Psychobiology: Development & Degeneration, WEEK 11 Flashcards
1
Q
Why is development important?
A
- Allows us to understand how our cognition develops in childhood + how/why neurodevelopmental disorders affect cognitive functioning
2
Q
Basic stages + principles of brain development
A
- 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
3
Q
Basic formation of nervous system
A
- 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
4
Q
Neurulation
A
- 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
5
Q
Birth of neurons
A
- 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.
6
Q
Proliferation
A
- Process of rapid cell division
- Growth/production of cells by multiplication of parts
7
Q
Neurogenesis
A
- Process of rapid cell division
- Growth/development of nervous tissue
8
Q
Progenitor cells
A
- Specific cell trying to differentiate into it’s target cell
9
Q
Neuronal migration & differentiation
A
- 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
10
Q
Neurons connect
A
- 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
11
Q
Neuronal & circuit refinement
A
- 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
12
Q
Visual cliff experiment
A
- 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
13
Q
Myelination
A
- 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
14
Q
Neurodegeneration
A
- 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
15
Q
Types of degeneration
A
- 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
16
Q
Brain get’s smaller with degeneration
A
- 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
17
Q
General causes for neuronal death & loss of synapses
A
- 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)
18
Q
Excessive brain activity
A
- 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
19
Q
Idipoathic/Sporadic ND
A
- 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
20
Q
Huntington’s disease
A
- 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.
21
Q
Forms of neuronal death
A
- 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
22
Q
PNS:Recovery varies in the nervous system
A
- 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/
23
Q
CNS: recovery varies in the nervous system
A
- 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
24
Q
Why is CNS recovery not typical?
Complexity of brain?
A
- 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
25
Q
Replacing dead neurons
A
- In contrast to injury, ND often + initially only affects neuronal loss > when neurons die they cannot reconnect
- Adult neurogenesis > we are not born w/ all the neurons we will ever have
- Evidence supporting this comes from animal studies showing adult neurogenesis is limited but possible > Hippocampus is associated w/ learning + memory
- Unclear where newly born hippocampal neurons are relevant to memory formation or represent a form of brain self-repair
- Research in adult neurogenesis wants to know the functional role of it on the hippocampus + potential treatment for ND disorder > evi comes from animals
26
Q
Neurogenesis & stem cell transplant for brain recovery
A
- Animal studies show that adult neural progenitor cells exist in the hippocampus + they can proliferate + differentiate to mature neurons
- All processes such as proliferation typical to brain dev can happen in adult brain
- not all newly generated neurons survive or mature
- Don’t fully know what regulates proliferation, survival + exact functional role of adult neurogenesis
- Growing evidence suggests early life exp w/ enriched habitat providing behavioural, cognitive stimulation + physical activity promotes adult NG + survival of newly generated neurons
- Consensus that adult NG indicates plasticity of adult brain + adult born neurons have a role in learning + memory
- Normal cognitive ageing is associated w/ some level of gradual decline in learning + memory > amplified in AD + mild cognitive impairment > MCI often precedes AD
- Neurogenesis might have some potential for brain recovery but we don’t know if we can stimulate adult NG in other parts of hippocampus other than cerebral cortex > still don’t know if lost connections can be restored
- One potential treatment is stem cell transplants > implanting exogenous cells which may become progenitors + stimulate new neurons > but don’t know if neurons will survive, form functional connections + restore things like lost memory.
