Week 12

Question 1

Neuroplasticity

Overview

Answer 1

• Brain is obviously plastic – it changes over time
• At a minimum the capability for declarative
learning and memory implicates functional and
structural plasticity of the adult brain
• Plasticity is essential for the development of the
nervous system and normal functioning of the
adult brain
• Plasticity provides flexibility in
• Development
• Learning
• Recovery
• Neural plasticity can be broadly defined as the
ability of the nervous system to adopt a new
functional or structural state in response to
extrinsic and intrinsic factors
Plasticity can potentially influence any point of
nervous system function - modulate
• Synapse strength
• Synapse number
• Signal timing
• Network connectivity
• Network composition
• Human nervous system functional at birth, but,
rudimentary
• Embryonic connectivity like a ‘rough draft’ of
neural circuits required
• Genetically determined connectivity followed by
experience dependent reorganisation
• Custom fit the nervous system to individual bodies
and unique environments
• Experience dependent maturation underlies the
abilities of the human brain

Question 2

Developmental Plasticity

Answer 2

• Cell proliferation and migration - neurogenesis mostly
done by 7th month prenatal (except olfactory bulb,
hippocampus and maybe some more elsewhere)
• Key part of development is axon growth and synapse
formation – connections - axons and dendrites grow
and must grow to appropriate targets
• Postnatal development mostly – synaptogenesis,
myelination, dendritic branching (then also neural loss
and synaptic loss – pruning)
• Critical periods
• Effects of deprivation and enrichment
• Rear animals in the dark – fewer synapses and
fewer dendritic spines in V1; deficits in depth and
pattern vision
• Rats raised in enriched environments had thicker
cortices – more spines and synapses per neuron

Question 3

Developmental Reorganisation

Answer 3

• Developing neural circuits require maintenance –
reorganised depending on activity
• Time-dependance: window of opportunity within which
experience can influence development
• Critical period – when it is absolutely essential that an
experience occurs within a given time limit – and then
other mechanisms follow on
• Sensitive period – when an experience can still have an
influence outside the interval
• Hubel and Wiesel - example of developmental
plasticity of visual circuits through studies of
monocular deprivation led to the discovery of the
critical period
• Activity-dependent development of the visual
system - development of visual systems requires
interplay between sensory experiences,
spontaneous neural activity, and genetically
encoded innate programs

Question 4

Developmental Reorganisation

Answer 4

• Deprive one eye of input for a few days early in
development – lasting effects on vision
• Column width of deprived eye decreases and other
increases – reorganisation of the system
• But if blindfold other eye – not
• Relative pattern of input to V1 is what matters –
competition for neural space
Cortical sensory maps
• Roe et al (1990) altered course of developing RGC
axons to MGN (ferrets) – visual input led to retinotopic
organisation in A1
• Knudson and Brainard (1991) – barn owls – raised with
displacement prisms on eyes – change in spatial map
• Early music training – expand auditory cortex that
responds to complex tones

Question 5

Developmental Reorganisation

Answer 5

Developmental Reorganisation
• Knudson and Brainard (1991)
• Reorganisation only in young owls – rewiring of
deep auditory nuclei involved in inter-aural time
difference mapping
• Critical period

Question 6

Developmental Reorganisation

Answer 6

Early experience has lifelong effects on social behaviours
• Spitz (1940s) compared infants raised in a foundling home
with those in a nursery attached to a women’s prison
• Main difference in contact with carers (low contact nurse
care in former, high contact mothers in latter) and
social/sensory deprivation (high in former, low in latter)
• 4 months – not much difference
• 1 year – prison infants far above in motor and cognitive
performance; foundling withdrawn and little curiosity,
prone to infection
• 2-3 years, prison kids equal with normal; foundling further
behind – unable to walk or speak

Question 7

Developmental Plasticity

Answer 7

Experience, particularly during critical
periods, fine tunes the developing
nervous system

Question 8

Activity Dependent Plasticity

Answer 8

• Synaptic modulation - long term memory

* Activity dependent myelination

Question 9

Synaptic modulation

Answer 9

• Memory is the result of changes in strength of
synaptic interactions among neurons in neural
networks
• Hebb – if a synapse is active when a postsynaptic
neuron is active – then synapse is strengthened -
neurons that fire together wire together
• Enduring changes in the efficiency of synaptic
transmission underlies long term memory

