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Normal & Abnormal Brain Development - Coggle Diagram
Normal & Abnormal Brain Development
What Controls Neurone Proliferation?
The Cell Cycle
Pinel (2013)
Cells triggered to enter the cycle, and ends with equal partitioning of genetic material and cleavage of the cell (mitosis)
G1 Phase
Mitogen chemical signals cell division. At checkpoint G1, DNA damage detected by variety signals, including increased levels protein expression tumour suppression gene p53.
If no increased level p53, cell passes through restriction point, where committed to replicate
S Phase
DNA unwinds into 2 strands. Newly formed adenine, thymine, guanine and cytosine attached to compliment bases.
On set DNA produced for each daughter cell (sister chromatids), with more checkpoints here where apoptosis occurs upon wrong
G2 Phase
Develop new cell organelles, DNA damage checkpoint, increased P53 leads to apoptosis
Mitosis
Chromatids separate, organelles split, more checkpoints and formation of daughter cells that enter either G0 (not dividing), or G1
What Makes Some Cells Divide and Not Others?
Mitogen signals
must be present for proliferation
50+ mitogens, most controlling broad spectrum (e.g., platelet derived growth factor), and some narrow (e.g., Erythropoietin, proliferates red blood cell precursors)
Most cells in G0. In mature organism neurones in permanent or semi-permanent G0 state, and other enter G0 only temporarily.
Parkinson's Disease
Stem cell ability develop different types of cells may be significant for therapeutic intervention in ageing and developmental disorders
(LaPerle et al., 2020)
generated induced pluripotent stem cells (iPSCs) from blood cells young-onset Parkinsons.
Used iPSCs to produce dopaminergic neurons which displayed accumulation protein alpha-synuclein, which occurs most forms Parkinson's.
And produce malfunctioning lysosomes, which membrane-bound cell organelle contains digestive enzymes which break down excess or worn-out cell parts. They may also be used to destroy invading viruses and bacteria, and help with apoptosis if a cell is damaged beyond repair
Combination accumulation alpha-synuclein and dysregulation lysosomal biogenesis and function = phenotype young-onset Parkinsons, and thus potential diagnostic tool
Has also helped identify drugs reduce intracellular alpha-synuclein levels in disease-derived cells that may even treat underlying cause YOPD, and could uncover things about neurodegenerative disorders
How Does Cell Differentiation Actually Happen?
Gene Regulation
(Elliot & Elliot, 2005)
Transcription Factors
- proteins bind to specific DNA sequences
Wnt and SHH
(morphogens) regulate transcription target genes, controlling flow genetic info
Switching on and off different sequences DNA results in control over structural and functional characteristics cell, e.g., gene regulation
SHH and Wnt
antagonistic
functions, thus concentration gradients key to how effect each other's transcription signals. Ratio SHH and Wnt unique value to each location, which is how massively intricate cellular differentiation occurs.
Exact ratio combination
constitutes
genetic identity code
for
each neurone
Gene Expression
- What makes that cell a particular cell is expression certain genes, which code for specific proteins that confer structure and function cell.
(National Human Genome Research Institute, 2019)
info encoded into gene turned into function
Proteins
- large (macro) molecules created by polymerisation monomers. (combination small molecule monomers into chain)
Proteins synthesised from menu 20 amino acids that must be put together in correct sequence. Number possible sequences infinite
Amino acids
= small molecules based around carbon chain, with amino and carboxyl group. There are 20, they are building blocks of proteins. Life is dependent upon each cell having complete set instructions for amino acid sequence of every protein in cell
Glycogen
- main type macromolecule comprised of chain glucose monomers. Order monomers joined in chain is unimportant. Essential energy storage in animals
Deoxyribonucleic Acid (DNA)
- DNA each gene carries chemical code tells cell sequence amino acids require produce protein gene codes for. This code contained in sequence bases nucleotides Adenine, Thymine, Guanine and Cytosine. Each protein may have hundreds amino acids, so DNA sequences approx 2m long each cell
RNA
- Messenger RNA (mRNA) brings messages from DNA to cytoplasm. Ribosomal RNA (rRNA) helps ribosomes connect to mRNA. Transfer RNA (tRNA) transports amino acids to ribosomes
Transcription
- Process occurs nucleolus cell.
