Neurobiologie Les 3
1st Master Biomedische Wetenschappen
Robrecht Raedt
• Introduction
• Synaptic plasticity
– Short term plasticity
– Learning and memory mechanisms
• Short-term sensitization/long-term sensitization
• Long-term potentiation
• Long-term depression
Intrinsic neural plasticity
Homeostatic plasticity
Memory systems in the mammalian brain
Cortical Neuroplasticity
Neuroplasticity and neuro-prostheses
Deep brain stimulation
Introduction on neuroplasticity
• Neuroplasticity = changes in activity and organization
of the brain due to ‘experience’
• Changes:
– Physiological
– Anatomical
• Previous dogma’s:
– The brain is rigid
– Plasticity is limited to the hippocampus
– Plasticity is limited to development/childhood
• All brain regions show some form of plasticity, even in
Synaptic plasticity
• Changes in input-output relationship in neuronal
networks due to changes in synaptic efficacy
– Excitatory/inhibitory
– Activity-dependent
– Different time scales: milliseconds, hours, days
• Short-term plasticity (msec-min)
• Long-term plasticity (min-lifetime)
Short-term plasticity
• Facilitation
• Augmentation
• Potentiation (post-tetanic)
- Form of plasticity depends on:
a. type of neuron
b. type of stimulation
Short-term plasticity
• Mechanism:
Changes in calcium-concentration
Changes in neurotransmitter release (quanta)
Repeated neuronal activity
- more: facilitation/augmentation/potentiation
-less: depression
Short term depression
• Vesicle depletion
– No depression in low
Ca2+ or high Mg2+
– High release probability
and small pool
Short term depression
* Inactivation Ca2+ channels
* Mobilization vesicles ↓
NT release ↓
Short term depression
• Autoinhibition via stimulation of presynaptic
• Receptor desensitization
Short term potentiation
Short term potentiation
• Residual Ca2+ remaining in active zones after
presynaptic activity
• Summating with Ca2+ peak during subsequent action
potentials at site triggering exocytosis
• More distant facilitation sites (second messengers
• Potentiation: longer period after strong tetanus
– Overloading of processes responsible for removing excess
• Ca2+ extrusion pumps
• Plasma membrane ATPase and Na+- Ca2+ exhange
• Ca2+ uptake in organelles
Learning and memory
• Long-term plasticity
• Repeated synaptic activity → changes last for
– Sensitization
– Long-term potentiation
– Long-term depression
– Intrinsic synaptic plasticity
– Homeostatic plasticity
Associative learning
Non-associative learning
• Habituation : reduction in response to a stimulus
• Dishabituation: restoration/recovery of a response due to
presentation of another strong stimulus
• Sensitization: enhancement of response due to presentation
of a strong stimulus
Aplysia studies
• Kandel: Nobel Prize in Physiology or Medicine in 2000
• Simple nervous system (few cells)
• Accessible for detailed anatomical, biophysical,
biochemical and molecular studies
• Neurons and neural circuits that mediate behavior
have been identified
• Changes during learning have been identified
• Memory mechanisms
– Induction
– Expression
– Maintenance (consolidation)
Short-term sensitization
• Heterosynaptic facilitation
• Secundary messenger
– Ion channel permeability
– Phosporylation of synapsin
(release of vesicles from
• Sensitization
– Action potential is broader
(inhibition of K-channels)
– More transmitter is
Long-term sensitization
• 5HT → activation of cAMP/PKA cascade
induction of gene transcription!
translocation of PKA to nucleus
cAMP responsive element binding protein (CREB1)
Autoregulation of transcription (promotor binding - feedback)
5HT → Tyrosine receptor kinase-like molecule (ApTrk)
MAPK: phosphorylation of CREB2 → derepression of CREB1
Long-term sensitization
• ApCAM (Homologue of NCAM)
Downregulation (reduced synthesis, increased internalization)
Additional connections can be made by sensory neuron
• Aplysia Tolloid/BMP-like protein (ApTBL-1)
Zn2+ dependent protease
Activate TGF-β family (mimics 5HT effects)
Positive feedback loop
• Aplysia Ubiquitin hydrolase (ApUch)
Intracellular feedback loop
Increased degradation of regulatory unit of PKA
Long-term vs. short-term sensitization
• Decreased duration of AP
• Structural changes: neurite outgrowth
• Increased high-affinity glutamate uptake
– Nt. available for release
– Nt. clearance (duration of EPSP/receptor desensitization)
• Changes in postsynaptic cell
Associative learning in Aplysia
Associative learning in Aplysia
• ‘Coincidence ‘ detection
• Postsynaptic
• Glutamate (delivered by presynaptic in response to CS)
• Depolarization (induced by US, serotonin)
Vertebrate studies: LTP
More difficult to link synaptic plasticity with learning
Increase in synaptic strength
Induced by brief burst of spike activity in presynaptic afferents
Responsible for information storage in several brain regions,
different animal models
• No uniform mechanism for inducing LTP
– Depending on experimental conditions
LTP at the CA3-CA1 synapse
• Mechanism:
Repeated activation
NMDA-receptor releases Mg2+
‘early ‘LTP (< 90 min)
[Ca2+] ↑ ↑
AMPA-receptors ↑ and ionic conductance ↑
‘late’ LTP (> 90 min)
Protein synthesis
Glutamate, depolarization
• Classical properties:
– Cooperativity: probability of LTP, magnitude of change
increases with number of stimulated afferents
– Associativity: LTP only induced at weak input when
associated with activity in strong input
– Input specificity: Unstimulated weak pathway not
facilitated after tetanus of strong pathway
Hebbian Mechanism
• Donald Hebb (1949):
‘When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes
part in firing it, some growth process or metabolic change takes place in one or both cells
such that A’s efficiency, as one of the cells firing B, is increased.’
