Transcript Long-term depression

Neural Plasticity
Lecture 7
Neural Plasticity
Nervous System is malleable
 learning occurs
 Structural changes
 increased dendritic branching
 new synapses
 Changes in synaptic efficiency
 Long-term potentiation
 Long-term depression ~

Neural Mechanism of Memory
Donald Hebb
 Short-term Memory
 Change in neural activity
 not structural
 temporary
 Reverberatory Circuits  cortical loops of activity ~

Reverberating Loops

Maintains neural activity for a period
 Activity decays ~
Hebb’s Postulate
Long-Term Memory
 required structural change in brain
 relatively permanent
 Hebb Synapse
 use strengthens synaptic efficiency
 concurrent activity required

• pre- & postsynaptic neurons ~
Long-term Potentiation
According to Hebb rule
 use strengthens synaptic connection
 Synaptic facilitation
 Structural changes
 Simultaneous activity
 Experimentally produced
 hippocampal slices
 associative learning also ~

Inducing LTP
Stimulating
electrode
Perforant
Pathway
Record
DG
Postsynaptic Potential
Single elec. stimulation
+
-70mv
-
100 stim. burst
Single stim.
Pattern Of Stimulation
Strong, high frequency stimulation
 Minimum stimulation
 1 + burst of 4
 4-7 Hz

• Theta

HC: Arousal & REM ~
LTP Duration
Experimentally-induced LTP
 Intact animals
 seconds - months
 HC slice
 40 hrs ~

LTP: Molecular Mechanisms
Presynaptic & Postsynaptic changes
 HC ---> Glutamate
 excitatory
 2 postsynaptic receptor subtypes
 AMPA ---> Na+
 NMDA ---> Ca++
 Glu ligand for both ~

NMDA Receptor
N-methyl-D-aspartate
 Glu binding opens channel?
 required, but not sufficient
 Membrane must be depolarized
 before Glu binds ~

Single Action Potential
Glu ---> AMPA
 depolarization
 Glu ---> NMDA
 does not open
 Mg++ blocks channel
 no Ca++ into postsynaptic cell
 Followed by more APs ~

Ca++
Na+
AMPA
G
G
Mg
NMDA
Mg
Na+
AMPA
G
Ca++
G
NMDA
Activation of NMDA-R

Ca++ channel
 chemically-gated
 voltage-gated
Mg++ blocks channel

Ca++ influx --->post-synaptic changes
 strengthens synapse ~
LTP: Postsynaptic Changes
Receptor synthesis
 More synapses
 Shape of dendritic spines
 Nitric Oxide synthesis ~

Before LTP
Presynaptic
Axon Terminal
Dendritic
Spine
After LTP
Presynaptic
Axon Terminal
less Fodrin
Less resistance
Dendritic
Spine
Nitric Oxide - NO
Retrograde messenger
 Hi conc. ---> poisonous gas
 Hi lipid solubility
 storage?
 Synthesis on demand
 Ca++ ---> NO synthase ---> NO
 Increases NT synthesis in presynaptic
neuron
 more released during AP ~

NO
cGMP
Glu
Ca++
G
NO
NOS
G
Ca++
The Cerebellum &
Long-term Depression
Cerebellum
Motor functions
 Coordination of movements
 Regulation of posture
 Indirect control
 Adjust outputs of descending tracts
 Also nonmotor functions
 memory/language ~

Cerebellum: Anatomy
Folia & lobules
 analogous to sulci & gyri
 Vermis - along midline
 output ---> ventromedial pathway
 Hemispheres
 output ---> lateral pathway
 Deep cerebellar nuclei
 fastigial, interposed, & dentate
 Major output structures ~

Cerebellum

Programs ballistic movements
 feed-forward control
no feedback during execution
direction, force, & timing
 long term modification of circuits
 Motor learning
 shift from conscious ---> unconscious ~

Cerebellum
Acts as comparator for movements
 compares intended to actual
performance
 Correction of ongoing movements
 internal & external feedback
 deviations from intended movement ~

Cerebellum: 3 layered cortex

Molecular layer
 parallel fibers
 axons of granule cells
runs parallel to long axis of folium

Purkinge cell layer
 large somas
 axons to underlying white matter
perpendicular to main axis of folium ~
Cerebellum: 3 layered cortex

Purkinge cell layer
 large somas
 axons to underlying
white matter
 perpendicular to
main axis of folium ~
Cerebellum: 3 layered cortex

Granular layer
innermost layer


small, densely packed granule cells
> # neurons in cerebral cortex ~
Cerebellum: 3 layered cortex
Molecular
Purkinje
Granule
Cerebellum: & Motor Learning
Purkinje cells only output from cerebellar
cortex
 inhibit deep cerebellar nuclei
 Input to Purkinje cells
 Mossy fibers via parallel fibers

from spinal cord & brainstem nuclei

climbing fibers
cerebral cortex & spinal cord
via inferior olivary nucleus ~
Cerebellum: & Motor Learning

1 Purkinje cell synapses..
 1 each with 200,000 parallel fibers
 Many with 1 climbing fiber
strong synaptic connections

Climbing fibers effects of mossy fibers
transient ~
Cerebellum: 3 layered cortex
Molecular
Purkinje
Granule
Climbing fibers
Mossy fibers
Cerebellum: & Motor Learning
Long-term depression (LTD)
 requires concurrent activity
 climbing & parallel fibers active together
  in activity of specific Purkinje cells
 Climbing fibers may carry error signals
 corrections ---> parallel fiber influence
 input specificity
 only affects active synapses of a parallel
fiber ~

LTD Mechanisms

Similar to LTP
 * changes are postsynaptic
 Glutamate receptors
LTD Mechanisms
*Requires concurrent activity
 Climbing fiber
1. Ca++ *influx - voltage-gated
 Parallel fibers activate
2. AMPA - Na+ influx
3. mGLUR1
 AMPA desensitized
  Na+ influx ~

LTD Mechanisms
mGluR1
 metabotropic
 cGMP-mediated
 intracellular Ca++ stores
 activation of phosphatases
 Knockout mice
 lack mGluR1
 loss of motor coordination ~