RNA polymerase enzyme makes RNA copy portion DNA, that RNA strand sent to cytoplasm via nuclear pores as mRNA. Transcription factors proteins bind to DNA near start transcription gene, either block or induce RNA polymerase in initiation transcription
RNA polymerase
- controls transcription. Unwinds short stretch double helical DNA to produce single-stranded DNA templated. Selects correct nucleotide and detects termination signals where transcript ends = produces correct code for protein
Translation
- process turning genetic message mRNA into protein (from nucleic acid to protein language). Takes place at ribosomes in cytoplasm. Ribosomes read mRNA and translate it into protein.
When Proteins Go Wrong
- protein codes at heart many neurodevelopmental disorders
AD
- amyloid-beta plaques from APP, NFTs faulty Tau protein. More in :warning: lecture 4 notes
Autism
- Most thalidomide victims Autism have abnormalities in structure ears, but not malformation arms or legs.
Miller & Stromland (1994)
- Embryonic ears develop day 20-33 and arms day 25-35, so able pinpoint developmental injury to 20-24 days after conception.
Most neurones developed this early are motor neurons that operate muscles eyes, ears, face and jaw. These cell bodies located in brain stem
Possible brain stem injury interferes with development higher cortical regions, thus cortical processing later development.
(Horev et al., 2011)
Human 16p11.2 copy number variations associated with autism. Chromosome engineering 16p11.2 CNV in mice, and mice with reciprocal duplication. 16p mice dose-dependent changes gene expression, viability, brain architecture and behaviour. For each phenotype, consequence deletion more severe than that of duplication. Half 16p deletion mice die postnatally. Those that survive are health and fertile but have alterations in hypothalamus and 'behaviour trap' phenotype. Insight into human neurodevelopmental disorders
Rett Syndrome
- Genetic disorder mental retardation and impaired movement caused by faulty copy MECP2 genes, lies on chromosome X.
Males mutated MECP2 do not usually survive beyond infancy, females usually have normal copy too.
Guy et al. (2007)
did with mice, block MECP2 and essentially couldn't move. When expression unblocked, went back to normal.
How Do Neurones Know Where To Go?
Chemoaffinity Hypothesis
Sperry (1963)
= Each postsynaptic surface releases a specific chemical. Each axon is attracted to its specific target by this chemical tag.
Supporting Evidence
Frog eye experiment
Sperry (1943)
- Cut optic nerve and simultaneously rotated eye 180 degrees eye socket. Optic nerve frog regenerates after cut.
Location in space seen by different location Frog retina, connected by optic nerve to different location in brain, causing different movement direction. Once rotated, part retina now looking forwards should connect to backward movement part of brain
After regeneration, frog responded to prey in front by turning around and going backwards. This behaviour continued throughout learning. So, pattern connections b/w retina and tectum and movement info represented is innate
Vitro Axon Guidance
Bolz (1994)
developing neurones grow to their normal targets in-vitro. Supports hypothesis since no other cues available in-vitro e.g., spatial
Axon Guidance Molecules
Stoeckli & Landmesser (1998)
many chemicals attract/repel growth cone identified e.g.,
(Kastenhuber et al., 2009)
repulsive Robo2/Slit signalling keeps dopaminergic axons away from midline. In absence, DA axons attracted towards midline by Netrin1 signalling. Thus, slit-based repulsion counteracts Netrin-mediated attraction to specify lateral positions DA diencephalospinal tract.
Problems
Target cells transplanted can become
innervated
by
incorrect cells
(Whitelaw & Hollyday, 1983)
:new: layout went weird here
Some axon growth
appears
circuitous or indirect
(Bastiani et al., 1985)
Info both eyes combined in binocular neurones of V1 and show
stronger response stimulation from one or other eye
.
(Weisel & Hubel, 1963)
Any electrode penetration perpendicular cortical surface, most or all observed cells preferred one eye and were grouped into ocular dominance columns. Early in development, there is no pattern, so clearly happening over time, and as such contradicts chemoaffinity
Deprive one eye cat and monkey, ocular dominance cell formation most severely degraded deprivation at 1-9 weeks, and deprivation afterwards had no long-term effect. Means
experience
leads to
changes in synaptic formation
.
