Module B - Structural and functional brain development Flashcards
(93 cards)
1
Q
How many neurons and glial cells are in the adult cortex?
A
10-20 billion neurons
50-200 billion glial (support) cells
2
Q
Describe neural tube differentiation:
A
Radial, circumferential and longitudinal direction
Precursor cells to neural tissues in neural plate are neuroepithelial cells
4-5 weeks neuroepithelial cells rapidly proliferate 250,000/minute (main driver of brain growth and defines ventricular and subventricular zones) following neural tube closure
3
Q
Describe the brain regions during development and what they develop into:
A
Telencephalon - hypocampus, cerebral cortex, basal ganglia
Diencephalon - thalamus (almost all circuits use to integrate)
Metencephalon - cerebellum and pons
Myelincephalon - medulla
4
Q
What forms the cerebral ventricles?
A
The cavity within the neural tube for the ventricles and central canal of the spinal cord
5
Q
When does the most rapid period of brain weight occur?
A
Immediately before and after 40 weeks’ gestation
From 28-40 weeks there is exponential brain growth (circuit formation)
6
Q
When does neuralation occur?
A
3-4 weeks post-conception
7
Q
When does cell birth occur?
A
6 weeks, continues in the majority of neurons until 12 weeks
Continues in fewer neurons (primarily in cortex) until a few months postnatal)
8
Q
When does migration occur?
A
~8 weeks until 24 months
Fewer neurons until birth
9
Q
When does axonal/dendritic outgrowth occur?
A
18 weeks until 6 months post-birth
Fewer neurons until 18 months
10
Q
When does programmed cell death occur?
A
~20 weeks until post brith
11
Q
When does synaptic production occur?
A
~26 weeks until 18 months post birth
12
Q
When does myelination occur?
A
Birth until 20 years
13
Q
When does synaptic elimination/pruning occur?
A
12 months until 16 years, fewer neurons until 24 years
14
Q
When do subplate neurons exist?
A
Prenatal period
15
Q
Describe the embryonic disk:
A
Endoderm, mesoderm and ectodern
Initial CNS development termed neuralation
2-3 weeks after conception
16
Q
Describe phase 1 of cell genesis:
A
Proliferation
Radial glia and IPC
17
Q
Describe phase 2 of cell genesis:
A
Neurogenesis and migration, ~8 weeks
Blood vessels and pericytes
Microglia
Glut+ neuron
18
Q
Describe phase 3 of cell genesis:
A
Neurogenesis and migration, up to ~6 months
GABA+ njeuron
Ependymal cell
19
Q
Describe phase 4 of cell genesis:
A
Gliogenesis and maturation from ~6 months
Astrocyte
Oligodendrocyte
20
Q
Describe the relationship between postconceptual age and absolute cortical GM volume
A
Positive
3x increase in volume over 12 weeks (extensive brain growth)
21
Q
When does neuronal migration occur?
A
Primary neuronal migration occurs weeks 8-20 of gestation (largely complete by week 25-29)
22
Q
Describe migration (cell displacement):
A
Oldest cells located farthest away from proliferative zone
Short distance
e.g. thalamus, dentate gyrus, brain stem
23
Q
Describe active migration:
A
Movement of younger cells past the older cells (inside out)
Long distance
e.g. cerebral cortex
24
Q
In active migration, how do neurons know how to get there?