Question 10

Synaptic modulation

Answer 10

Long term potentiation (LTP)
• Facilitation of synaptic transmission following high
frequency presynaptic stimulation
• Measure response of neuron to single low intensity
electrical pulse to presynaptic neuron; deliver high
intensity high freq stim for 10 sec; measure response to
single low intensity after various delays
• Response increases – synapse has been strengthened
Long term potentiation (LTP)
• LTP lasts months after multiple stimulations
• Only develops if firing of presynaptic is followed by
firing of postsynaptic – correlated activity is the
critical factor

Question 11

LTP Process

Answer 11

• 2 types of ionotropic Glu receptor
• AMPA – Na+ channel opens with Glu binding - EPSP
• NMDA requires 2 things – binding of Glu and postsynaptic
neuron is already depolarised
• Simultaneous activity and postsynaptic likely to fire
• NMDA channel results in Ca2+
influx – intracellular
messenger – signalling cascade to induce LTP
• Ca2+ effects are highly local – only want to affect a
single connection
• Involves presynaptic and postsynaptic changes
• Structural changes – increase number and size of
synapses and postsyn spines, changes in presyn and
postsyn membranes, changes in dendritic branching
• Epigenetic changes

Question 12

Long Term Depression

Answer 12

• Don’t remember everything forever
• Mechanism to downregulate synapse strength
• LTD induced by prolonged low freq stim
• Also – if EPSP after postsynaptic cell fires – synapse not
contributing to firing so weakened
• Also NMDA – but lower Ca2+ conc – activates different
pathways

Question 13

Activity Dependent Myelination

Answer 13

• Changes in white matter observed during learning
• Cellular studies show that myelination can be influenced by
action potential firing in axons
• Conduction velocity modifiable through changes in myelin to
optimize timing of info transmission through neural circuits
• Spike-time arrival is of fundamental importance in neural
coding, neuronal integration and synaptic plasticity
• Myelination - effective mechanism for manipulating spiketime
arrival
• Optimal synchrony of spike-time arrival through
nodes in a network is what maximizes performance
• Adjust conduction velocity by
• myelinating unmyelinated axons
• modulating the thickness of the myelin sheath
• modulating structure of nodes of Ranvier
• Through activity-dependent feedback

Question 14

Activity Dependent Myelination

Answer 14

Myelinated vs
unmyelinated
Modulate
thickness of
the myelin
sheath
Modulate
length and
spacing of
segments
• When neurons fire - cascade of events promotes
myelination
• Neuronal activity influences ODCs and Schwann cells,
their progenitors, and other glia (e.g. astrocytes)
• Ion channels and receptors for various growth
factors, neurotransmitters, and other signalling
molecules
Activity stimulates progenitor cells to become
oligodendrocytes
In early neuronal
development, ATP
released from axons
Converted to
adenosine and activate
receptors on ODC
progenitors
Promotes
differentiation to ODC

Question 15

Activity Dependent Myelination

Answer 15

Activity regulates myelination by mature ODCs
After the progenitors
have differentiated
into oligodendrocytes,
action potentials
increase myelination
through signalling
astrocytes
Activity regulates myelination adhesion to the axon
Activity modulates expression of L1-CAM cell adhesion
molecule
Social isolation of juvenile mice - alterations in white matter
development of the mPFC (Makinodan et al., 2012)
• 4 wks isolation - expected deficits in social interaction task
• Microscopy in the mPFC
• dramatically reduced mature ODCs
• reduced internodes per ODC
• thinning of myelin sheaths
• Critical period during the first 2 weeks after weaning
• Myelin abnormalities not rescued by social reintroduction
• Adaptive myelination may play a role in learning
• Structural imaging studies identified white matter
microstructural changes in human adult volunteers
• learning to juggle (Scholz et al., 2009)
• who have undertaken musical training (Steele et al., 2013)
• learning a second language (Schlegel et al., 2012)

Question 16

Neuronal Damage

Answer 16

• Many causes of central nervous system damage
• Tumour, CV (stroke), closed-head injury, infection,
neurotoxin, genetic
• Grey matter damage occurs but most of the neuron
is axon so white matter damage typical – mostly
will consider impacts of this
• Results in grey and white matter loss

