development and degeneration - week 11 Flashcards
brain development
formation of the nervous system
first step
cell proliferation
- forms embryo
- cells can differentiate into different layers
- eventally one of these layers = neural plate
brain development
formation of the nervous system
2nd step
neurulation
neural plate folds –> neural tube
neural tube –> CNS
posterior forms spinal cord
anterior forms brain
what cells are neurons born from
progenitor cells
brain development
proliferation
progenitor cells divide asymmetrically
1 neuron and 1 progenertor cell
at the end of neurogenesis cells divide into two neurons
brain development
anterior end has swellings (known as vesicles)
each of these 5 vesicles form a predicitable region of the brain
error?
any error likely to have profound effects
MAM model of schizophrenia in rats
brain development
neural migration
neurons move and group together
specific neuroanatomy
- 6 layered cortex constructed in an inside out sequence
cerebral cortex
early generated neurons for deep cortical layers are bypassed by later born neurons that migrate to more superfivial layers
dev of cc progresses with successive waves of neuronal migration
this positions neurons within the different layers of the cortical plate
brain dev.
differentiation
newly born neurons change
not all neurons the same
generates large diversity of functionally specified neurons
what ensures specific neuroanatomy and specification
migration and differentation
brain dev.
neurons connect
migrating neurons dont have long axonal processes
axons need to form
- axonal growth
extent to target regions
- difficult to replicate in adulthood
- spinal injury
brain dev.
synaptogenesis
formation of synapses
rapid and explose in 1st 2 years after birth
issues with synapse formation –> autism and ADHD
brain dev.
neuronal and circuits refinement
only about 50% of neurons end up becoming part of brain
rest are intentially linked
brain dev.
neuronal and circuits refinement
- apoptosis
programmed cell death
eliminates defective / excessive
continues after birth
brain dev.
neuronal and circuits refinement
- synaptic pruning
enables neuronal connectivity and shaping functional wiring of brain during development
brain dev.
neuronal and circuits refinement
- is it automatic?
yes
early in life
brain dev.
neuronal and circuits refinement
- critical period?
when connectivity happens due to sensory experience
- visual dev.
- visual cliff experiment - depth perception
brain dev.
myelination
final process
provides both structural and metabolic support
the ensheathing of the axons by the spiral wrapping of the membrananous processes of obligodenrocytes
estimated to not complete until teenage years
underlies microstructural masturation of white matter pathways
brain dev.
stages
proliferation
neuralation
migration
differentiation
axonal growth (neurons connect)
synaptogenesis
refinement
myelination
neural degneration
refers to any pathological conditions affecting loss of neurons
a progressive deteriation of structural and functional integrity of neurons
neural degneration
occurs?
neurotraumatic
neurodegenerative
neuropsychiatric
neural degneration
neurotraumatic
sudden lack of o2
alteration in ion homeostasis
quick drop in key metabolites (AT, Glucose)
minutes - hours
eg. stroke
unspecific
- depends on place of injury
neural degneration
neurodegenerative
gradual accumalation of pathological changes
takes longer
many years
specific populations of neurons
parkinsons, alzhemers, huntingtons
neural degneration
age related
normal
multiple parts of brain
repeated concussions
brain often gets smaller due to unspecific atrophy caused by neural loss
- fewer neurons, takes up less space therefore smaller
neural degneration
loss of synaptic connections
axons degenerate
less white matter
- because no point in maintaining non functional connections
therefore smaller brain
2 progesses that cause neural death
apoptosis
necrosis
what causes neural death?
genetic
environmental
or combination
what causes neural death?
hyproxia
lack of o2
cant generate enough energy
neurons die
strokes
transient ischemic attacks
what causes neural death?
excessive activity
excitotoxic lesions in rodents
glutamate hypothesis in epilepsy
what causes neural death?
idiopathic / sporadic
disease with no identifiable cause/
/
occurring at irregular intervals or only in a few places; scattered or isolated.
what causes neural death?
neuronal dysfunction
protien aggregations
cause apoptosis
not beneficial
what causes neural death?
monogenetic (huntingtons)
mutation in a single gene
‘simpler than other neurodegernative disorders
mutation in huntington gene
inital degradation in basal ganglia
functional effects of loss related to…
site of loss
extent of neurodegeneration differs because
depends on circumstances
eg. how long brain is starved of o2
repair and recovery
varies in nervous system
peripheral cells can regenerate
limited / absent in CNS
- spinal injury
- brain injury / degeneration
repair and recovery
why not ?
