Lifespan Development of the Brain and Behavior PDF

Chapter 7: Life-Span Development of the Brain and Behavior Development of the Nervous System - overview - 7 developmental processes - neurogenesis - migration - differentiation - synaptogenesis - apoptosis - synaptic rearrangement - myelination - e...

Chapter 7: Life-Span Development of the Brain and Behavior Development of the Nervous System - overview - 7 developmental processes - neurogenesis - migration - differentiation - synaptogenesis - apoptosis - synaptic rearrangement - myelination - experience and epigenetics Aging - ongoing neurogenesis - AAMI - vascular dementia - stress - Alzheimer’s disease 1 Development of the Nervous System - zygote: egg fertilized by sperm, single cell - blastocyst: hollow sphere of pluripotential cells - gastrula: 3-layered form of partially differentiated blastocyst - embryo: 3 layers, ectoderm, mesoderm, endoderm Embryo 2 2 Development of the Nervous System - zygote: egg fertilized by sperm, single cell - blastocyst: hollow sphere of pluripotential cells - gastrula: 3-layered form of partially differentiated blastocyst - embryo: 3 layers, ectoderm, mesoderm, endoderm Day 51 - fetus: recognizable in relation to mature form Day 15 Day 21 Day 23 Day 40 3 3  Development of the Nervous System - neurulation: - dorsal epithelial layer (ectoderm) thickens to form neural plate - the neural plate folds to form neural groove and neural tube, and ultimately CNS ~18 days: induction of neural plate from ectoderm ~ 20 days: neural plate folds to form neural groove 4 4 Development of the Nervous System - neurulation: - dorsal epithelial layer (ectoderm) thickens to form neural plate - the neural plate folds to form neural groove and neural tube, and ultimately CNS ~22-24 days: lips of neural groove fuse to form neural tube 5 5 Development of the Nervous System - dorsal epithelial layer (ectoderm) thickens to form neural plate - neurulation: the neural plate folds to form neural groove and neural tube, and ultimately CNS neural plate neural groove neural groove somites notochord neural tube6 6  Development of the Nervous System - cells of neural crest break off and migrate to form PNS, directed by chemical signals neural crest ectoderm migrating neural crest cells notochord 7 7 Development of the Nervous System - differentiation of neural crest cells from biochemical signaling during migration 8 8 Development of the Nervous System - sensory organs arise (at least partly) from sensory placodes 9 9  Development of the Nervous System - as neural plate closes into neural tube, constrictions appear dividing off anlagen of forebrain, midbrain and hindbrain - rhombomeres form in hindbrain anlage - cell patterning occurs, where region-specific cell types are produced at predictable times, in predictable positions, and with predictable patterns of migration, final positions, etc. - fine-tuned later by apoptosis, synapse rearrangement, but original patterning is highly precise day 29 day 40 10 10 Development of the Nervous System 7 developmental processes: - neurogenesis, production of new cells - migration, movement to final location - differentiation, modifications to neuronal/glial type - synaptogenesis, growth of axons/dendrites/synapses - apoptosis, programmed cell death - synaptic rearrangement, fine tuning - myelination, formation of myelin sheath (not all neurons) 11 11 Development of the Nervous System neurogenesis, production of new cells - some progenitor cells in ventricular zone migrate short distance to formulate subventricular zone by symmetrical division - later (~7 wks in humans) cells in ventricular zone start dividing by asymmetrical division, first into radial glia, then asymmetrically into ongoing progenitor cells and precursors of non-dividing neuroblasts and glioblasts - rate and timing varies from one region of tube to another over developmental time - 3 swellings at anterior pole by 24-40 days 12 12  Development of the Nervous System migration, movement to final location - radial glia extend temporary network of projections from ventricular zone to pial surface to guide outward migration in CNS - provides scaffold for migration into columnar organization of cortex 13 13 Development of the Nervous System migration, movement to final location - migration occurs in waves 1) preplate zone (PP) established by wave of migration from ventricular zone (VZ) 2) second wave migrates through intermediate zone (IZ) to split preplate into marginal zone (MZ) and subplate (SP) 3) successive waves migrate out to expand cortical plate (CP) in inside-out manner (layers 1-6-5-4-3-2) 14 14 Development of the Nervous System migration, movement to final location - migration occurs in waves 1) preplate zone (PP) established by wave of migration from ventricular zone (VZ) 2) second wave migrates through intermediate zone (IZ) to split preplate into marginal zone (MZ) and subplate (SP) 3) successive waves migrate out to expand cortical plate (CP) in inside-out manner (layers 1-6-5-4-3-2) 15 15  Development of the Nervous System migration, movement to final location - focal cortical dysplasia 16 16 Development of the Nervous System migration, movement to final location - additional tangential migration to form subcortical neurons and interneurons of cortex CP VZ LGE MGE LGE= lateral ganglionic eminence MGE = medial ganglionic eminence VZ = ventricular zone CP = cortical plate 17 17 Development of the Nervous System differentiation, modifications to neuronal/glial type - dividing pluripotent precursor cells differentiate into non-dividing neuroblasts and glioblasts that further mature into specialized neuronal and glial cell types - remaining ventricular zone cells differentiate into ependymal cells, forming the linings of the ventricles and spinal column 18 18  Development of the Nervous System differentiation, modifications to neuronal/glial type - dividing pluripotent precursor cells differentiate into non-dividing neuroblasts and glioblasts that further mature into specialized neuronal and glial cell types - remaining ventricular zone cells differentiate into ependymal cells, forming the linings of the ventricles and spinal column Gliogenesis (radial glia) 19 19 Development of the Nervous System synaptogenesis, growth of axons/dendrites/synapses - extension and contraction of filopodial structures from the growth cone - chemoaffinity: postsynaptic target releases chemical label that attracts growing axon - dissociated neurons can innervate appropriate targets in vitro 20 20 Development of the Nervous System synaptogenesis, growth of axons/dendrites/synapses - extension and contraction of filopodial structures from the growth cone - chemoaffinity: postsynaptic target releases chemical label that attracts growing axon - reversal of spinal cord in chick embryo does not alter target innervation 21 21  Development of the Nervous System synaptogenesis, growth of axons/dendrites/synapses - extension and contraction of filopodial structures from the growth cone - chemoaffinity: postsynaptic target releases chemical label that attracts growing axon - regrowing frog retinal ganglion cells will innervate original targets - netrins identified retina optic tectum netrin gradient 22 22 Development of the Nervous System synaptogenesis, growth of axons/dendrites/synapses - extension and contraction of filopodial structures from the growth cone - fasciculation: stereotyped axonal pathfinding wherein pioneer growth cones interact with NCAMs that guide along the length of the path, and subsequent neurons follow this blazed trail - helps to explain complex paths followed by some growth cones - destruction of pioneer axons in fish spinal cord disrupted subsequent axon pathfinding 23 23 Development of the Nervous System apoptosis, programmed cell death - early exuberant proliferation, then apoptosis (including termination of progenitors) - cells that do not contact appropriate target undergo apoptosis 24 24  Development of the Nervous System apoptosis, programmed cell death - early exuberant proliferation, then apoptosis (including termination of progenitors) - cells that do not contact appropriate target undergo apoptosis 25 25 Development of the Nervous System apoptosis, programmed cell death - cells shrink, chromatin irreversibly condenses, cytoplasm and nucleus break up into membrane bound apoptotic bodies that are phagocytized - phagocytosis triggered by surface expression of death signals - since phagocytosis prevents release of individual cellular contents , immune response is not elicited 26 26 Development of the Nervous System apoptosis, programmed cell death - CNS neuronal survival is competitive 27 27  Development of the Nervous System apoptosis, programmed cell death - Additional cells are implicated in apoptotic mechanisms - glial cells can undergo apoptosis - apoptosis is also the mechanism for ending career of progenitor cells - recent finding, progenitor cells still exist in some parts of adult human brain 28 28 Development of the Nervous System apoptosis, programmed cell death - in surviving cell, Bcl-2 family of proteins inhibits release of Diablo from mitochondria - inhibitor of apoptosis proteins (IAPs) inhibit caspases - in apoptotic cell, lack of growth factor inhibits expression of Bcl-2 - Ca2+ influx / intracellular Ca2+ release activates mitochondrial release of Diablo - lack of Bcl-2 inhibition of Diablo allows Diablo to bind to IAPs, preventing inhibition of caspases - caspases activate endonucleases (fragmenting nuclear DNA), and breakdown of cytoskeleton - apoptosis initiated by lack of growth factor, loss of growth factor, DNA damage, protein misfolding, specific chemical signaling through death receptors 29 29 Development of the Nervous System synaptic rearrangement, fine tuning - neurons that fire together, wire together (Hebb, 1949) - open spaces on postsynaptic neurons are filled in by sprouting axon terminals of surviving neurons - diffuse pattern of synaptic contact is characteristic of early stages of development - more focused pattern of synaptic contact is present after synapse rearrangement - synaptic density peaks at about 1 year 30 30  Development of the Nervous