Download Functional and structural adaptation in the central nervous system

Functional and structural
adaptation in the
central nervous system
Anthony Holtmaat
The Central Nervous System
The Central Nervous System
Controls and Responds to Body Functions and
Directs Behavior
The brain is the body’s most complex organ. 2% of the total body weight
There are a hundred billion neurons in the human brain.
1011 neurons (compare to for example less than 1 million in honey bee)
Each neuron communicates with many other neurons to form circuits and
share information.
1000-10.000 synapses per ‘typical’ neuron.
Proper nervous system function involves coordinated action of neurons in
many brain regions.
The nervous system influences and is influenced by all other body systems
(e.g., cardiovascular, endocrine, gastrointestinal and immune systems).
This complex organ can malfunction in many ways, leading to disorders that
have an enormous social and economic impact.economic impact.
Brain disorders are an enormous
burden on our society
Neurons communicate using both electrical
and chemical signals.
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.s among neurons.
Final processor
Higher thinking
Autonomic
functions
Information gates
Cerebral hemisphere
(Neo)cortex
Diencephalon
Midbrain
Pons
Cerebellum
Medulla
Highway
Reflexes
Spinal cord
Integration
The cerebral cortex
20 billion neurons; 77% of brain volume; 2.500 cm2
I
II/III
IV
V
VI
Cortical neuronal layers
Cortical cytoarchitecture
Layer I - molecular layer, dendrites, axons
Layer II - external granule cell layer, small neurons
Layer III - external pyramidal cell layer, send axons
to other parts of cortex
Layer IV- internal granule cell layer, granule cells
that receive input from deeper brain regions or
other superficial cortical layers
Layer V - internal pyramidal cell layer, larger cells
than layer III, output, feedback projections
Layer VI - polymorphic or multiform layer,
heterogeneous cells
PS. There are many
projection neurons as
White matter
well as interneurons
The brain develops with enormous speed over
weeks to months to its final size, and then its
circuits are optimized over many years
Examples of short- and long-range
chemoattraction and chemorepulsion
Ligand
Receptor/ligand
Attraction/repulsion
Robo
N-CAM
Integrins
Eph receptors
Repulsion
Attraction
Attraction
Repulsion
DCC
Neuropilins
Attraction
Repulsion
Repulsion
Repulsion
Short-range
(contact mediated)
Slit
N-CAM
ECM adhesion prot
Ephrins
Long range
(diffusible ligand)
Netrin
Semaphorins
Slit
Netrin
Example of axon guidance during
neuronal development
Collapse assay
EGFP
Sema3A
Repulsion assay
EGFP
EGFP-Sema3A
In vivo
Critical periods
•A critical period is a limited time in which a event can occur,
usually to result in some kind of transformation
•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
The cerebral cortex governs higher mental functions
Ouch!
!!
He hurt me;
I want to
kick him..
Touch
Muscle contraction
Lateral sulcus
Lateral sulcus
The cerebral cortex - cognitive functions
Precentral gyrus
Postcentral gyrus
Lateral sulcus
•Four lobes, named after after the skull bones that encase them
•Frontal - planning, movement
•Parietal - somatic sensation, body awareness
•Occipital - vision
•Temporal - hearing; learning, memory, emotion (hippocampus, amygdala)
•About 1010 (10 billion) neurons, and 1014 (100 trillion) connections
Korbinian Brodmann (1868-1918) : cytoarchitecture of the brain
The cerebral cortex has functionally distinct regions
somatosensory
vision
hearing
motor skills
short term memory,
decision making
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
Amyotrophic lateral sclerosis
Alzheimer’s
Stroke
Huntington’s
Parkinson’s
Multiple Sclerosis
Creutzfeldt-Jacob disease
Spinal Cord Lesion
Brain Tumor
Spinocerebellar ataxia
Regrowth of damaged neurons in the CNS is very difficult
and complicated
Functional recovery after peripheral damage,
and more….
Cortical map plasticity can be
maladaptive: 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
video
http://www.youtube.com/view_play_list?p=1EE
802FC3F997400&search_query=ramachandra
n+phantoms+in+the+brain
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
Functional expansion of motor and sensory
areas after extensive training
Piao player
tapping
finger
Blind person
reading Braille
Control
person
tapping
finger
Normal sighted
person reading
Braille
Hund-Georgiadis and von Cramon,
1999 Exp Brain Res
Gizewski et al. 2003 NeuroIamage
The topographic map is functionally adaptive
Merzenich, Kaas, et al
How sensitive are these maps?