Taxi drivers
significantly more grey matter in mid-posterior hippocampi and less volume in anterior hippocampi compared to bus drivers. Years navigation experience correlated with hippo grey matter only in taxi drivers. Shows changeability with experience
(Maguire et al., 2006)
Synaptogenesis
. Pre-natal tuning found systematic moving patterns neural activity generated in retina
(Wong, 1999)
and such predictable pattern change over time provided excellent training data tuning connections b/w visual maps. Mimics neural activity infant would see actually born
Blueprint Hypothesis
= underdeveloped NS contains chemical/mechanical trails that axons follow to targets. Pioneer growth cones follow trails using cell adhesion molecules
(van Vactor, 1998)
and subsequent axons follow this path. Termed fasciculation
Problems
Clear evidence chemoaffinity means this hypothesis cannot be exclusive mechanism axon guidance. Cannot explain successful axon guidance in-vitro, and cannot explain that some axons reach correct targets when transplanted
(Lance-Jones & Landmesser, 1980)
Topographic Gradient Hypothesis
= axon growth from one sheet cell bodies to another determined by relative position bodies on original sheet, and position described by two intersecting gradients
Supporting Evidence
Topographic characteristics preserved across 'sheets' such as retina and tectum during neurodevelopment
(Reh & Constantine-Paton, 1984)
one-to-one mapping.
Regeneration studies show lesions in retina result in remaining neurones spreading out to targets across tectum, counter to Sperry or blueprint.
Function Wnt and SHH not restricted morphogenesis. Low concentrations SHH promote retinal ganglion cells to move to outer part optic nerve, and high promote movement to inner
(Avies et al., 2013)
Similar patterns effects true of Wnt in retina, meaning not only responsible gene expression, but also for where neurones should go
Postnatal Development
= synaptogenesis b/w birth and 6 years sees lots of synapses, but by 14 synaptic pruning occurs which contradicts chemoaffinity hypothesis. Most neurones adult brain developed by 7th month foetal development, however brain volume quadruples between birth and adulthood
(Johnson, 1997)
due to:
Myelination
= formation myelin sheath around nerve to allow significantly improved conduction
(Sarnat & Sarnat, 2014)
Dendritic Arborisation
tree-like branching out of dendrites allowing for new synaptic connections. Sign of complexity due to increased no. synaptic connections allows for
(Jan et al., 2011)
Synaptogenesis
- formation new synapses dependent on glial cells.
Correct synaptic connections guided by complex chemical signals between pre and post-synaptic neurones
Happens on basis gene expression, can undergo long-term potentiation or depression
Increase synaptogenesis
immediately after birth, and differences in synaptogenesis across cortical area
(Huttenlocher, 1994)
V1 and primary auditory cortex larger increased month 4, max synapse density month 7 (150% adult density)
PFC steady rate synaptogenesis reaching maximum density 24 months, unsurprising since these areas require more complex processing
Synapse loss later development heterogeneous. V1 leads to adult-level density by 5 years, and in PFC not until adolescence
(Huttenlocher, 1990)
Functional Development
- some synaptogenesis phases mirror functional development, auditory cortex precedes Wernicke's area which precedes Broca's, since response to sounds precedes language comprehension which precedes motor speech
(Huttenlocher, 2000)
Synaptogenesis Neuro-Muscular Junction
- slow and fast twitch muscles synapse accurately by slow and fast motor neurones. Main method synaptic signalling in NMJ through use neurotransmitter Acetylcholine and its receptor. Glial Schwann cells PNS intrinsic to guidance these synapses
(Cao & Ko, 2007)
Specificity in Brain
- mediated by glutamate and its receptors, especially NDMA. Activation NDMA receptor initiates synaptogenesis through activation of downstream products
(Ghiani et al., 2007).
Heightened NMDA receptor activity during development results in large influx calcium, acts as secondary signal, thus genes activated by transcription factors and proteins required for neuronal differentiation are translated.
Fragile X
Arises non-expression FMRP protein controlled for by FMR1 genes mutated in these patients
(Verheji et al., 1993)
Mature frajile x patients long thin post-synaptic spines similar to those seen early on normal neo-cortical development
(Comery et al, 1997)
.
Knock-out mice FMR1 gene disrupted, dendrites mice longer and thinner normal wild mice. Dendric spine density increased (less pruning?), and concluded this reflects impaired developmental organisational process synapse stabilisation and apoptosis or pruning.
SUMMARY
Genetic factors and activity dependent factors play a role in developing brain architecture and circuitry
Gene expression and transcription factor gradients critical in early neural development
Errors transcription ultimately responsible for many neurodevelopmental disease processes
Initial gene expression critical to normal neurodevelopment - huge scale process leaves it vulnerable to coding errors that can yield grave consequences