axon regrowth not possible
following injury axons deteriorate
the ones that dont deteriorate become dysfunctional due to their loss of insulating myelin
cellular debris and bleeding results in a fluid filled cavity/cyst filling space where neurons and axons used to be
glial cells proliferate abnormally
- forming clusters of glial scars
together cysts and scars create a barrier to axons
- so prevent regrowth
repair and recovery
why not in CNS
complexity of connections
connections in adulthood not the same as developing brain,, comapred to the stable connects in PNS
- synaptic plasticity over many years
- therefore functional recovery difficult as no way to reconnect and restore all the function
- where PNS based on simple connections and basic anatomy
potenially possible in spinal cord
repair and recovery
replacing dead neurons?
reconnecting neurons only helps so much
neurons whose cell bodies have died cannot reconnect
repair and recovery
generation of new neurons
adult neurogenesis
in some areas of brain (adult) neurons continue to proliferate
eg. dentate gyrus of hippocampus
repair and recovery
neurogenesis for brain recovery?
from animal studies
new neurons are functional
- eg. in hippocampus
they differentaiate
they migrate
they form connections
they are myelinated
but if able to stimulate neurogenesis or introduce stem cells
- will correct / usefull connection be made?
- might rebuild better capactity for relearning and behavioural recovery
- unlikely to recover lost memory or skills
repair and recovery
what does potential for recovery depend on
where in the nervous system the damage is
parkinsons disease
features - motor function
tremor
rigid muscles
brodykinsea
hypokinsea
initally unilateral
v. early symptoms in facial expressions
parkinsons disease
features - non motor function
cognitive and emotional effects
2ndary as triggered by a loss in motor function
but not just a consequence of being aware of movement problems, can characterise a general slowing of brain function
explained as a general loss of brain function
sleep deficits
depression
related to pathological processes that cause it
parkinsons disease
causes
thought not to be a single condition but several underlying
parkinsons disease
causes - idiopathic
no identifiable cause
most common
combination of lifestyle factors and old age
parkinsons disease
causes - drug induced
slightly different from normal PD
can be caused by anti-psycotic medication
drug would need to have strong affect on the dopaminergic system
–> particularly blocking action of dopamine
features differ
- tremor, slow movement but dont progress into more severe symptoms
- clearly triggered by medication
most patients recover in months/weeks/days after stopping drug
parkinsons disease
causes - genetic
less than 5% of cases
inherited
mutation s
increase likelihood
early onset disease (under 40)
only for a small minority genetic links
parkinsons disease
causes - enviromental
factors can increase risk
presticides, heavy metal
infection (influenza)
alcohol / caffine?
parkinsons disease
degeneration - substantia nigra pars compacta (SNpc)
all patient exhibit loss
region of midbrain
this nucleus is a component of the basal ganglia
- a group a interconnected structures found in various parts of brain
- mediates a viarity of functions (including contrubuting to motor control)
- neruons of SNpc appear darker because they contain the pigment melanin
—> byproduct of synthesis of neurotransmitter dopamine
—> dopamine is a catecholamine neurotransmitter
parkinsons disease
degeneration - lewy bodies
gradual accumalation of cellular inclusions lnown as lewy bodies
—> composed of aggregates of a no. of protiens (incl. alpha-synuclein)
parkinsons disease
degeneration - SNpc and lewy bodies
progressive accumulation of lewy bodies throughout the brain and loss of dopaminergic neurons ultimately results in the signs and symptoms that form basis of an initial pre mortem diagnosis of PD
parkinsons disease
degeneration - how much loss until behavioural changes
evidence suggests behavioural changes not seen until 80% lf nigral dopamine is lost
parkinsons disease
advances in technique
by labelling the dopamine transporters normally found on healthy presynaptic terminals of dopaminergic neurons can assess if indivduals show the cardinal signs of PD also has signs of degneration of nigral neuron terminals
parkinsons disease
not just dopamine
other monoamines
- altered seretonin and noradrenaline
some studies suggest cholinergic transmission via basal nucleus of meynert may be affected (particulary later stages)
suggested that non-motor symptoms caused by non-dopaminergic changes
parkinsons disease
not just SNpc
basal nucleus of meynet
cholinergic transmission
parkinsons disease
drug treatment
aim of replacing / increasing dopamine
but dopamine isnt rapidly metabolised and doesnt cross blood brain barrier
parkinsons disease
drug treatment - Levodopa
can cross blood brain barrier
dopamine precursor
effectivness diminshes as PD progresses
only effective of still dopaminergic neurons left
adverse effects
parkinsons disease
drug treatment - dopamine agonists
target postsynaptic neurons so can still be effective
but eventually PD progressive degeration also leads to post synaptic degeneration
- neurons not recieving inputs will die
(secondary / transneuronal degeneration)
parkinsons disease
treatment - cell transplantation
replacing lost neurons
attactive for PD as appears to be confined to distinct anatomical locations
the only suitable treatment as drugs dont work long term
parkinsons disease
treatment - cell transplantation
stem cells
introduce into brain
right now not standard treatment
- unknown long term effects
parkinsons disease
treatment - deep brain stimulation
aim of enhancing the function of remaining dopamine circuits
approach revisited after discovery of long term limitations of L-dopa
the stimulation delievered affects the neurons of the basal gangllia structure into which the electrode is implanted
causing a cascade of changed to the firing characteristics of the structures of the basal ganglia activity
if no longer benefitting for l-dopa this is considered
alzheimers disease
most common form of dementia 5% of pop.