27
Q
Parkinson’s disease
A
- 2nd most common neurodegenerative disease
- Affects 2-3% of world pop aged 65+
- PD is an age related ND disorder as most people w/ it develop symptoms when they are over 50/60 > but some case are found in people under 40
- PD is associated w/ cognitive deficits
- Characterised by motor tremor > stiffness + slow movement
28
Q
3 main types of PD
A
- PD isn’t a single condition but several featuring similar symptoms like tremors
1. Idiopathic PD: most common type + no known cause > speculation is that combination of lifestyle factors, old age + unknown neurobiological causes contribute to development of idiopathic Parkinson’s > can’t predict someone will get PD + no identifiable cause
2. Genetic PD: 5% of people inherited the disease > inherited form of PD is linked w/ genetic causes, mutations or other forms of genetic variance - Genetic type of PD indicates the condition can be passed down families
- Sometimes genetic causes are associated w/ early onset disease which begins before age 50/40 > as some genetic variance underlying PD is known, genetic testing can detect predispositions to PD in some
3. Drug induced PD: PD can be induced by some medication, commonly anti-psychotic drugs. > because these drugs have a strong effect on the brain dopaminergic system, particularly blocks action of dopamine - Drug induced form of PD differs from typical look of PD > tremors + stiffness etc are there but don’t increase in severity
- Patients can recover from months to days after stopping use of drug
- Parkinsonism is used to describe other conditions w/ tremors etc.. but w/ underlying causes different from PD (e.g. vascular Parkinsonism)
29
Q
Clinical characteristics of PD
A
- Motor symptoms are seen as primary symptoms of PD as disease progresses, non-motor function symptoms develop
- Motor symptoms include involuntary shaking (tremors), stiff muscles
- PD symptoms occur gradually + worsen over time
- Reduction in expressiveness of facial expression caused by change in movement of facial muscles
- As disease progresses, symptoms become bilateral +more severe with people having difficulty walking/talking
- Secondary symptoms refer to non-motor function symptoms triggered by primary symptoms > affects mood + ability to think clearly
- Primary + secondary symptoms characterised by general slowing of brain functions affecting ability to execute movement + cognitive processes
30
Q
Degeneration in PD
A
- PD is a neurodegenerative disorder as its symptoms link to neuronal loss of dopaminergic neurons
- In PD neurons are lost in substantia nigra in basal ganglia is latin for black substance > because there is a lot of pigment in DA neurons > in PD loss of DA neurons = depigmentation of SN
- Discovery of role of DA in PD is linked to when 7 adults in 1982 injected themselves w/ new synthetic heroin causing dev of severe + irreversible symptoms similar to PD > analysis of the heroin showed it contained MPTP > MPTP was indicated as a cause of permanent Parkinsonism
- Animal studies show MPTP itself isn’t one of the direct causes in death of DA neurons > once in the brain MPTP converts to MPP+ (neurotoxin)
- ND affecting DA neurons in SN is one of 2 neuropathic hallmarks of idiopathic PD > second is intracellular alpha synuclein accumulation leading to formation of protein aggregates in different parts of the brain (occurs in many forms of dementia)
31
Q
Potential early diagnosis of PD
A
- Degeneration is extensive before symptoms appear > Loss of dopaminergic neurons progress as the disease progresses > dramatic loss of DA neurons occur early in the disease + degeneration in SN starts before motor symptoms > found from post-mortem analysis of brain of patient w/ early Parkinson
- Tells us brains can cope w/ large loss of neurons before any visible symptoms + that early diagnosis of PD is difficult as by the time patients are diagnosed they already have dramatic loss > recently diagnosed patients w/ mild symptoms may have lost 80% of DA neurons already
- Need development of method enabling early detection + visualisation of DA decrease in suspected PD patients
- One way to measure DA transporter activity is with PET > based on visualisation + quantifying uptake of radioactive DA
- DA transporter is relevant for re-uptake of DA to synaptic cleft > less DA neurons = less DAT activity = less reuptake = less signals (visualised in image)
32
Q
Other neurotransmitters
A
- Other neurotransmitters are implicated in symptoms of PD: monoamines such as serotonin, noradrenaline and acetylcholine
- Not just basal ganglia related to PD but other brain areas are affected by PD such as basal nucleus of Maynart and cholinergic transmission in it
33
Q
PD treatment: Replacing/increasing DA
A
- substituting DA loss via systemic administration of dopamine precursor amino acid (L-DOPA) > used to treat PD
- DA precursor is used + not actual DA as DA metabolises quickly + cannot pass blood brain barriers > DA injections alone are ineffective > DA precursor passes blood brain barrier + after reuptake converts to DA
- Effectiveness of L-DOPA diminishes as PD progresses > treatment is only effective as long as DA neurons are still left
- Dopamine agonist don’t have this issue ^ > targets post-synaptic dopamine receptors so they can effective even if there are no more pre-synaptic DA neurons
34
Q
PD treatment: cell transplantation & deep brain stimulation
A
- Degeneration eventually occurs in post-synaptic receptors as neurons aren’t receiving any inputs + die
- Loss of synaptic input leads to cell death = transneuronal degeneration
- Only option for treatment in late stage of PD is replacing lost neurons by introducing stem cells into the brain
- Initial results from animal + clinical studies are strong but effectiveness need to be seen long term so it can become a standard treatment
- Treat w/ deep brain stimulation > brain surgery involving implantation of electrodes in brain to modulate dysfunctional activity > in PD is used to control motor systems
- DBS cannot cure or stop progression of PD but can help control motor symptoms.