System synaptic rearrangement, fine tuning - synapse survival is competitive 31 31 Development of the Nervous System synaptic rearrangement, fine tuning - topographic gradients: integrity of neuronal map is maintained from source to target, - adjustments made as source and target grow at different rates - organized by chemical gradients - when half retina lesioned and optic nerve cut, RGCs from remaining retina projected systematically over tectum - when half optic tectum lesioned and optic nerve cut, retina optic tectum RGCs projected systematically over remaining tectum - gradient-based organization of inputs - explained by spontaneous waves of activity across electrically-coupled cells 32 32 Development of the Nervous System myelination, formation of myelin sheath (not all neurons) - commences around 24 weeks after conception - commences in spinal cord, spreads successively to hindbrain, midbrain and forebrain - intense phase of myelination in the early postnatal period 33 33  Development of the Nervous System correlating neural development with behavior - massive synaptogenesis and myelination of Broca’s speech area from 15-24 mos, and large changes from 2-12 yrs - changes in dendritic complexity in language areas among most extensive in brain - coincides with massive changes in language ability - developing ability to grasp strongly correlated with myelination of motor areas (probably also associated with other neural events, dendritic arborization, etc.) 34 34 Development of the Nervous System environmental enrichment/impoverishment - visual deprivation = fewer synapses and fewer spines in primary visual cortex, with deficits in depth and pattern perception. - visual enrichment = thicker cortex, more dendrites, and more synapses laboratory enriched standard environment housing housing 35 35 Development of the Nervous System environmental enrichment/impoverishment - visual deprivation = fewer synapses and fewer spines in primary visual cortex, with deficits in depth and pattern perception. - visual enrichment = thicker cortex, more dendrites, and more synapses 36 36  Development of the Nervous System experience shapes functional organization in the visual cortex - monocular deprivation impairs organization of ocular dominance in PVC layer 4 - competitive process whereby active (Hebbian) synapses predominate - sensitive period starts ~3 wks, starts to close ~6 wks - a few days of monocular deprivation is enough to cause almost complete shift in ocular dominance - after 1 year of age, monocular deprivation no longer has any effect - effects of monocular deprivation during sensitive period do not recover 37 Development of the Nervous System epigenetics - 20,000 genes = human genome - gene expression influenced by environment - DNA methylation - addition of methyl group to adenine or cytosine in embryonic development to confer stable decreases in expression of genes as cells divide and differentiate - involved in imprinting, X-chromosome inactivation - addition of methyl group to cytosine (especially CpG) to suppress/silence gene expression in mature cells - decrease gene expression by physically interfering with transcription, or by recruiting methyl-CpG-binding proteins 38 38 Development of the Nervous System epigenetics - histone acetylation - DNA coiled around histones - acetylation of histone tails determines how tight DNA is coiled, determining availability of DNA for transcription - changes can last throughout lifetime 39 39  Development of the Nervous System a sensitive period for shaping the temperament of rats - adult offspring of ABN/LG mothers during first week of rat pup life exhibit decreased fearfulness and more modest HPA responses under conditions of mild stress - effects reversed by cross-fostering - in hippocampus of offspring of ABN/LG mothers, decreased methylation of GR promoter and increased histone acetylation causes higher GR expression - methylation patterns persist throughout adulthood not stress resilient offspring stress resilient offspring 40 Development of the Nervous System Developmental Disorders, 2 brief comments - Wrong, wrong, wrong, wrong, wrong, wrong, wrong, wrong Fragile X: - not more common in boys than in girls, but more severe in boys - X chromosome is not prone to breaking - CGG repeats cause methylation of FMR1 gene, silencing FMRP 41 Development of the Nervous System Developmental Disorders, 2 brief comments - Wrong, wrong, wrong, wrong, wrong, wrong, wrong, wrong Phenylketonuria (PKU): - dietary control should not be relaxed after age 2, or even in adulthood 42  Aging ongoing neurogenesis, migration, and learning - until recently, scientists believed neurogenesis stopped in embryonic development - now known that neurogenesis and migration continue in hippocampus, caudate nucleus, olfactory bulb, and (to a lesser degree) some other brain regions - rats injected with BrdU (200 mg/kg; labels dividing cells) - eyeblink conditioning experiment 7 days later - terminated after 1 day or 60 days - no between-groups differences in rate of neurogenesis in dentate gyrus - cells survive in rats