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OUTLINE

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Kevin Fox. Presented by: Stephanie Hornyak-Borho. York University. April 2009. OUTLINE ... Constraint-Induced Therapy (CIT) (Cramer & Riley, 2008) ... – PowerPoint PPT presentation

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Title: OUTLINE


1
(No Transcript)
2
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

3
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

4
  • INTRODUCTION
  • Somatosensory cortex (SSC) serves
  • several key functions in the brain.
  • Integration and analysis of somatosensory
    information leads to perception of these stimuli.
  • Enables planning, execution and dynamic
    modulation of coordinated movement (via motor
    cortex).
  • Governs the sense of body ownership and leads to
    a sense of self (with insular and visual
    cortices).

5
  • INTRODUCTION
  • Cortical reorganization occurs naturally during
    recovery (or partial recovery) from stroke
    (Nelles et al., 1999).
  • Treatments aimed at improving recovery from
    stroke is comprised of three stages
  • Neuroprotection
  • Neuronal Repair
  • Functional Rehabilitation

6
  • INTRODUCTION
  • Increasing Plasticity Behavioural Training
    Rehabilitation
  • Constraint-Induced Therapy (CIT) (Cramer Riley,
    2008).
  • Functional brain mapping studies indicate that
    CIT causes an increase in remapping of arm
    function in peri-infarct cortex (Sutcliffe et
    al., 2007).
  • EXPERIENCE-DEPENDENT PLASTICITY

7
  • INTRODUCTION
  • Much research in this area comes from studies in
    the rodent BARREL CORTEX, which receives input
    from the vibrissae.
  • Barrel cortex also provides a useful model for
    stroke research
  • Area affected by the infarct can be defined quite
    accurately with reference to the barrels.
  • Ability to stimulate the whiskers provides an
    easy method for checking whether stimulus-induced
    increases in blood flow are affected by stroke.

8
INTRODUCTION
9
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

10
ANATOMICAL PATHWAYS MEDIATING PLASTICITY 1.
Pathways for Potentiation and Horizontal
Transmission 2. Pathways for Depression and
Vertical Transmission
11
ANATOMICAL PATHWAYS MEDIATING PLASTICITY Pathways
for Potentiation and Horizontal Transmission
  • A characteristic feature of plasticity in the
    SSC is the
  • Horizontal spread of the body representation
    spared by the injury.
  • Deprivation that causes a rearrangement in the
    cortical map of the body surface.

12
ANATOMICAL PATHWAYS MEDIATING PLASTICITY Pathways
for Potentiation and Horizontal Transmission
  • Experience-dependent plasticity is CORTICAL in
    nature.
  • Lesions of the septal region lying between the
    edges of two neighboring barrels have been found
    to be sufficient to prevent HORIZONTAL
    TRANSMISSION displaying strong evidence for
    INTERCOLUMNAR CONNECTIONS.
  • Horizontal pathways have been shown to form in
    extragranular layers of cortex following STROKE
    and PERIPHERAL AMPUTATION.
  • Layer II/III cells have large dendritic spread
    spanning the same horizontal dimensions as the
    width of a barrel.

13
ANATOMICAL PATHWAYS MEDIATING PLASTICITY
Pathways for Depression and Vertical
Transmission
  • Deprived or missing sensory pathways contract,
    displaying weaker responses to stimulation in
    corresponding columns.
  • Due to minimal layer IV plasticity in older
    animals, depression is likely to occur in
    VERTICAL PATHWAYS projecting out of layer IV to
    layer II/III above and to later V below.
  • Layer V cells in deprived columns also show
    centre receptive field (principal whisker)
    depression following whisker deprivation.

14
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

15
MOLECULAR PATHWAYS MEDIATING PLASTICITY 1.
Mechanisms for Potentiation a) NMDA and
metabotropic glutamate receptors (mGluRs) b)
Calcium/calmodulin-dependent kinase type II
(CaMKII) c) Nitric oxide synthase (NOS) 2.
Mechanisms for Depression a) Protein Kinase A
(PKA) and GluR1 b) Cannabinoid
receptor-dependent mechanisms
16
  • MOLECULAR PATHWAYS MEDIATING PLASTICITY
  • Mechanisms for Potentiation
  • a) NMDA and metabotropic glutamate receptors
    (mGluRs)
  • NMDA receptors are involved in LTP and some forms
    of LTD, therefore, may be involved in both
    potentiation and depression mechanisms in vivo.
  • NMDA receptors play a role in synaptic plasticity
    of the layer IV to II/III pathway, and reveals a
    role for mGluRs.
  • LTP is restored in this pathway if NMDA
  • receptors are antagonized, which could
  • indicate that NMDA-dependent LTD is
  • enhanced in spared columns and overwrites
  • any LTP that might occur.

17
  • MOLECULAR PATHWAYS MEDIATING PLASTICITY
  • Mechanisms for Potentiation
  • b) Calcium/calmodulin-dependent kinase type II
    (CaMKII)
  • Appears to be necessary for LTP in the
    hippocampus and neocortex due to its ability to
    phosphorylate AMPA receptors.
  • Experience-dependent potentiation in the barrel
    cortex has been found to be dependent on CaMKII,
    raising the possibility this is related to LTP
    mechanisms.
  • CaMKII retains a memory of past synaptic
    activity by phosphorylating itself (threonine-286
    site), prolonging its activity.

18
  • MOLECULAR PATHWAYS MEDIATING PLASTICITY
  • Mechanisms for Potentiation
  • c) Nitric oxide synthase (NOS)
  • LTP and experience-dependent plasticity
  • in the cortex appear to be strongly dependent
  • on the neuronal form of NOS.
  • NOS is the source of the retrograde messenger NO,
    implicated in LTP in the hippocampus, and a
    substrate for phosphorylation by CaMKII.
  • NOS is required for plasticity in the layer IV to
    II/III pathway, and when blocked, prevents
    pre-synaptic potentiation leaving the
    post-synaptic component intact.

