Psychobiology: Development & Degeneration, WEEK 11 Flashcards
Why is development important?
- Allows us to understand how our cognition develops in childhood + how/why neurodevelopmental disorders affect cognitive functioning
Basic stages + principles of brain development
- Stage before brain development is formation of nervous system during embryonic dev
- Brain development and formation of cerebral cortex
- Birth of neurons
- Neuronal migration, differentiation and formation of cerebral cortex
- Formation of precise axonal pathways (axonal growth) + synaptic connections (synaptogenesis) = formation of brain cirtcuits/networks
- Myelination of neurons
Basic formation of nervous system
- Humans + animals first develop during embryonic development as single diploid cell > zygote
- Zygote undergoes many rounds of cell division, forming spherical multi-cellular embryo (initially formed of identical cell)
- Eventually, some cells differentiate into different layers and one of these layers give rise to neural plate > neural plate is important for neurulation
- As dev continues, neurulation occurs
Neurulation
- Where edges of neural plate elevate to form neural folds
- Next neural fold curves + forms a U shape where there is a neural groove (bottom of U)
- Neural groove closes which puts the neural folds together and this forms the neural tube > neural tube eventually becomes CNS
Birth of neurons
- Brain neurons originate from pool of neural progenitor cells
- In CNS dev, some cells in neural tube differentiate + become neural progenitor cells > these cells want to be neurons
- Neural progenitor cells divide rapidly so they undergo cell cycles > proliferation + neurogenesis
- End of neurogenesis is where progenitor cells aren’t needed anymore > deplete themselves by symmetrically dividing into 2 neurons
- Initially, neural progenitors propagate itself (make more of itself) increasing pool of progenitors > if they start dividing asymmetrically, giving rise to one progenitor cell + one neuron
- Some early progenitor cells can give rise to glial cells
- Errors in proliferation can lead to brain + cerebral cortex malfunctions (errors like change in proliferation rate, change to symmetric/asymmetric division pattern)
- e.g: MAM model of SZ suggests a neurodevelopmental component > something affecting neurogenesis leads to change in dev of prefrontal cortex contributing to SZ.
Proliferation
- Process of rapid cell division
- Growth/production of cells by multiplication of parts
Neurogenesis
- Process of rapid cell division
- Growth/development of nervous tissue
Progenitor cells
- Specific cell trying to differentiate into it’s target cell
Neuronal migration & differentiation
- Pattern of neurogenesis is specified during dev + 6 layered cerebral cortex is constructed in an inside-outside sequence.
- Neuronal migration > brings cells to group w/ other cells + move to target location
- Early generated neurons form deep cortical layers bypassed by later-born neurons that migrate to make more superficial layers > dev of cortex progresses w/ successive waves of neuronal migration which position neurons in different layers of cortical plate which later become cerebral cortex
- Newly generated neurons migrate to form other parts of dev brain + self-organise into different brain structures like cerebellum
- In first stage of neuronal migration, newly born neurons give rise to those specific to various parts of the brain > during this stage, neurons migrate to final locations where they will differentiate + make specific connections w/ other neurons
- Either during or at end of migration, neurons differentiate into neurons expressing different receptors + releasing different neurotransmitters
- Process of differentiation can generate functionally specialised neurons
- Migration + differentiation ensure specific neuro-anatomy + functional specialisation of parts of the brain
Neurons connect
- Brain develops following a sequence of spatially + temporally regulated events
- After migration + differentiation, next is axonal growth, synaptogenesis + synaptic pruning > lead to formation of neural connectivity + functional neuronal circuits
- Growth of axons + dendrites start when neurons reach their final destination > enables them to establish connectivity w/ eachother
- Process is typical to development + rarely happens in adulthood > regeneration of connectivity is difficult to replicate in adulthood
- Establishing connectivity w/ other neurons require formation of synapses
- While synaptogenesis occurs in brain during dev, there is a period of rapid + explosive SG
- SG + neuronal connectivity forms in human cortex before birth, it completes + happens after birth, mainly in first 2 years but timing depends on region of brain
Neuronal & circuit refinement
- 2 processes underlie neuronal + connectivity refinement during normal dev: apoptosis + synaptic pruning
- Apoptosis (programmed cell death) is regulatory mechanism evolved to eliminate defective or excessive cells > in normal dev, more than 1/2 of neurons undergo apoptosis > indicates key role of apoptosis in dev
- Eliminates unnecessary progenitors, excessive neurons during migration + when neuronal circuits are being formed > enables elimination of cells which have gone wrong during division or differentiation
- Apoptosis continues after birth when neurons compete for synaptic targets.