1:6 people over 80
alzheimers disease
characteristics - memory
impairment in learning and memory 1st sign of disease
- initally poor memory for recent events
- more so than age related decline
followed by later impairment in attention, exectuative function, language and visual spatial function (including spatial navigation)
as progresses patients become worried, depressed or experience personality changes (become angry/violent)
alzheimers disease
spatial navigation
although memory probs considered earliest sign in some cases spatial navigation probs are the 1st early impairment
some reseachers suggest it should ne considered a preclinical signs
(10-20 years before clinial onset)
alzheimers disease
2 types
sporalic / late onset
early onset
alzheimers disease
late onset
no obvious cause
most common (more than 90% of all cases)
later than 65
genetic predisosition + environmental factors contribute
alzheimers disease
environmental factors
in addition to age
significant head injuries
heavy metals , fungicides, hypothermia
no single factor emeraged as a key candiate
keeping brain active can offset as loss i smore noticable
lifestyle risks - inactivity, smoking diet, low educational attainment
alzheimers disease
early onset
1-2% caused by varients
less than 10% of all cases
1-2% inherited
under 40
alzheimers disease
genetic factors
is associated with specific gene mutation
amyloid percursor protien (APP)
1 of the 2 presenilin genes
mutations in these genes thought to result in abnormal accumulation of beta-amyloid formations of amyloid plaques
alzheimers disease
neurodegneration - temporal lobe
inital area of degeneration
alzheimers disease
neurodegneration - what is the disease associated with
abnormal accumulation of beta-amyloid and tau protiens
- forming amyloid plaques and neurofibrially tangles
- aggregates of amyloid plaques form in extra cellular space between neurons
- neurofibilarly tangles from inside cell bodies and inside neuntes, axons and dentrates
- thought that plaques and tangles increase risk of degeneration
direct link not fully understood
AD
neurofibilarly tangles from …..
inside cell bodies and inside neuntes, axons and dentrates
AD
aggregates of amyloid plaques form….
in extra cellular space between neurons
alzheimers disease
neurodegneration - tau accumalation
in temporal lobes
- entrotinal cortex and hippocampus (memory)
- damages memory parts 1st
alzheimers disease
neurodegneration - interplay between tau and beta-amyloids accumalation?
level of beta-a accumulation reaches a tipping point
then rapid spread of tau happens
leading to more widespread neurodegeneration
so further cognitive decline
alzheimers disease
neurodegneration - synaptic loss
corrolates with coginitve impairment
particularly effects chlolinergic and glutamatergic synpases
alzheimers disease
neurodegneration - synaptic loss linked to…
learning and memory
and is the principle correlate of disease progression and cognitive impairment
alzheimers disease
neurodegneration - synaptic loss where?
loss of cholinergic neurons in basal buccal of meyert and other subcortical structures shown to contribute to memory and attention deficits in AD
alzheimers disease
neurodegneration - unanswered qs
know that amyloid plaques affect cellular function of neurons including synaptic activity (synaptic loss)
but many studies failed to find corrolation between levels of amyloid plaques and cognitive impairment
alzheimers disease
treatment - successful? why?
currently no successful interventions which can prevent pprogression of AD
due to complexity of AD unlikely one drug can treat it
current approaches focus on helping patients to manage and maintain mental function and slow down memory loss
alzheimers disease
drug treatment
inital aim of boosting cholinergic transmission (acetylcholine)
prolong presence of remaing acetylcholine in synapse
acetylcholinestease inhibitors
- prevent breakdown of Ach or niotinic agonists
—-> continues to stimulate receptors (minics actions)
not very effective –> helps to reduce cognitive symptoms
- dont change underlying disease progression
only help for limited time
alzheimers disease
treatment - nicotine patches
smoking seems to incease risk of dementia
but some studies suggest that nicotine patches could improve memory in early stages of AD
alzheimers disease
treatment - targeting pathology
pathological modification
divert Amyloid percurosor protein away from amlyoid
antibodies away from amyloid
not v. effective
is amyloid actually causal for AD ??
treatments targeting pathology aim to reduce the existing deposits or further accumulation of beta amyloid / tau proteins
- inclused beta-amyloid directed immotherapy using antibodies targeting these proteins and inhibitors taget APP
- lots of side effects