19
MOLECULAR PATHWAYS MEDIATING PLASTICITY 1.
Mechanisms for Potentiation a) NMDA and
metabotropic glutamate receptors (mGluRs) b)
Calcium/calmodulin-dependent kinase type II
(CaMKII) c) Nitric oxide synthase (NOS) 2.
Mechanisms for Depression a) Protein Kinase A
(PKA) and GluR1 b) Cannabinoid
receptor-dependent mechanisms
20
  • MOLECULAR PATHWAYS MEDIATING PLASTICITY
  • Mechanisms for Depression
  • Protein Kinase A (PKA) and GluR1
  • Inhibition of PKA does not affect the magnitude
    of LTP in the columnar IV to II/III pathway in
    mouse barrel cortex.
  • However, following whisker deprivation, LTP is
    larger in magnitude and sensitive to inhibition
    of PKA (DESATURATION).
  • Mechanisms involved in PKA-dependent potentiation
    could also act via the GluR-1 subunit of the AMPA
    channel (ser-845).

21
  • MOLECULAR PATHWAYS MEDIATING PLASTICITY
  • Mechanisms for Depression
  • b) Cannabinoid receptor-dependent depression
    mechanisms
  • Blocking cannabinoid receptors prevents LTD
    induction.
  • This form of plasticity requires pre-synaptic
    NMDA receptors.
  • Due to the fact that pre-synaptic receptors only
    occur in cortex early in life, it is possible
    that cannabinoid-dependent depression is limited
    to early life.

22
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

23
  • STRUCTURAL PLASTICITY IN THE SSC
  • 1. Dendritic Spine Plasticity
  • 2. Effect of Experience in Cortical Pre-Synaptic
    Structure
  • 3. Dendritic Plasticity

24
STRUCTURAL PLASTICITY IN THE SSC Dendritic Spine
Plasticity
  • Most () synapses are located at dendritic
    spines making them a major site for plasticity in
    the cortex.
  • Can be gauged by how rapidly new spines appear
    and disappear, which is an AGE-DEPENDENT PROCESS,
    is modulated by SENSORY EXPERIENCE, and display a
    faster turnover rate in the peri-infarct area.

25
STRUCTURAL PLASTICITY IN THE SSC Dendritic Spine
Plasticity

26
STRUCTURAL PLASTICITY IN THE SSC Effect of
Experience in Cortical Pre-Synaptic Structure
  • In addition to dendritic spines, axons are
    presumed to show plasticity.
  • Changes in spines are presumed to occur
    alongside changes in pre-synaptic terminals.
  • Newly-formed spines make contact with
    pre-synaptic boutons and form synapses.
  • Axonal arbours are largely stable in barrel
    cortex over long periods of time, however, some
    classes of axons reshape often and branches can
    elongate and retract by tens of microns/month.

27
STRUCTURAL PLASTICITY IN THE SSC Effect of
Experience in Cortical Pre-Synaptic Structure
  • Sensory experience affects the morphology of
    intracortical axons.
  • Peripheral nerve lesions also affects
    intracortical axon trajectories in mature
    animals.
  • Correspond with findings in monkey SSC, where
    long-term digit amputation, arm amputation and
    even wrist fracture can alter distribution of
    intracortical axons.

28
STRUCTURAL PLASTICITY IN THE SSC Dendritic
Plasticity
  • Lesion-induced plasticity also affects dendrites
    in the cortex.
  • EXAMPLE Denervation of vibrissae follicles
    causes a re-orientation of dendritic arbours in
    layer III and layer IV of adult rats.

Tailby et al., 2005, Proc. Natl. Acad. Sci., Vol.
102
29
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

30
  • PLASTICITY, STABILITY AND GENE EXPRESSION
  • 1. Epigenetic Mechanisms for Providing Synaptic
    Stability
  • 2. Experience-Dependent Gene Expression
  • Effects of HDAC (histone deacetylase) inhibitor
    trichostatin on plasticity, and the role of CREB
    as an example of gene expression leads to lasting
    changes in synaptic transmission.

31
PLASTICITY, STABILITY AND GENE EXPRESSION Epigenet
ic Mechanisms for Providing Synaptic Stability
  • Several molecules present at the synapse directly
    involved in synaptic transmission are
    continuously turned over and recycled.
  • GluR2
  • PKA
  • HDAC

32
PLASTICITY, STABILITY, AND GENE
EXPRESSION Experience-Dependent Gene Expression
  • CREB regulates transcription when it is caused to
    dimerize following phosphorylation of PKA.
  • Appears to be required for late-phase
    protein-dependent aspects of plasticity
    (hippocampal LTP).
  • Inducible cAMP early repressor (ICER) is a (-)
    feedback gene that requires CREB for activation,
    but then acts to reduce any further CREB
    expression.
  • BDNF (maturation of silent synapses) and
    neuritin-1 (CPG15) (regulates growth of axonal
    and dendritic arbours) are genes associated with
    plasticity that have promoters that bind to CREB.

33
  • OUTLINE
  • Introduction
  • Anatomical pathways mediating plasticity
  • Molecular pathways mediating plasticity
  • Structural plasticity in the somatosensory cortex
  • Plasticity, stability and the role of gene
    expression
  • Remaining questions

34
  • REMAINING QUESTIONS
  • Differential plasticity mechanisms (e.g.,
    hippocampal vs. neocortical).
  • Inhibitory plasticity mechanisms.
  • Molecular mechanisms that control spine growth
    and retraction.
  • Bias towards mechanisms in younger animals.

35
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