that learn eyeblink conditioning, less in control rats untrained trained 1 day after training CS = 83dB 250 msec EMG US = 0.7mA 100 msec 60 days after training periorbital shock 43 43 Aging age-associated memory impairment (AAMI) - AAMI varies from mild cognitive impairment to profound dementia - in normal aging, most cognitive function remains intact until advanced age - challenges in identifying AAMI due to individual variability - estimates 4.6-38.4% of population over 65 experiences AAMI - confounded with lifetime differences, pre-AD - differences in decline of specific aspects of cognitive function - long term memory and working memory decline, vocabulary does not - NIMH criteria; memory performance on at least one test measure at least one SD below performance for healthy young - recall of word lists - recognition of associations between words delayed recall - recall of paragraph-length material (high score = better) - slower cognitive performance - impaired executive function - acquisition/retrieval of recent information 44 44 Aging aging factors that correlate with AAMI - intellectual profession and advanced education may be protective - mood state cluster strongly correlates with cognitive decline - depression history trait does not correlate strongly, but may promote decline in patients with active depression - treatment for depression in elderly may improve cognitive function 45 45  Aging aging factors that correlate with AAMI - widely distributed cortical and limbic neurofibrillary tangles and amyloid plaques identified in non-demented and mildly demented individuals - supports preclinical changes in progression of AD or transitional pathology from aging to AD - correspondence between white matter lesions and degree of AAMI in aged - lesions predominantly located in frontal tracts - loss of estradiol in females beyond approximately 52 years of age - estradiol supports growth of dendritic spines, new synapse formation in hypothalamus, cortex, and hippocampus - estradiol has trophic actions on cholinergic neurons - cholinergic neurons lost in normal aging and in AD - ERT improves some, but not all indices of AAMI - oxidative damage and inflammatory responses - age-associated increases in numbers and reactive state of microglia - possible protective actions of anti-oxidants, free radical scavengers, NSAIDs, but results are preliminary or controversial 46 46 Aging vascular or multi-infarct dementia - large infarct (>50 ml) clearly associated with cognitive impairment, but strategically placed small lacune (1 ml) may have equivalent impact - risk factors include: hyperlipidemia, diabetes mellitus, hyperhomocysteinemia, smoking, elevated C-reactive protein, cerebral amyloid angiopathies 47 47 Aging stress, glucocorticoids and hippocampal atrophy - chronically elevated glucocorticoids in stress, Cushing’s disease, major depressive disorder, or glucocorticoid therapy - glucocorticoid cascade hypothesis - probably shrinkage of dendritic arbor etc., rather than actual cell loss 48 48  Aging Alzheimer’s Disease - most common form of age-associated dementia (50% of all cases) - 4 million cases in US, 26 million worldwide - 10% of population over age 65, 25% of population over age 85 - alert and generally responsive in early stages, followed by progressive decline in multiple domains - initial signs involve medial temporal lobe function - distant past memory relatively preserved, but impaired consolidation of new declarative memories - impairments in identifying word meaning, uses for common objects, meaning of numbers - additional signs include confusion, agitation, delusions, social disinhibition, paranoia - progressive loss of language abilities - in end stage, patients often mute, severely disabled 49 49 Aging Alzheimer’s Disease - Amyloid β-containing extracellular amyloid plaques - surrounded by dystrophic neurites w/ multiple glia - high prevalence of Aβ42 and Aβ40, that are highly prone to aggregation - neurofibrillary tangles - pairs of twisted hyper-phosphorylated tau filaments with highly regular periodicity - localized intracellularly - swollen soma and displaced nucleus, and deficits in trafficking - in early stages, plaques and tangles are generally restricted to the hippocampus and overlying cortical areas - pathology is more widespread later neurofibrillary tangles amyloid plaques 50 50 Aging Alzheimer’s Disease - aggressive early onset form reveals genetic predisposition - 3 autosomal dominant gene mutations identified for early onset AD - amyloid precursor gene on chr 21 (pathology in trisomy 21 in 4th decade), presenilin 1 gene on chr 14, and presenilin 2 gene on chr 1 - all 3 genes affect processing of amyloid precursor protein - in late onset AD, apolipoprotein E gene on chr 19 is implicated - 3 alleles (ApoE2, ApoE3, ApoE4) - increasing number of copies of ApoE4 increases risk for late onset AD - mechanism unknown, but perhaps role of ApoE in scavenging and clearing amyloid peptides from extracellular space in brain - 0 copies = low risk - 1 copy = 4-fold higher risk - 2 copies = 8-fold higher risk 51 51