• ‘Cells that fire together, wire together’
• Coincident activity in two synaptically coupled neurons increases
the synaptic strength between them
• Not all forms of LTP obey Hebb’s law:
e.g. Mossy fiber-CA3 synapse
LTP: mechanisms for induction,
expression and maintenance
• Multiple mechanisms for induction
• Increased [Ca2+ ]I
• AMPA and NMDA (Hebb)
• Cooperativity : strong
synaptic input necessary to
depolarize membrane,
• Associativity/input
selectivity: weak input in
itself does not relieve Mg2+
• Mechanisms for L-LTP highly
conserved across species
(cfr Aplysia)
LTP expression
• CA3-CA1 synapse:
– (5) increase of functional AMPA
– (4) P of AMPA receptor: increased conductance
– (4) TARPs: AMPA receptor trafficking
LTP maintenance
• E-LTP: phosphorylation of substate protein
• L-LTP: alteration in gene expression
– Transcription factors (fos, zif268)
– Cytoskeletal proeins (arc)
– Signal transduction molecules (CaM kinase II)
– Critical time window (<2h)
– Synapse specificity: tagging by kinase(s)
– Positive feedback/re-activation of L-LTP mechanisms
Long term depression
Repeated activity
(Hippocampus: 10 min, 1 Hz)
NMDA-receptor releases Mg2+
[Ca2+] ↑
AMPA-receptor defosforylatie
internalisation AMPA-receptors
• Learning mechanism in cerebellum
(eye-blink reflex: decrease in synaptic strength in a postsynaptic
inhibitory neuron)
• Reversal of LTP
• NMDA-dependent and – independent mechanisms
Depends on:
- Brain region/type of neuron
- Increase in [Ca2+]
- mild -> LTD (protein phosphatase)
- high-> LTP (protein kinase)
- Characteristics of repeated activity
- High frequencies-> LTP
- Low frequencies (≤ 1Hz) -> LTD
Intrinsic neural plasticity
• Changes in input-output relationship in neuronal networks
due to changes in density or functional properties of voltagegated ion channels
• Probability that a cell fires in response to depolarization by
• EPSP to spike coupling
• Different between neural dendrites, soma and axons
Intrinsic neural plasticity
Intrinsic neural plasticity
• Dendritic ion channels
– Voltage attenuation of EPSPs, EPSP to AP
– Voltage attenuation and filtering of backpropagating AP
• STDP (spike-timing dependent plasticity)
– Voltage gated Na+ and Ca2+ channels allow
dendrites to generate own spikes (dendritic
Intrinsic neural plasticity
• A type K+ current
(IA current)
– Active at
potentials lower
than AP threshold
– Activated by
dendritic EPSP
– EPSP attenuation
– b-AP attenuation
Homeostatic plasticity
• Allow neurons to sense how active they are are
and to adjust their properties to maintain stable
• Stabilizes the activity of a neuron or neuronal
circuit in the face of perturbations that alter
excitability (e.g. changes in number of synapses)
Synaptic scaling
Regulation of intrinsic neuronal excitability
Regulation of synapse number
Synaptic plasticity and instability
Synaptic scaling
• Blocking GABAergic transmission
– Initial bursting of neurons
– Firing rates become normal again
• Transfection with inwardly rectifying potassium channel
– Decreased firing rates
– Recovery over time
Synaptic scaling
Regulation of intrinsic neuronal excitability
Regulation of synapse number
Learning and memory:
brain systems
Learning and memory:
brain systems
Severe amnesia for recent events
Unable for form new memories
Unaffected IQ score, no defective perception
Only retention of information if actively rehearsed
Childhood memory relatively intact
Acquire new motor skills
• Declarative (explicit) memory
– episodic memory
• personal events
– semantic memory
• learning new facts
• Procedural (implicit) memory
• Hippocampus
• the subiculum
• hippocampus = hippocampus proper =
Ammon’s horn
• dentate gyrus
– a thin band of cortex that lies on the upper surface of the
parahippocampal gyrus.
