neuroplasticity neurobiologie les 3 1 st master biomedische wetenschappen robrecht raedt

Neuroplasticity

Neurobiologie Les 31st Master Biomedische Wetenschappen

Robrecht Raedt

Overview• 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 adulthood

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)

•Depression

- Form of plasticity depends on:a. type of neuronb. type of stimulation

• Mechanism:

Repeated neuronal activity

Changes in calcium-concentration

Changes in neurotransmitter release (quanta)

PRESYNAPTIC

- more: facilitation/augmentation/potentiation- less: depression

Short-term plasticity

Short term depression

• Vesicle depletion– No depression in low

Ca2+ or high Mg2+ environment

– High release probability and small pool

* Inactivation Ca2+ channels* Mobilization vesicles ↓ NT release ↓



• Autoinhibition via stimulation of presynaptic autoreceptors

• Receptor desensitization

Ca2+Ca2+

Ca2+

Ca2+

Ca2+

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 systems/kinases)

• Potentiation: longer period after strong tetanus– Overloading of processes responsible for removing excess Ca2+

• 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

hours/days– 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

systems– Ion channel permeability– Phosporylation of synapsin

(release of vesicles from pool)

• Sensitization – Action potential is broader

(inhibition of K-channels)– More transmitter is

available

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

LTP (E-LTP; L-LTP)• Mechanism:

Repeated activation

Glutamate, depolarization

NMDA-receptor releases Mg2+

[Ca2+] ↑ ↑

AMPA-receptors ↑ and ionic conductance ↑

Protein synthesis

POSTSYN

APPTISCH

‘early ‘LTP (< 90 min)

‘late’ LTP (> 90 min)

LTP

• 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, AMPAR)

• Associativity/input selectivity: weak input in itself does not relieve Mg2+ block

• VGCC • 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)

Depolarization

NMDA-receptor releases Mg2+

[Ca2+] ↑

AMPA-receptor defosforylatieinternalisation AMPA-receptors

POSTSYN

APPTISCH

• Learning mechanism in cerebellum (eye-blink reflex: decrease in synaptic strength in a postsynaptic inhibitory neuron)

• Reversal of LTP • NMDA-dependent and – independent mechanisms

LTP or LTD

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 voltage- gated ion channels

• Probability that a cell fires in response to depolarization by EPSP

• EPSP to spike coupling• Different between neural dendrites, soma and axons


• Dendritic ion channels– Voltage attenuation of EPSPs, EPSP to AP – Voltage attenuation and filtering of back-

propagating AP• STDP (spike-timing dependent plasticity)

– Voltage gated Na+ and Ca2+ channels allow dendrites to generate own spikes (dendritic spikes)

Intrinsic neural plasticity • A type K+ current (IA

current)– Active at

membrane 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 function

• Stabilizes the activity of a neuron or neuronal circuit in the face of perturbations that alter excitability (e.g. changes in number of synapses)1. Synaptic scaling2. Regulation of intrinsic neuronal excitability3. Regulation of synapse number4. ‘Metaplasticity’

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

Metaplasticity

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

Hippocampus

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).

• subiculum– transitional area between 3-layered hippocampus and 5-

layered parahippocampal gyrus– area essential for flow of information into hippocampal

formation

Hippocampal formation

• dentate gyrus and hippocampus– 3-layered– external layer: molecular layer with afferent axons and

dendrites– 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


• 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

gyrus


• 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

– subiculum receives input from amygdala


• efferent fibres– outflow from subiculum and hippocampus towards fornix– from subiculum → postcommissural → mammillary

bodies– 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

Striatum

Cerebellar cortex

Amygdala

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 agnosia

• second: hyperorality: tendency to examine objects by mouth

• 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.

Amygdala dysfunction

Cerebral cortex

• Perceptual learning– tone discrimination – repetition priming

• Both not-affected in HM

Cortical plasticity during development

• Brain developmentSensory information = crucial

‘Unused‘ synaptic connections -> disappear(= ‘pruning’)

‘Used’ synaptic connections -> strenghtened

Visual input -> activation retina -> optical nerve -> input at the level of primary visual cortex (occipital lobe) -> development visual system


# 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-> repair?# 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

• Sensory and motor cortex:

Cortical map: homunculus

Cortical plasticity and phantom pain

Phantom pain= after amputation; sensation (of movement) in

amputated extremity; sometimes pain

Causes:– 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

• 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 numbers

Neuroplasticity and synesthesia

Synesthesia- Familial disorder- 5% of the population- artists, poets,…

Early development: connection between different brain areas

‘pruning’

Normal: Connections disappearSynesthete: no complete disappearance of

connections between ‘number-regions (green) ’ and

‘color-region’ (red)

Neuro-prostheses

• 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) Visualb) Auditoryc) Motord) Sensorye) Cognitive

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 clipb. Microphonec. Speech processor d. Transmitter coile. Receiver coil f. Lead wiresg. Cochlea (hearing organ)h. Auditory nerve

c) Motor neuroprosthesis

= depends on which part of the motor system is defective

• Bvb.– Paralyzed limb:

stimulation of intraspinal nervesstimulation 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 + stimulator

Training

Amputation -> bionic arm

Will to move-> signal brain to spine-> signal to muscles-> muscle contraction

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 stimulationintramuscular diaphragma stimulation

- Incontinence & micturition problems:stimulation of bladder muscles

c) Other motor neuroprostheses

d) Sensory neuroprosthesisSensory organ for balance

= vestibular system – semicircular channels

Liquid in channels -> cilia-> nervus vestibularis -> vestibular nuclei -> bv. Correction of eye position during movement

• Injury (unreparable) in vestibular system-> sensation of ‘continuous falling’

‘BrainPort®’ (=sensoric substitution):accelerometry (head)connected to ‘grid’ of 144 stimulation electrodes on tongue

e.g. Bend to front: stimulation in front of tongue Bend to back: stimulation at the back of the

tongue etc…

d) Sensory neuroprosthesis

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 neuroprosthesisBrain-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 movement

e) Brain-computer interface

Neurostimulation• Deep brain stimulation

Deep brain stimulation

1973: chronic pain1987: movement disorders (eg. Parkinson’s disease)1992: epilepsy1999: Gilles de la Tourette1999: obsessive-compulsive disorder2003: cluster headache2005: addiction2005: depression2007: obesitas2007: hypertension2008: memory-improvement-> ethical??

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Deep brain stimulation for Parkinson’s disease

neuroplasticity neurobiologie les 3 1 st master biomedische wetenschappen robrecht raedt

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