35
Q
Alzheimer’s disease
A
- AD is most prevalent form of dementia > irreversible + progressive brain disorder gradually destroying memory, thinking skills + eventually ability to carry out simplest daily talks
- Affects 5% of pop > 1 in 6 people over 80 years old
- Characterised by failing memory
- Spatial navigation + language skills affected
36
Q
Clinical characteristics of AD
A
- Usually impairment in learning + memory are some of the first signs of the disease followed by later impairment in attention, executive function, language + spatial function
- As AD progresses, some patients become worried, depressed, or experience personality changes becoming angry/violent
- Cognitive decline is an inevitable result of ageing + all older adults will experience some kind of memory issue > but some only have gradual or non-substantial drop in memory whereas others see a rapid decline like in AD
- Some w/ memory problems have MCI > can be an early sign of AD > but not everyone w/ MCI will develop AD
- In some case spatial nav is first early impairment > some argue spatial navigation impairment is a sign of pre-clinical AD (disease stage before onset of symptom) > can be 10-20 years before onset of symptoms
- Compared to PD, AD profoundly affects cognitive functioning > PD may lose ability to do anything on their own due to motor problems whilst AD patients lose ability to do anything do to cognitive deterioration
37
Q
Types of AD
A
- AD can be classified as sporadic (late onset) or familial (early onset)
- Most common type is sporadic characterised by late onset, over 65 years old or later where both genetic predisposition + EV contributes to the disease > sporadic AD account for 90% of cases > most often in those w/o family history of AD
- Genetics of late AD isn’t understood > but genetic variant apolipoprotein E(APOE) gene is known to increase likeliness of AD > but inheriting APOE4 won’t guarantee you get AD > just higher likelihood as APOE4 affects formation of amyloid plaques
- Early onset AD occurs at younger age between 40-65 > 1-2% of cases caused by inherited mutation in three genes: amyloid precursor, presenilin I and presenilin 2 > mutations in these genes are though to result in abnormal accumulation of beta-amyloid + formation of amyloid plaques
38
Q
Causes of AD
A
- Weak link between some cases of sporadic AD + APOE genes whereas small amount of early onset AD runs in families cause by APP genes or presenilin genes
- Lifestyle factors such as diabetes, obesity, physical + mental inactivity, depression, smoking, low ed attainment + poor diet are related to risk factors for AD > but we don’t know the extent this factor contribute to AD
- Increasing research tries to discover this ^ but issue is that the disease develops over a long time before onset of symptoms
39
Q
Neurodegeneration in AD
A
- Extent of ND atrophy in AD is far greater than others
- AD is associated w/abnormal accumulation of beta-amyloid + tau proteins forming amyloid plaques + neurofibrillary tangles > this accumulation is primary neuropathological hallmark of AD
- Initially, accumulation happens in temporal lobes + AD seems to first destroy neurons in parts of brain involved in memory in entorhinal cortex + hippocampus (in temporal lobe)
- Interplay between tau + beta amyloid accumulation as level of beta amyloid accumulation increases + reaches a certain tipping point, a rapid spread of tau throughout the brain follows > leads to more widespread neurodegeneration + further cognitive dec
40
Q
Neurodegeneration in AD: synaptic loss
A
- Amyloid plaques affect cellular function of neurons including impaired synaptic activity + lead to synapse loss but studies fail to find correlation between amyloid plaques + cognitive impairment
- Synaptic loss, particularly cholinergic + glutaminergic synapses are linked to learning + memory > principle correlate of disease progression + cognitive impairment in AD
- Loss of cholinergic in basal nucleus of Maynart + other structures have been shown to contribute in memory + attention deficits in AD
41
Q
Treatment for AD
A
- No intervention can successfully treat or prevent progression of AD atm
- Complexity of AD suggests there will likely never be a single drug to treat it successfully
- Approaches focus on helping patients maintain mental function, manage behavioural symptoms + slow memory loss
- Drug induced treatment + targeting pathology
- These treatments haven’t been successful or well tolerated by patients
- Treatment relies heavily on beta amyloid + tau hypothesis > as we don’t know if amyloid plaques + neurofibrillary tangles are causing AD or are a product of it (symptoms) we don’t know what we are treating
42
Q
Drug induced treatment for AD
A
- Drug treatment: ND of cholinergic neurons thought to cause cholinergic deficit + contribute to attention + memory dysfunction > drugs targeting cog dysfunction aim to increase synaptic levels of acetylcholine + cholinergic transmission > by continuing stimulation of cholinergic receptions, could stop or delay ND of cholinergic neuron
- Many of these drugs are acetylcholine + erase inhibitors prevent breakdown of acetylcholine or nicotinic agonists (drugs mimicking action of acetylcholine + nicotinic receptors are type of acetylcholine receptor)
- Drug of nicotinic agonist = nicotine > smoking it increase likeliness of dev dementia but nicotine patches may help improve memory early in AD
- Medication targeting cholinergic transmission help reduce some cognitive symptoms but they don’t change the underlying disease > effective for some patients + help for a limited time typically
43
Q
Targeting pathology treatment for AD
A
- Aims to reduce existing deposits or further accumulation of either beta amyloid or tau proteins
- Includes beta amyloid or tau directed immune therapy using antibodies > targets these proteins + inhibitors target APP processing