– an input centre and receives signals that are relayed to it via
the enthorhinal cortex and its cells project to cells in the
hippocampal formation.
dentate gyrus (1)
cornu ammonis (2)
Their three layered cortex is continuous
below with the subiculum (3) which has
four, five then six layers as it merges
with the parahippocampal gyrus (4).
Hippocampal formation
• subiculum
– transitional area between 3-layered hippocampus and 5layered parahippocampal gyrus
– area essential for flow of information into hippocampal
Hippocampal formation
• dentate gyrus and hippocampus
– 3-layered
– external layer: molecular layer with afferent axons and
– middle layer: granule cell layer in dentate gyrus and
pyramidal layer in hippocampus with efferent neurons
– inner layer: polymorphic layer: axons of granule and
pyramidal cells, intrinsic neurons and many glial cells
Hippocampal formation
• 4 regions: CA1-CA4 (CA: cornu Ammonis)
– CA1: located at subiculum-hippocampal interface
– CA2 and CA3: located in hippocampus
– CA4: located at junction of hippocampus and dentate
Hippocampal formation
• afferent fibres
– major input in hippocampus from parahippocampal gyrus
via ‘perforant path’: terminates in molecular layer of
dentate gyrus
– granule cells in dentate gyrus→ molecular layer of CA3 of
hippocampus → CA1 of hippocampus → input to
– subiculum receives input from amygdala
Hippocampal formation
• efferent fibres
– outflow from subiculum and hippocampus towards fornix
– from subiculum → postcommissural → mammillary
– from hippocampus → precommissural → septal nuclei,
frontal cortex, hypothalamus, nucleus accumbens
Hippocampal function
• Emotion
• patients with hippocampal lesions:
– anterograde amnesia
– able to perform tasks for sec or min
– when distracted they don’t remember what they
were doing
• learning and memory
• consolidation of long-term memories from
immediate and short-term memories
• spatial memory
• Place cells: video
Cerebellar cortex
Amygdala function
• Fear and negative emotional reactions
• Appetitive, emotional reactions
– Association of tone with food
• Taste (rewarding)
association affected by lesion of basolateral nuclei
• Visual appearance (non-rewarding)
association not affected
• Context conditioning (place-preference)
– Place cues
– Hippocampus (binding a variety of sensory
information about place)
Amygdala function
• Unconscious emotional state
– Connection with hypothalamus and ANS
• Conscious feeling
– Connection with cingulate gyrus and prefrontal cortex
• Arousal
– Direct projection to various nuclei
– Indirect projections to nucleus basalis
• β-adrenergic blokker (propanolol) impaired
memomry for emotional but not neutral story
Amygdala dysfunction
• Kluver-Bucy syndrome
• behavioural changes due to bilateral temporal lobe
lesions (abolishment of amygdala and the hippocampal
formation, as well as the nonlimbic temporal cortex)
• first: visual agnosia, sometimes tactile and auditory
• second: hyperorality: tendency to examine objects by
Amygdala dysfunction
• third: hypermetamorphosis: compulsion to intensively
explore the immediate environment and overreact to
visual stimuli
• fourth: placidity: no more fear or anger
• fifth: hyperphagia: eat in excessive amounts even
without hunger and objects that are not food
• sixth: hypersexuality: augmentation in sexual
behaviour: suggestive behaviour, talk, attempts at
sexual contact
• amnesia, dementia, aphasia
Amygdala dysfunction
• Urbach-Wiethe disease
– Calcium deposition in amygdala
– Lesion early in life : fail to learn the cues that
normal persons use to discern fear in facial
expression and to discriminate fine differences in
other facial expressions.