Question 17

Neuronal Degeneration

Answer 17

Damage usually involves complete or partial axotomy - 3 types of
degeneration following axotomy:
1. Anterograde degeneration – distal to the transection
• Cut off from the metabolic centre of the cell (soma)
• Fast – distal segment swells in hours and fragments in days
2. Retrograde degeneration – proximal to the transection
• Slower and progressive – 2-3 days changes in soma – can be degenerative
or regenerative
• Degen – decrease in size – cell will usually die by apoptosis, necrosis or
both
• Regen – increase in size – massive protein synthesis to replace losses –
must make synaptic contact to survive
3. Transneuronal degeneration – spread anterograde and retrograde
• Degeneration spreads to other neurons due to loss of synaptic contacts

Question 18

Neuronal Regeneration

Answer 18

• Mammals – essentially no regeneration in CNS and
partial in PNS
• 2-3 days after damage – regrowth from stump
depends on myelin sheath (Schwann cells)
• Transplant CNS neurons to PNS – regeneration –
Schwann cells clear debris and promote regen with
neurotrophic factors and CAMs – stimulate growth
and guide; ODCs release factors that actively block
regen
Sheath intact – axon grows through to original target
2-3mm per day
Complete but small separation in sheath – axon tips
can grow into wrong sheaths and so to wrong targets
– difficulty regaining coordinated use of muscle
Widely separated – no meaningful regen – tangled
mass and neurons ultimately die

Question 19

Recovery From Damage

Answer 19

• Most recovery from brain damage not quite
recovery
• Early improvement (1-2 weeks) often due to decline in
cerebral oedema (swelling)
• Gradual improvement over months often learning new
strategies
• Cognitive reserve – rather than recover lost function,
complete tasks in alternative ways
• Actual recovery best if small lesion and young
patient
• Block neurodegeneration
• Possible to reduce damage by blocking degeneration
• Apoptosis inhibitor protein, nerve growth factor,
estrogens
• Promote regeneration
• Regeneration in CNS in mammals can be induced
• Implant Schwann cell sheaths into spinal cord injuries
in rats
Rehabilitation training
• Small strokes produce core of damage surrounded by
penumbra
• Damage slowly expands into penumbra over time –
early and intensive use reduces – neurons compete for
synaptic sites and neurotrophins
• Taub – constraint induced therapy – tie down working
arm for 2 weeks
• Spinal injury – supported on treadmill with support
gradually reduced – 90% trained patients became
independent walkers, 50% of conventional physio
patients

Question 20

Cortical Reorganisation

Answer 20

• Cortical maps retain a level of organisational
plasticity beyond early development
• Remodeling of physiological maps and cortical
structure (Draganski et al., 2004, Xu et al., 2009) in
response to alterations in central and peripheral
inputs as well as behavioural experience
• Typically observed in primary sensory and motor
areas
Sensory and
motor
homunculus

Question 21

Sensory Reorganisation

Answer 21

• Transection of the median nerve in monkeys led to
an expansion of cortical areas responsive to
neighbouring fingers (Merzenich et al., 1983)
• Similar changes were evident in the topographic
map in barrel cortex after selective sensory
deprivation in rodents
• Kaas et al – retinal lesions – V1 neurons that had
RFs in the lesioned field in a few months had RFs
adjacent to – change began minutes after lesioning
• Merzenich & Jenkins
(1995) - individual digit
representations revealed
by single unit recordings
• Two fingers of one hand
are sewn together
• Months later the cortical
maps change so that the
sharp border once
present b/w the two
fingers is now blurred

Question 22

Motor Reorganisation

Answer 22

• Reorganization of M1 motor maps (Monfils et al.,
2005; Nudo et al., 1996a) and changes in spine
turnover (Xu et al., 2009) were found after motor
skill acquisition
• Sanes et al – transect nerves supplying whiskers –
stimulation of M1 neurons that previously
activated the whiskers now activated other face
muscles
• Jenkins et al. (1990)
• Train monkeys in
task that uses tips of
digits 2 and 3
• Substantial increase
in cortical
representation of
the trained fingers
(dark is tips)
• Jenkins et al. (1990)
• Train monkeys in
task that uses tips of
digits 2 and 3
• Also, increase in
number of RFs in
distal tips