A
Via radial glial cells (act as guides)
Migrating cells are immature, lacking dendrites
Neurons propel along surface of glial cell
Neuron recognises by way of chemical signals that is has reached final destination and stops migrating
Cells finished migrating align themselves with other cells and forms structures (aggregation)
25
Describe radial migration:
From VZ/SVZ cortex in radial direction (radial glia)
| 90% of cells
26
Describe tangential migration (parallel):
GABAergic interneurons migrate from MGE and LGE into cortex
| Last cells in cortex (~18-36 weeks complete)
27
Describe neuronal differentiation:
Neuroblasts have simple morphology
| Begin to differentiate during migration and once reached their final location (~25 weeks until adolescence)
28
Describe the four main overlapping events of neuronal differentiation:
1. Dendritic growth/arborisation (post-synpatic connections with axons of other neurons)
2. Axonal growth and targeting (short and long range fibre pathways)
3. Synapse formation (synaptogenesis)
4. Neurotransmitter receptor expression
29
Describe human dendritic development:
3-fold increase in dendrite length 30 weeks to term
30
Describe axonal guidance:
```
Guidance cues (fixed or diffusible chemical)
Attract or repel
Netrins, Slits (secreted), ephrins, semaphorins (cell surface)
```
31
Describe highly motile growth cones (which detect cues in the ECM):
Dynamic extension of developing axon
| Contains sensory, motor, intergrative and adaptive functions required for axonal growth and targeting
32
Describe synaptogenesis:
Axons (with growth cones on end) and dendrites form a synapse with other neurons or tissue
Neurobiological substrate of almost all cell-cell communication
33
Describe the density of synapses in the brain:
Each neuron forms thousands of synapses
| ~28 weeks - 2-3 years ~40,000 synapses per second
34
Describe neuronal connectivity/circuitry:
Set of integrated components that serve a specific function
Cognition, emotions and behaviour all controlled by brain circuits
Circuit formation started prenatally
35
What are the two key pathways in the brain:
Thalamocortical
| Corticothalamic
36
What is the function of the TC pathway?
Relays sensory and motor information form receptors in retina, cochlea, muscle, or skin to the thalamus and cortex
37
What is the function of the CT pathway?
Completes feedback loop by transmitting information back to thalamus
38
Describe the development of the TC/CT pathways:
Develop in second trimester in humans, main neurogenic event in the late fetal period
Creates a structural substrate for various sensory experiences, including pain
39
Describe TC connectivity and the subplate, and its timing:
~22 weeks - afferent fibres growing from thalamus initially synapse with SP neurons (waiting zone until neuronal migration to higher cortical layers complete - still active cortical circuit)
~24-30 weeks onwards, axons break connections with SP and form new connections (synapses) with final targets (L4) in overlying cortex
SP neuron apoptosis and SP largely disappears by term
40
What is the subplate?
Thick transient layer of neurons during fetal life (plays a critical role in formation of TC pathway)
41
Describe brain apoptosis:
During proliferation, number of neurons created exceeds that needed in the mature CNS, some cells must be removed (50-70%)
Neurons die due to failure to compete for chemicals produced at synaptic sites (neurotrophins)
Tightly regulated process
Selective
No inflammation
Energy dependent signalling pathway
42
What % of the adult brain volume is present at birth and by the end of the first year?
25% and 75%
43
Name the main processes in postnatal cerebral development:
```
Neurogenesis?
Dendritic branching
Synaptogenesis - synaptic elimination
Gliogenesis/proliferation
Myelination
```
44
Describe the two main postnatal proliferative zones:
Subventricular zone:
Lining of the lateral ventricles
Neuroblasts migrate to olfactory bulb via the RMS
Subgranular zone:
Dentate gyrus of hippocampus
Neuroblasts migrate migrate from subgranular layer to nearby granular layer
45
Why might neurogenesis continue to adult life in a very small population?
