Download Functional and structural adaptation in the central nervous system

Functional and structural adaptation
in the
central nervous system
Anthony Holtmaat
CNS function in a nutshell
Sensory stimuli are converted into electrical signals
Action potentials are electrical signals carried along neurons
Synapses are chemical or electrical junctions that allow electrical
signals to pass from neurons to other cells
Changes in the amount of activity at a synapse can enhance or reduce
its function
Communication between neurons is strengthened or weakened by an
individual’s activities, such as exercise, stress, and drug use
All perceptions, thoughts, and behaviors result from combinations of
signals among neurons
The vast network of cortical neurons
communicates through synapses
20 billion neurons;
77% of brain volume; 2.500 cm2
1000-10.000 synapses per ‘typical’ neuron.
Feldmeyer et al. J. Phys. 2006
Fluorescent proteins have revolutionized the way
we can image neurons and synapses
Expression of fluorescent proteins allows one to see
all microstructures on neurons
Muller lab
Muller lab
Holtmaat lab
Knott lab
How does this complex system develop?
How does this complex system allow us to learn?
Can the network adapt or repair itself to an insult?
Key terms:
Functional and Structural
Neuronal Plasticity
The brain develops with enormous speed over
weeks to months to its final size, and then its
circuits are optimized over many years
Growth cone with
filopodia
Filamentous actin
drives filopodia
protrusion and
mobility
Examples of axon guidance during
neuronal development
Collapse assay
EGFP
Sema3A
Repulsion assay
EGFP
EGFP-Sema3A
In vivo
Axons are guide via a myriad of (chemo)attractants,
neurotrophic factors and (chemo)repellants
Axons compete with one another for targets
The axon that loses the battle retracts
Life imaging of fluorescent axons in the ‘young’ muscle illustrates this effect
Neurons receive information through dendrites
Why do neurons have complex dendrites?
Dendritic protrusions (spines)
They are very motile during development
They ‘look’ for input
" . . . it is almost impossible to do experiments whose conditions approach the normal
physiological state, during which the changes in position and form of the neuronal
arborizations could be fleeting and erased"
Santiago Ramon y Cajal, 1899, on the motility of
dendrites and spines.
Axon-dendrite contacts depend on partnering adhesion
molecules
Wiring depends on activity as well:
Hebbian Learning
"when an axon of cell A ... 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" (Hebb, 1949)
Cells that fire together, wire together
Hebb’s original drawing
From: the Molecular Biology of the Cell
Synaptic circuits are the building blocks
for plasticity
dendritic arbor
Axonal Bouton
axonal arbor
synaptic
current
glu
action
potential
B
postsynaptic
neuron
NMDA-R
Other stabilizing
components
A
AMPA-R
0.5 µm
Dendritic Spine
presynaptic
neuron
LTP: long term potentiation
Critical periods
• A critical period in developmental psychology and biology represents early
stages in life during which a system is highly sensitive to environmental
stimuli, affecting the way it develops
• The effects of the lack of appropriate stimuli during a critical period might
have long lasting and irreversible effects on the functioning of the system
• Different components of a neuronal circuit (cell types, nuclei, layers) can
have distinct critical periods
• Activity-dependent or experience-dependent development of sensory
systems
• The most well-known examples are: binocular vision (between one and two
years for humans); hearing; parental imprinting; bird song; first language
acquisition vs second language acquisition
Every neural system as some sort of a critical period
Different types and different regulation
Formation of ocular dominance columns
Activity-dependent
and
Hebbian-like plasticity
Conceptually first postulated by Hubel and Wiesel in 1960s
Axons from the deprived side permanently
lose space
After only a week of monocular deprivation, axons terminating in layer 4 of the primary visual cortex
from LGN neurons in the thalamus driven by the deprived eye have greatly reduced numbers of
branches compared with those from the open eye
Developmental plasticity in the owl auditory cortex
Young owl with prisms
work by Eric Knudsen in the 90s
Auditory stim
before
42 days prism
Typical projections
Visual stim
1 day prism
prism removed
Head turning angle
Projections after prism
Conclusion:
Structural and functional plasticity during critical
periods of development
But what about plasticity in adults?
The body surface is functionally represented in the
cortex in a topographical fashion
Homunculus
Wilder Penfield
(1891-1976)
from Kandel, Schwartz and Jessell
Marshall, Penfield, Woolsey
Importance of the modality
~ Size of the representation
The body surface is represented in the cortex in a
topographical fashion in sensory and motor cortex
Somatosensory map
Marshall, Penfield, Woolsey
Motor map
Each area has its own very detailed map
Cortical map plasticity is reversible and associated with
optimized performance
Hand
Cortical map
digits
Stimulating digits 2-4
on rotating disk
Pairing digits 2-4
Merzenich, Kaas, Jenkins et al
Cortical map plasticity might be involved in phantom
limb sensations
A. Stimulation of the
face elicits sensation
referring to the
phantom limb
B. Referred sensation
localized to distinct
areas in the stump
Ramachandran, Taub
Extreme forms of cortical map plasticity after
amputations
Amputee with
Phantom sensation
Amputee without
Phantom sensation
Healthy subject
Lip touch
Lotze et al. Brain 2001
Merzenich, Kaas, Taub and many others
How can we study and manipulate these
processes in laboratory animals?
Special case:
The whisker to cortex projections
The representation of the snout
in the rodent SI is very large
The mouse and rat barrel cortex
Woolsey, Van der Loos!