Question 23

Phantom Limbs

Answer 23

• After amputation, patients can still feel as though they
have the limb and can feel pain and other sensations in
or on it
• After time elapses, they still feel as though it exists, it
“reduced in size” / telescoped. If the amputated part is
hurt, the limb can feel enlarged again
• Ramachandran (1993) studied a patient with an
amputated left arm. When parts of his cheek were
stroked, reported sensations in his left hand

Question 24

Reorganisation Mechanism

Answer 24

• Continuous competition for cortical space by
functional circuits
• Reorganisation by
1. release from inhibition
2. collateral sprouting

Question 25

Mechanism

Answer 25

• Initially some
overlap at cortical
boundary
• Infiltrating
branches are
inhibited
• Damaged nerve no
longer active
• Intact nerve
released from
inhibition
• Early response –
too fast for neural
growth
• Only extends mm
• Longer term
reorganisation too
great to be explained
by existing
connections
• Collateral sprouting
• Upstream changes
(e.g. thalamus) could
exert an even greater
effect over longer
time

Question 26

Adult Neurogenesis

Answer 26

Santiago Ramon y Cajal – in the CNS “everything may
die, nothing may be regenerated.”
Well into the 1980’s the almost universal view that
there is NO adult neurogenesis
“It is for the science of the future to change, if
possible, this harsh decree.
• Neurogenesis is the process by which new neurons
are formed in the brain
• Neurogenesis is crucial when an embryo is
developing
• 1990s – immunohistochemical markers – adult
neurogenesis in rat hippocampus
• Then neurogenesis in rat olfactory bulb
• Ernst & Christie
• Rat hippocampus (dentate
gyrus)
• Mature neurons – blue
• Mature glia – green
• New neurons - red
Adult neurogenesis is known to occur in three regions in
the mammalian brain:
• the subgranular zone (SGZ) of the dentate gyrus in the
hippocampus, which is a region that is involved in
regulating learning and memory
• the subventricular zone (SVZ), which is situated
throughout the lateral walls of the brain’s lateral
ventricles – these migrate to the olfactory bulb
• the amygdala

Question 27

Adult Neurogenesis - Amygdala

Answer 27

• Neural stem cells in basolateral amygdala (BLA) of adult
mouse (Jhaveri et al. (QBI))
• Give rise to mature and functional interneurons that
persist in the BLA
• Amygdala activity linked to fear regulation, fear
learning, depression, and anxiety disorders such as
PTSD
• Manipulating neurogenesis could lead to novel
treatments
Newly generated twin neurons in the adult amygdala. This is the first time
that newborn neurons have been found in the adult amygdala, a brain
region important for emotions and fear learning.

Question 28

Adult Neurogenesis

Answer 28

• Preventing adult neurogenesis in the SVZ has been
shown to impair cognitive functions including
olfactory memory
• New neurons in the hippocampus play crucial roles
in regulating mood, memory and spatial learning
• Possibility that new neurons in the amygdala
contribute towards fear-related memory
• Exercise increases neurogenesis in the dentate
gyrus, resulting in the increased production of
newborn neurons
• Depression has been found to decrease
neurogenesis
• Adult neurogenesis has also been shown to decline
with age

Question 29

Exercise

Answer 29

• Preserve cognitive function in elderly populations (Kramer
et al. 1999)
• Promote functional recovery after CNS traumatic injury
(Jones et al. 1999)
• Induce neurogenesis in the adult CNS (Kempermann et al.
2000)
• Have anti-depressant effects and improve outcomes in
animal models and for patients with stroke and
neurodegenerative diseases such as Parkinson’s Disease or
Alzheimer’s disease

Question 30

BDNF

Answer 30

Brain-derived neurotrophic factor (BDNF) is a neurotrophin
vital to the survival, growth, and maintenance of neurons in
key brain circuits involved in emotional and cognitive function
• BDNF signalling pathways a major contributor to the
processes of learning and memory formation
• BDNF promotes the differentiation, neurite extension and
survival of a variety of neuronal populations in culture
including hippocampal, cortical, striatal, septal and
cerebellar neurons
• BDNF can enhance brain plasticity

Question 31

Exercise and BDNF

Answer 31

• Physical activity (or neuronal activity) enhances Bdnf gene
expression in the brain increasing BDNF protein
• In animal models, exercise induces Bdnf mRNA expression
in multiple brain regions (Cotman et al., 2007), most
prominently in the hippocampus.
• Blocking BDNF signaling attenuates the exercise-induced
improvement of spatial learning tasks, and exercise-induced
expression of synaptic proteins (Vaynman et al.).
• How BDNF is selectively increased after physical activitydependent
changes in the nervous system is not well
understood.