- Synaptic pruning > synaptic elimination refining neuronal connectivity + shaping functional wiring for our brains during dev > refine neural circuit early in life
- These processes form basis for key stages of dev during childhood > critical periods when refinement happens due to sensory experience we gain
- Critical period is defined as time in early childhood when dev of functional properties of the brain happens > illustrated by visual cliff exp
Visual cliff experiment
- Used to investigate infants ability to detect depth
- Experiment uses raised glass surface w/ one part making glass look solid + other part made visual illusion of a cliff
- In the exp, the child is put on the solid part + mother stand on other side by cliff > assumption is, if child has developed depth perception, they will be reluctant to crawl to the mother
- demonstrates critical period for depth perception in infant occurs around when they begin to crawl
Myelination
- Myelin sheath provide structural + metabolic support including axon myelination > facilitating nerve impulse conduction + communication across functional neuronal circuits
- Myelination is an important process underlying microstructural maturation white matter pathways which begin before birth w/ myelination of cranial nerves + continues throughout life
- White matter pathways are part in the brain w/ myelinated bundles of nerve fibres
- Major changes in myelination occur from 3 weeks to 1 year for all brain regions > but continues throughout childhood to adulthood
- There is considerable regional variation in pattern of maturation (e.g. front-temporal connections develop slower than other regions)
- Microstructural maturation continue till early-mid 20s
Neurodegeneration
- degeneration of neurons > any pathological conditions affecting loss of neurons
- Neurodegeneration = progressive deterioration of structural + functional integrity of neurons occurring in neurotraumatic, neurodegenerative + neuropsychiatric disease
Types of degeneration
- Degeneration can be classed as fast or slow
- Neurotraumatic disease (e.g. stroke) > neurons degenerate rapidly in minutes to hours > due to sudden lack of oxygen, alteration in ion homeostasis + quick drop in metabolites
- Neurotraumatic degeneration is unspecific > can affect any neuronal population depending on location of injury
- In strokes, lack of key metabolites lead to energy starvation leading to fast neuronal death
- Repeated episodes of concussion associated w/ contact sports may lead to increased risk of slow degeneration + developing AD
- Neurodegenerative disease (e.g. AD) involve gradual accumulation of pathological changes + takes longer like many years + at first only affects specific populations of neurons > unspecific + affects many areas
- Slow + gradual degeneration happens due to normal healthy ageing > brain loses neurons + gets smaller but this isn’t as extensive as ND disorders
Brain get’s smaller with degeneration
- As we age, our brains get smaller due to unspecific atrophy > losing neurons means less space is taken up leading to smaller brain
- Generally, brains get smaller due to all types of ND > 2 processes underlie this > neuronal loss + loss of synaptic connections
- Our brains consist of grey matter containing all the neuronal cell bodies, dendrites + axonal terminals
- White matter is made up of axons forming white matter pathways, interconnecting different parts of the brain
- As neurons die we don’t lose grey matter due to loss of cell bodies + all synapses > also lose white matter due to progressive degeneration of axons of dying neurons
- Loss of synapse + subsequent axonal degeneration also happen when neurons become dysfunctional > e.g. AD when neurons are dysfunctional, often their synapses can no longer function > axons may degenerate as there is no point maintaining non-functional connections > leads to white matter loss + decrease in brain size
General causes for neuronal death & loss of synapses
- Hypoxia=depletion of O2 supply to brain results in energy starvation leading to neuronal death
- Hypoxia is often a result of restriction in blood supply to the brain + can be caused by many conditions like stroke