Learning and memory
| Altered in adult neurodegenerative disorders
46
Describe dendritic spine formation:
Aborisation of both pyramidal neurons and GABAergic inter-neurons continues postnatally
Marked elaboration of spines in first 1-2 years
Drives postnatal expansion of the cerebral cortex and other GM structures
47
Describe the removal of synapses postnatally:
Makered production of synapses up to 3-4 years (~40,000 synapses per second)
By adolescence synaptic density is ~60% of maximum density at age 2
Critical for fine tuning of brain circuits
48
List the main types of CNS glia:
Neuroglia - astrocytes, oligodendrocytes, NG2 cells (oligodendrocytes precursors)
Microglia (CNS macrophages)
Schwann cells
49
Describe the roles of radial glia and microglia:
Radial glia - scaffolding for neuronal migration
Microglia - clean up debris after apoptosis
Genesis of radial glia and microglia occurs in parallel with neurogenesis prenatally
50
Describe the role of astrocytes and oligodendrocytes progenitors:
Develop well after intial neurogenesis
Glial progenitors genesis, migration, and differentiation starts prenatally, but predominately postnatal process
Unlike neurons, glial progenitors continue to proliferate as they migrate and at final destination
51
Describe astrocytes presence and function in the brain:
20-50% brain volume
Process-bearing cells in nervous system - lack axons and dendrites
Maintain viable microenvironment for neurons
Regulatory functions
CNS signalling
52
Describe oligodendrocytes in the brain:
```
OPC produced in two waves
Ganglionic eminence (prenatally - tangential migration into WM)
SVZ (postnatally - radial migration into cortex)
```
Differentiation into myelin producing state begins once reach destination following axogenesis
53
Describe the impact myelination has on signal transduction:
Myelinated axons - 100m/s
| Unmyelinated axons - 1m/s
54
Describe the longevity of myelination:
Lasts up to 30 years
Axonal myelination begins around 6 months gestation, but not completed until adolescence
Sensory pathways myelinate prior to motor pathways
Postnatal motor development linked to myelination
55
Describe brain plasticity:
Marked improvements in perceptual, language and cognitive abilities
Development and refinement of functional brain networks (plasticity)
Postnatal events altered by experience (plasticity)
Correct development of visual and auditory circuits requires correct visual and auditory input
Incorrect and lacking input can alter correct circuit formation
56
Describe the kitten input deprivation study:
Induces detrimental effects
| Visual experience in early life determines wiring of visual cortex
57
Methods for assessing CNS structure/function:
Post mortem tissues - prenatal development
Structural MRI - diffusion tensor imaging
Functional MRI - identify which parts of the brain are involed in a task and the regions which higher levels of oxygen in the blood
PET
Electroencephalograph (EEG)
58
Describe diffusion-weighted imaging:
Water diffusion reflects tissue microstructure
Used to map diffusion of water in biological tissues
High resolution
Contrast between tissues
59
Describe DWI in terms of fractional anisotropy:
Scale of 0 (isotropic) - 1 (diffusion along 1 axis)
Gives degree of water diffusion directionality (degree to which water diffusion is restricted in one direction relative to other)
60
Describe how fMRI shows brain development:
Infants begin to learn native language in 1st few months of life
fMRI determines brain regions that support this language processing
Many adult speech circuits already active in infancy
61
Describe EEG sleep-wake cycles:
Development of integrated and coordinated patterns of sleep-wake cycles (used to assess degree of brain maturation/function - premature birth)
62
Describe sleep cycling in neonates:
Neonates mainly cycle between awake and REM sleep
In neonates, majority of sleep is REM (~25% in adults)
REM: low voltage, high frequency brain activity, associated descending muscular atonia
REM brain activation considered important for brain/synaptic development, without associated motor consequences
REM deprivation during infancy causes behaviour/cognitive deficits in later life
63
Describe neurodevelopmental disorders:
Impairments in growth and development of the CNS
Can occur in prenatal or postnatal life
Neural tube defects, neuronal migration/proliferation, synaptics disorders, myelin disorders
64
List the potential causes of neurodevelopmental disorders:
```
Genetic
Trauma
Immune dysfunction
Infectious disease
Nutrition
Toxin/Environmental/Teratogens
Metabolic disorders
Associated with a wide range of mental, emotional, and physical problems
```
65
List the types of genetic disorders (4):
Variation or a mutation in a gene - random gene mutations, environmental exposure, inherited
Neural tube defects
Neuronal migration disorders - lissencephaly, subcortical band heterotopia, focal cortical dysplasia
White matter myelin disorders - leukodystrophies, phenylketonuria (metabolic disorder)
66
Describe neural tube defects:
Most common birth defect (1:500-1000 live briths)
Brain and/or spinal cord exposed at birth
-Defect in skull or vertebrate
-Incomplete closure of the neural tube
Anencephaly, encephaloceles, hydranencephaly, spina bifida
67
Describe the relationship between folic acid and neural tube defects:
```
Folic acid (vitamine B9), required for cell production and maintenance during neural tube development (neuraltion)
Folate prior to and during pregnancy
```
68
What is ancencephaly?
