticoids) pass through the placenta and can affect brain development. glucocorticoids are important for normal brain maturation, axon and dendritic remodeling, and neuronal survival. However, abnormal levels of glucocorticoids can alter brain maturation with long term consequences as deficits in learning, mood (anxiety, depression), and sensitivity to addiction. Postnatal Stress a potent stimulus in animal experiments is separation of pups from the mother. This can alter glucocorticoid levels in the young with long term consequences on brain maturation and behavioral and emotional control. An environment of stable, stimulating, and protective relationships builds a strong foundation for a lifetime of effective learning. In contrast, when young children are burdened by significant adversity, stress response systems are overactivated, maturing brain circuits can be impaired, metabolic regulatory systems and developing organs can be disrupted, and the probabilities increase for long-term problems in learning, behavior, and physical and mental health. J.P.Shonkoff, Harvard Univ. Other recent studies have shown that supportive caregiving during the preschool years is associated with an increased size of brain areas involved in memory and learning. 11

12 Image References: 1. University of Leicester School of Medicine: 2. J.L.Driesen, PhD at 3. Dr. Patricia Phelps, Dept. of Physiological Science, UCLA and the Crump Institute for Biological Imaging. 12