- Severity of ND will be different in different conditions + depends on how long the insufficient oxygenation lasts for + how big was the part of the brain deprived of oxygen
- Excessive activity
- Idiopathic/sporadic
- Neuronal dysfunction + protein aggregations
- Monogenesis (Huntingtons disease)
Excessive brain activity
- Animal studies suggest excitotoxic lesions result from over-excitation of neurons leading to neuronal death
- Excessive brain activity is believed to be a cause of ND in epilepsy > excessive activity causes neurotoxicity > explained by glumate hypothesis
- Glutamate hyp suggests that seizures induce elevation in extracellular glutamate + contributes to excitotoxic damage leading to neuronal death
Idipoathic/Sporadic ND
- Indicates neurodegeneration w/ unknown cause
- Although we often don’t know what provoke ND, evidence suggest abnormal aggregation of proteins inside or outside the neurons may lead to neuronal loss in some disorders like AD
Huntington’s disease
- Progressive disorder causing uncontrolled movements + gradually cause emotional + cognitive problems
- symptoms include uncontrollable movement of face/head/arms/legs associated w/ ND of basal ganglia > HD starts early compared to AD or PD around 30s-40s
- HD is monogenetic > caused by mutation in HTT (inherited) > is autosomal + dominant disorder so inheriting only one copy of mutated gene leads to HD
- Mutation of HTT is abnormally long version of huntington protein > prone to fragmentation
- We know the gene causing HD but we don’t know the function of huntington protein thus how the mutation leads to ND
- Hypotheses suggest fragments of abnormal proteins bind + accumulate in neurons, disrupting normal function causing cell death.
Forms of neuronal death
- Necrosis + apoptosis > differ in specific molecular mechanisms, signalling cascades which are triggered by different events
- Necrosis > often triggered by cytotoxic, neurotoxic or neurotraumatic events > e.g. hypoxia, stroke is a form of excitotoxic seizures.
- In dev, apoptosis is triggered by specific signalling cascade in neurons > aggregation of certain proteins inside neurons > Some ND diseases trigger apoptosis leading to neuronal death
PNS:Recovery varies in the nervous system
- Potential for recovery varies in the NS + is different depending on where in the NS
- PNS refers to parts of the NS outside CNS like hand
- Neural damage can be repaired in PNS + function can be recovered
- Axons can regrow so if you for example cut your finger deep, the axon may be severed leading to perhaps loss of movement but this can regrow and function can be regained.
- Axons regrow and reconnect to the same areas > enables function or sensation to be restored/
CNS: recovery varies in the nervous system
- Neuronal damage cannot be repaired in CNS
- Damage to spinal cord cannot be easily recovered especially if it is completely severed
- Higher up on the spine the injury is the more severe the resulting paralysis will be
- No known way to reverse spinal cord damage
- Following injury, many axons disintegrate + others remain intact but become dysfunctional due to loss of insulating myelin
- Cellular debris + bleeding result in fluid filled cyst filling space where neurons + axons were.
- Glial cells proliferate abnormally creating clusters of glial scars
- Together, the cysts + scars form a barrier to axons preventing regrowth + reconnection to cells > axons have ability to regrow in spinal cord but are prevented
Why is CNS recovery not typical?
Complexity of brain?
- Difficulty w/ recovery from brain injury is the complexity of both structured + functional organisation of the adult brain w/ millions of neurons + billions of connections
- Complexity of connection is a result of developmental refinement in life experiences > connections are strengthened or weakened based on exp due to synaptic plasticity > re-establishing what took long to make is hard even if axons regroq
- CNS differs from PNS as the connection in PNS are driven by simple basic anatomy which doesn’t change based on life exp + there is very little individual difference
- Challenge for CNS recovery is to correctly reconnect lost connections > harder in the brain as we need to know which certain group of neurons connect to others
- More straightforward in spinal cord if we can overcome barriers to axonal growth