Question 32

Exercise

Answer 32

• Consider effect of exercise and enrichment
separately on rats (Bechara & Kelly, 2013)
• Physical enrichment – moving treadmill
• Cognitive enrichment – nest and toys
• Novel object recognition test
• Neurogenesis in hippocampus
• BDNF activity in hippocampus
Novel Object
Exercise and
environmental
enrichment have
an additive
effect
Neurogenesis
Exercise, but not
enrichment,
increases the
number of
dividing cells in
the dentate
gyrus of the
hippocampus
BDNF Expression
Exercise, but not
enrichment,
increases BDNF
mRNA in the
dentate gyrus

Question 33

Exercise and Humans

Answer 33

• Using MRI generate cerebral blood volume (CBV)
maps over time of hippocampus (HC) in exercising
humans
• Also measure cardiovascular and cognitive changes
• First – mice to establish that
• Exercise increased CBV in HC
• CBV increase correlates with neurogenesis
Exercise selectively
increases dentate gyrus
CBV in humans
Exercise-induced increases in dentate gyrus CBV
correlate with aerobic fitness and cognition

Question 34

Exercise

Answer 34

• Aerobic exercise induces neuroplasticity at molecular,
cellular, and systems levels of analyses.
• Chronic aerobic exercise increases neurogenesis and
synaptogenesis, which may be a result of increased BDNF,
IGF-1, and VEGF.
• Exercise is associated with increased grey matter volume in
the hippocampus, cerebellum, basal ganglia, cingulate,
frontal, parietal, occipital, temporal, and insular cortices
• Chronic exercise also increases white matter volume in the
frontal, parietal, and occipital lobes

Question 35

Exercise and Depression

Answer 35

• Convergent evidence indicates that neuroplastic
mechanisms involving BDNF are deleteriously altered in
depression and animal models of stress
• Neurotrophic hypothesis of depression - stress-related
alterations in BDNF levels occur in key limbic structures to
contribute to the pathogenic processes
• Upregulation of BDNF occurs in the amygdala and nucleus
accumbens
• Downregulation of BDNF in the hippocampus and mPFC
• Dysfunction of astrocytes and microglia in depression circuits.
• Serum levels of BDNF tend to normalize in response to
several treatments
• antidepressants
• electroconvulsive therapy
• exercise
• Exercise reduces the risk for depression, mitigates
symptoms, facilitates recovery, lowers the incidence of
relapse, and decreases overall caregiver burden
• Effects may derive from ability to optimize central levels of
BDNF, particularly in the hippocampus
• Suggest that moderate exercise—a target that is
practical, well tolerated, and likely to optimize
adherence—optimizes BDNF and plasticity,
particularly in persons with depression
• Relative low-risk profile, ease of implementation,
and absence of side effects have led to the
incorporation of exercise into basic clinical
management protocols for MDDs

Question 36

Key Learnings

Answer 36

• The brain is plastic – it changes over time and this
experience dependent maturation underlies the abilities of
the human brain
• Plasticity is achieved by modulation of multiple points in the
neural network
• Developmental plasticity – long lasting effects of
deprivation or enrichment, particularly during critical
periods
• Ocular dominance; spatial maps; social effects
• Activity dependent plasticity – LTP (memory) and
myelination
• LTP – synaptic strengthening if correlated activity
• Myelination – modulate conduction speed to optimise
synchronicity
• Axotomy leads to anterograde, retrograde, and
transneuronal degeneration
• May get regeneration in PNS depending on state of myelin
sheath
• Cortical reorganisation – sensory and motor maps
reorganise in response to changed input and experience
• Reorganisation mechanism – release from inhibition and
collateral sprouting
• Adult neurogenesis – new neurons in hippocampus and
olfactory bulb, also amygdala
• Exercise increases BDNF – drives gliogenesis, neurogenesis,
synaptogenesis
• Neurotropohic hypothesis of depression