Cerebral cortex
• Perceptual learning
– tone discrimination
– repetition priming
• Both not-affected in HM
Cortical plasticity during development
• Brain development
Sensory information = crucial
‘Unused‘ synaptic connections -> disappear(=
‘Used’ synaptic connections -> strenghtened
Cortical plasticity during development
Visual input -> activation retina -> optical nerve -> input at the
level of primary visual cortex (occipital lobe) -> development
visual system
Cortical plasticity during development
# Blind at birth (or <2yr)
visual cortex unsufficiently developed,
optical system intact -> not reparable
# Blind at later age (>2 jr)
1. eye defect (cataract, diabetic retinopathy…):
visual cortex sufficiently developed->
visual prothesis (‘bionic eye’ – see further)
2. occipital lobe damage:
damage of visual cortex, eye intact->
# Developmental disorder
‘Lazy eye’ (amblyopy)
• Defect at the level of the brain
• During sight development -> no optimal
coordination/cooperation of both eyes
• Treatment:
-> stimulating of visual cortex receiving input from
ambyope eye
Cortical plasticity and phantom pain
• Sensory and motor cortex:
Cortical map: homunculus
Phantom pain
= after amputation; sensation (of movement) in
amputated extremity; sometimes pain
– in the stump
• Defective blood supply
• Stimulation of pain (Aδ) nerve fibers (neuroma)
– in the brain
• Reorganization of somatosensory cortex
Phantom pain
• Ramachandran – mirror box
• Mirror Box and Phantom Limb Pain #1.mp4
Neuroplasticity and synesthesia
• Synesthesia:
= by stimulating 1 sensory/cognitive pathway, a second
sensory/cognitive pathway is activated automatically
beyond our will
E.g. Color-grapheme synesthesia: ‘seeing’ color with
- Familial disorder
- 5% of the population
- artists, poets,…
Early development:
connection between different brain areas
Normal: Connections disappear
Synesthete: no complete disappearance of
connections between
‘number-regions (green) ’ and
‘color-region’ (red)
• Device that replaces sensory, motor or cognitive
function that is damaged by disease or injury
• Links machine with nerve system (via interface)
• Prosthesis types:
a) Visual prosthesis
= bionic eye
External or implanted camera
Interface for signal processing
stimulator :
retina, optical nerve, visual cortex
a) Visual prosthesis
b) Auditory prosthesis
• Stimulation: cochlea, auditory nerve,
auditory cortex
a. Ear clip
b. Microphone
c. Speech processor
d. Transmitter coil
e. Receiver coil
f. Lead wires
g. Cochlea (hearing organ)
h. Auditory nerve
c) Motor neuroprosthesis
= depends on which part of the motor system is
• Bvb.
– Paralyzed limb:
stimulation of intraspinal nerves
stimulation of muscles
– Amputated limb : bionic limb
Stimulation muscles:
Will to move -> signal brain to spine
-> signaal to muscles-> muscle contraction
Detect signals from spine by interface -> ‘translate’ (training
necessary ) -> (percutaneous) muscle stimulation ->
muscle contraction
- Cerebral palsy
- Hemiplegia
- Tetraplegia
Sufficient force by limbs
Interface +
Amputation -> bionic arm
Will to move-> signal brain to spine-> signal to muscles-> muscle
Capture signals from spine by interface -> ‘translate’ (training
necessary) -> bionic arm movement
Bionic arm -> sensory feedback -> interface -> optimization of
bionic arm movement
c) Other motor neuroprostheses
– Respiratory problems
(eg. by spine injury):
‘diafragma pacing’
nervus frenicus stimulation
intramuscular diaphragma stimulation
c) Other motor neuroprostheses
- Incontinence & micturition problems:
stimulation of bladder muscles
d) Sensory neuroprosthesis
Sensory organ for balance
= vestibular system – semicircular channels
Liquid in channels -> cilia
-> nervus vestibularis -> vestibular nuclei -> bv.
Correction of eye position during movement
d) Sensory neuroprosthesis
• Injury (unreparable) in vestibular system
-> sensation of ‘continuous falling’
‘BrainPort®’ (=sensoric substitution):
accelerometry (head)
connected to ‘grid’ of 144 stimulation electrodes on
Bend to front: stimulation in front of tongue
Bend to back: stimulation at the back of the tongue
Signal from stimulation-electrodes ->
Sensory neurons of tongue-region in brain ->
Interpretation of movement-> correction of body
movement by vestibular system
-> finally (after training): vestibular system is
directly sensitive for sensory information from
tongue (active interpretation no longer necessary)
e) Cognitive neuroprosthesis
Brain-computer interface:
‘turning thought into action’
E.g. Locked-in patient can surf the internet
via thoughts
Signal from EEG of EcoG (subdurale grid)
Patient intention for movement of cursor
on screen
-> training interface
-> translate intention in cursor
e) Brain-computer interface
• Deep brain stimulation
Deep brain stimulation
1973: chronic pain
1987: movement disorders (eg. Parkinson’s disease)
1992: epilepsy
1999: Gilles de la Tourette
1999: obsessive-compulsive disorder
2003: cluster headache
2005: addiction
2005: depression
2007: obesitas
2007: hypertension
2008: memory-improvement-> ethical??
DBS for Parkinson’s disease
Deep brain stimulation for Parkinson’s

similar documents