• The dense neurpil of the projections can be seen by various staining procedures
• Whiskers are individually represented in barrel-related cortical columns
The whisker to barrelcortex pathway
Information flows through the (1) trigeminal nucleus (cranial nerve V) in the brain stem,
(2) VPM of the thalamus to the (3) cortex
The layers of the barrel cortex
• 
• 
Thalamocortical input in layer 4
Layer 5 and 6 are themain output to subcortical somatosensory and motor
areas such as thalamus, pons and striatum
Activity dependent development of the
barrel cortex
• 
• 
• 
• 
• 
Formation of the barrel pattern by the
thalamocortical afferents
No pattern at one day after birth (A)
At 2, 3 and 4 the patterns becomes increasingly
clear
Deprivation, genetic lesions, or transections of
the peripheral nerve during the thalamacortical
ingrowth disturbs the the formation of barrel
patterns
Later in life this has no effect
Cranial windows in mice
skull
coverglass
dura
S1
Mice in the microscope
Revisiting
dendrites
and spines
Transient and persistent spines in the
adult neocortex
At least two classes of spines (L5B neurons):
1.  Persistent spines: large, stable spines
Survival fraction
2.  Transient spines: thin spines that appear and
disappear
1
Transient
fraction
0.8
0.6
0.4
Persistent
fraction
0.2
0
0
4
8
12
16
20
24
28
Time (days)
Trachtenberg et al 2002. Nature; Holtmaat et al 2005. Neuron; Grutzendler et al 2002. Nature
Experience-dependent plasticity in barrel cortex
Trim all whiskers
except D1
Fox, Simons, Ebner, Diamond et al
Representations change upon peripheral manipulations
Inducing experience-dependent plasticity
combined with long-term imaging
Control or Trimmed
Fraction Persistent Spines Gained
Spine density (mm-1)
16
12
Control
500
*
*
400
100µm
m
300
A1
*
*
*
*
*
*
*
200
*
* *
*
*
*
0*
*
*8
16*
PND 69 Time (days)
*
24 *
α
β
γ
C1
* 0.15
D1
δ
E1
0.05
0
28
24
α*
* 0.2
β
*
0.15
C1
A1
* 0.2
* B1
*
20
Trimmed
0.25
0.25
* 0.1
*
*
100
0*
8
Fraction Persistent Spines Lost
4
0
Imaging day
*
control
*
*
*
*
*
* *
*
*
*
*
*
trimmed
PND 165
B1
*
*
*
*
*γ
*
D1
0.1
δ
*
0.05 *
0
*
*
Spared
Deprived
E1
*
*control trimmed *
*
*
5 µm
day0
8
12
16
20
28
Holtmaat et al. 2006, Nature
Experient dependent spine and synapse formation in the
barrel cortex could underly map plasticity
Barrel C1
Barrel D1
deprived
spared
spared
SELECT
SAMPLE
activity change
due to whisker
clipping
trimming
Spine dynamics after monocular deprivation
New stabilized spines can be potentiated more
easily by a second MD
Hofer et al, Nature 2008
Motor learning induces spine formation and
stabilization
Stabilization of new spines is
enhanced by training
Xu et al, Nature 2009
Yang et al, Nature 2009
Ziff and Ahissar, Nature 2009
Structural plasticity after whisker follicle lesions
Functional expansion of spared whisker representations
Before follicle ablation
2 months after follicle ablation
X
X
X
X
E1!
E1!
X
X
D1!
B
1!
X
X
D1!
X
X
A
1!
B
1!
A
1!
Schubert, Lebrecht and Holtmaat, in progress
Dendritic or axonal branch dynamics
after whisker follicle ablation?
*
L5
New persistent
spines on L2/3
L5B cells lesion
ctrl
lesion
spared
depr
δ
Marik et al. PLoS
2010
Tailby et al. PNAS 2005
depr
Structural plasticty after retinal lesions
Thus, our brain can to some extent cope with
permanent peripheral nerve damage
Can it adapt or recover from damage of itself?
Central nervous system lesions
Alzheimer’s
Stroke
Amyotrophic lateral sclerosis
Huntington’s
Parkinson’s
Multiple Sclerosis
Creutzfeldt-Jacob disease
Spinal Cord Lesion
Brain Tumor
Spinocerebellar ataxia
Peripheral versus central regeneration
Peripheral nerves can regenerate after lesion
Peripheral nerves can regenerate after a lesion
Henry Head’s peripheral nerve regeneration
experiment (year 1905). Henry lesioned his
radial nerve. Initially the region that was
insensitive to painful stimuli was large. Large
part of this region had recovered sensation after
6 months (but it was not complete, even after 2
years).
Regrowth of damaged neurons in the CNS is very difficult and
complicated
Central glial cells, myelin and other scar-components
most likely prevent regeneration
Peripheral nerve grafts in the central nervous system
might be a solution
The growth promoting properties of Schwann cells facilitate growth of damaged optic
nerve fibers that would normally not regenerate. They even make synapses upon regrowth
into the superior colliculus. This indicates that central neurons have not lost their capacity
to grow.
Cortical map plasticity can be useful:
recovery from stroke
Overlaid images of control and stroke patients. Blue is the normal representation
of finger tapping, red the adapted response after stroke!
10 days
4 months
2 years
Jaillard, A. et al. Brain 2005
motor cortex activity upon finger tapping measured with fMRI
patients recovered from stroke
controls without stroke
This is linked to structural changes
Brown et al, J. Neurosci 2007, 2008
Murphy-lab
Induction of ‘Hebbian’ plasticity using neural implants in the
motor cortex
Conditioning period
Summary
1.  The nervous system develops guided by chemical cues and
activity
2.  Critical periods define important events during CNS
development in which activity-driven plasticity permanently
impacts its circuit function
3.  Plasticity remains present in a limited form during adulthood and
serves adaptation to new experiences and learning
4.  Peripheral nerves regenerate pretty well
5.  Central nerves do not regenerate in a CNS environment
6.  The central nervous system can use ‘plasticity’ to deal with
partial loss of function