Without brain (do not survive hours past birth)
69
What is hydranencephaly?
Missing cerebral hemispheres, replaced by sacs of fluid
70
What is encephaloceles?
Protrusion of brain through skull in a sac like membrane, surgery effective, intellectual disability
71
What is spina bifida?
```
Opening of the spinal cord, meninges or spinal cord herination
Most common (~50%)
```
72
Describe neuronal migration disorders:
Majority of neuronal migration between 12-24 weeks
Failure of normal neuroblast migration often causes neurons to accumulate in unusual areas (heterotopias)
Lissencephaly, polymicrogyria, focal cortical dysplasia, schizencephaly
Epilepsy, intellectual disabilities
73
Describe the different types of heterotopias:
Focal (nodular heterotopias) - basically clumps of neurons located in the wrong part of the brain (all levels of the migration pathway, VZ to CP)
Diffuse band heterotopias (band of neurons formed in the WM beneath the cortex)
74
Describe lissencephaly (smooth brain):
Absent (agyria) or decreased (pachygyria) cortical folding
Most cases results from LIS I gene disruption, encodes B-acetylhydrolase and degrades platelet activating factor
Accumulation of PAF impairs neuronal migration
Early developmental delay, early diffuse hypotonia, spastic quadriplegia, seizures, severe intellectual disability
75
Describe type I LIS lissencephaly:
Migratory defect occurs 12-16 weeks gestation
Very thick 4-layered cortex
Hypotonia at birth, develop progressive spasticity
Seizures start within first few months of life
76
Describe subcortical band heterotopia:
Bands of neurons are located in the white matter between the cortex and the lateral ventricles
Majority of cases due to mutations of the doublecortin (DCX) gene
-Encodes DCX protein expressed in migrating neuroblasts
-Regulates cytoskeletal dynamics and neuroblast migration
77
Describe focal cortical dysplasia:
Spectrum of abnormalities of the laminar structure of the cortex
Various cytopathological features
-Giant neurons
-Dysmorphic neurons
-Balloon cells (enlarged cell bodies but no dendrites/axons)
Abnormal migration, mutation and cell death
Intractable epilepsy in children
Developmental delays
78
Describe the myelin disorder leukodystrophies:
Progressive white matter degeneration
Mutations in genes that produce or maintain myelin - oligodendrocyte death and myelin degeneration
Manifest during childhood (incurable, premature death)
-Symptoms vary according to the specific type of leukodystrophy
-Progressive decline in motor, cognition, language skills
-MRI pathology typically hypomyelination
79
Describe the myelin disorder vanishing white matter disease:
Oligodendrocyte cell death, diffuse disappearance of white matter, loss of myeline
Mutations in eIH2BI-5 genes (oligodendrocyte survival/apoptosis)
Childhood ataxia (gait difficulties)
Rapid cognitive decline (2-5 years)
80
Describe the myelin disorder Phenylketonuria (PKU):
Also a metabolic disorder (1:10,000) mutation in phenylalanine hydroxylase
Baby cannot digest amino acid in milk
Phenylalanine accumulates in brain
-Inhibits HMG-CoA reductase to decrease cholesterol synthesis
-Oligodendrocytes do not produce myelin
Hypomyelination/demyelination
Impaired brain development and intellectual disability
Strict diet with no phenylalanine
81
Describe infectious diseases and brain disorders:
Transmitted congenitally or in early childhood and can cause serious neurodevelopmental disorders including schizophrenia
Congenital toxoplasmosis - domestic cat
Congenital syphilis can progress to neurosyphilis and brain defects
Measles can progress to subacute sclerosing panencephalitis
Congenital rubella syndrome linked to schizophrenia
82
Describe immune dysfunction and brain disorders:
Immune reactions during pregnancy can produce neurodevelopmental disorders
-Syndenham's chorea
-Pediatric autoimmune neropsychiatric disorders associated with streptococcal infections
Both are autoimmune reactions against brain tissue following group A streptococcus bacteria infection
Kill neurons in the corpus striatum of the basal ganglia
Abnormal movements of the body, emotional disturbances, altered cognition, tics, OCD etc.