Do they change in reponse to other types of stimuli?
Does this happen in other species as well?
Plasticity of motor areas after lesions
•The functional organization of the
primary motor cortex changes after
transection of the facial nerve (cranial
nerve VII)
•Areas devoted to forelimb and
periocular control have increased, and
expanded into the area previously
devoted to whisker control
Each area has its own very detailed map
The maps are plastic - expansion
•Somatosensory cortex, hand
representation
•Extensive training - expansion of
the representations
•Repeated use of the tip of the digits
2, 3, and occasionally 4 - substantial
enlargement of the cortical
representation of the stimulated
fingers after training
•After training the number of
receptive fields in the distal digits 2,
3 and 4 is larger than before training
The maps are plastic - reduction
•Fusion of the digits simplification of the
representations
•Areas that were distinct now
commonly respond to both digits
•The common area remains
immediately after seperation of
the digits - the changes occur
centrally
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
Critical periods in the visual cortex
Ocular dominance distribution in normal
monkeys
•Right eye closed at
•Closure of one eye at 2 weeks
(monkey)
•Columns of the closed eye are
narrower than normal
•Arborization of geniculate axons is
reduced
21 days for 9 days
•Subsequent 4 years
of vision has not
restored the original
response distribution
Plasticity in the auditory cortex after
misguiding input
Cortical plasticity during
adolescence and adulthood
Assessment of barrel cortex plasticity
•Increased responses of neurons in the barrels
neighboring the spared barrel
•The spared whisker recruits neurons from the
deprived barrels
Plasticity in the barrel cortex
•Plasticity in the barrel cortex becomes apparent after whisker clipping
•Clipping of whisker but leaving one or more intact will cause increases in the
representation of the spared whiskers
What are the cellular correlates of this type
of functional plasticity?
Feldmeyer et al. J. Phys. 2006
Three type of changes that could correllate with
experience dependent plasticity?
Local  Fixed
connectivity
e.g. synapse growth
or
changes in
transmitter
release/receptor
composition
Short range  Fixed
potential connectivity
e.g. generation of new
synapses through spine
or bouton growth
Long range  Flexible potential connectivity
e.g. new connections through dendritic or axonal sprouting
Challange : visualization and the dimension time
" . . . 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.
Solution1
Thy1-XFP transgenic mouse lines:
expression in pyramidal cells
GFP-M
YFP-H
Solution 2: 2-photon absorption microscopy
excitation only in the focal volume
Single-photon
excitation
Two-photon excitation
nIR
Localization of excitation
single photon excitation
two-photon excitation
from Zipfel et al, Nat Biotech 2003
80% of absorption
in focal volume
green
blue
absorption
absorption
~ exc.
~ (exc.
intensity
intensity)2
Reviews:
Denk & Svoboda, Neuron 1997; Zipfel, Williams & Webb, Nat Biotech 2003
Helmchen and Denk, Nature Methods 2005; Svoboda and Yasuda, Neuron 2006
Solution 3: Cranial window
skull
coverglass
dura
S1
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
Persistent
fraction
0.4
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 of transient spines
Fraction Persistent Spines Gained
4
8
*0.25
* 0.4
*
*
*
*
*
* *
*
*
0.3
0.2
*
0.15
0.2
*
*
*
0.1
0.1 *
*
*
PND 69
0
16
Control
0.5
100µm
12
A1
*
*
*
*
*
20
β
γ
C1
D1
*
A1
*
0.2
*
*
0.15
*
*
δ
*0.1
E1
* *
0.05
0.05
24
28
Trimmed
0.25
α
B1
*
Fraction Persistent Spines Lost
Imaging day 0
*
α
*
β
B1
*
C1
*
*
*
*
*γ
*
D1
δ
*
*
E1
*
*
*
*
* 24-28*
0 *20-24
* 00-4 * 4-8 8-12 12-16 16-20
*
*
PND
165
*
Time
(days)
control
trimmed
control trimmed
*
*
Spared
Deprived
*
*
5 µm
day0
8
12
16
20
28
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
Structural plasticity: chaning of spines,
axonal boutons and synapses
Is this a general phenomenon?
Does it work for real lesions?
Structural plasticty after retinal lesions
And what about central nervous system lesions?
Plasticity after stroke in mice
•Stroke in the fore limb representation result
initially in a silent area
•The receptive fields expand: cells in the hind
limb area start to respond to both, fore and
hind limb
END