83
Describe perinatal systemic infection:
Chorioamnionitis (maternal infection)
- Inflammation of fetal membranes due to bacterial infection
- Bacteria ascending into the uterus
- Typically non-pathogenic
- Associated with high rates of motor (cerebral palsy) and neurocognitive deficits
- Fetal/newborn inflammation (inflammation response syndrome)
Neonatal sepsis (bacterial infection spread via blood stream)
84
Describe fetal inflammatory response syndrome:
Chorioamnioitis associated with elevated levels of inflammatory molecules in fetus/neonate
FIRS important cause of in utero postnatal brain injury
CNS inflammation following systemic infection
85
Describe the influence of metabolic disorders on the fetus:
Fetal metabolism altered by:
Maternal nutrition (folate deficiency)
Maternal neurotoxins/teratogens (nicotine, alcohol) exposure, diabetes
Many inherited metabolic disorders
-In-born errors of metabolism, single gene defects in biochemical pathways
-Lysosomal storage disorders (IC structures responsible for breakdown of metabolic waste products)
Cause neurodevelopmental disorders, major effects during gestation
86
Describe the effects of diabetes mellitus on brain development:
In utero, a non-diabetic fetus can also be subjected to glucose effects if its mother has undetected gestational diabetes (~6% of all pregnancies)
- 10-fold increase in congenital abnormalities if during 1st trimester
- CNS defects including anencephaly and spina bifida
- Seizures
- Delays in motor and cognitive function in childhood
87
Describe how nutrition and the 1944 Dutch Famine leads to brain defects:
Severe 5 months of undernutrition, consuming tulip bulbs and sugar beets
Children who were affected in the second trimester of their mothers pregnancy had 10x increased incidence of schizophrenia as adults
At 56-59 years of age, showed impaired cognitive ability due to accelerated brain aging
88
List the toxic and environmental factors (teratogens) on brain development:
Retinoic acid
Alcohol
Nicotine
Heavy metal poisoning (mercury)
89
Describe the effect of retinoic acid on brain development:
Retinoids include alcohol, aldehyde and acid forms of vitamin A
Metabolic precursors or derivstives of vitamin A are teratogenic
Hearing and visual impairment, intellectual disability
90
Describe fetal alcohol spectrum disorders:
1-2/1000 infants
50+% of women who could become pregnant are drinking
2% of women drink significantly during pregnancy, 10% drink some
Fetal brain damage occurs at regular doses of 1-2oz/day (2-4 drinks)
Infant - problems with sleep, feeding, milestones, muscle tone, sensory information processing
Child - hyperactive, poorly coordinated, learning delays
Adolescent/adult - poor judgment, attention, problems with arithmetic, memory, abstraction, frustration/anger
91
Describe the effects of maternal smoking (nicotine) on brain development:
Increases risk of infants being born with low birth weight
20-30% of all LBW infants due to maternal smoking
Nicotine targets nicotinic ACh receptors
Impairs cell proliferation and differentiation, synaptogenesis, induced neuronal apoptosis
Constricts placental blood vessels, to reduced blood flow/nutrients to fetus
Decreased IQ, depression, criminal behaviour
92
Describe the effect of heavy metal poisoning (mercury) on brain development:
Spectrum of nervous system damage including neurodevelopmental behavioural disorders in children, visual impairment, impaired coordination, hallucinations, intellectual disability, depression, and death
93
Describe the effect of heavy metal poisoning (lead) on mental development index:
Lead accumulates and stored in bones for decades
Women exposed to lead can cause elevated fetal lead even well after exposure
Neuronal, astrocyte, and oligodendrocyte apoptosis
Altered neurotransmitter storage/release
