synaptic plasticity

Basic Neuroscience NBL 120

classical conditioning

CS (neutral)- no response

US- UR

After pairing:CS- CR

ability to learn the relationship between different stimuli / events so that we can make reasonable predictions if we are faced with a certain situation

learning & memory => goodaddiction => bad

associative learning

learning & memory in taxi drivers

PET study during recall of London route

(Maguire et al, 1997)

place cells

some pyramidal cells in the hippocampus have preferred spatial orientations fire in bursts

(O’Keefe & Dostrovsky, 1971)

muscle

motor neuron

pre

post

control

muscle

motor neuron

nmj

how is a synapse plastic?

synapses “remember” previous activity short-term, e.g. post-tetanic potentiation at the nmj

time

Hebbian learning

longer term plasticityHebbian learning

Hebb (1949) hypothesized that “ if one neuron frequently takes part in exciting another, some growth process or metabolic change takes place in one or both cells and the strength of their connection increases ”

Johnson & Wu (1995)

hippocampal “integrated circuit”

in reality…..

before after

ampl

itude

time (hrs)

first demonstration of LTP

high-frequency train

rapid induction lasts weeks in vivo

Bliss & Lomo (1973)

properties of LTP

cellular mechanisms underlying LTP

inductionmaintenance

excitatory synaptic transmission

NMDA vs non-NMDA synaptic transmission

AP5

AP5

control

LTP depends specifically on NMDA receptor activation

AP5 prevents high frequency-induced LTP

(Collingridge et al, 1983)

what is special about NMDA receptors?voltage-gated channels: voltageligand-gated channels: transmitterNMDA receptors: both

+ - +

+++

- - -

out

in

Mg+

Mg+

NMDA receptor: a molecular switch

co-incidence detector requires both presynaptic

activity (glutamate) and postsynaptic depolarization (relieve Mg block) satisfies Hebbian co-incidence rules explains LTP properties:

specificity associativity / co-operativity spatial/temporal requirements

how does the NMDA receptor cause a change in synaptic strength?

synaptic transmission is unreliable

increased transmitter releasealtered or new receptorsnew synapses

NMDA receptors, hippocampus and LTP learning and memory

NMDA receptor-dependent learning

spatial memory task visual task

“Morris” water maze

Morris et al (1990)

LTP and learning

saturation of LTP prevents learning a new spatial task

new learning can occur after LTP decay

LTP decay

Castro et al (1989)

a natural LTP? animals raised in a complex environment show

enhanced synaptic responses in the hippocampus

Sharp et al (1985)

hippocampus= temporary memory storage

new patterns stored rapidly and transientlygradual transfer to neocortexlong-term storage with reduced interference

diffuse storage in cortex?

computational theoriesMarr (1970’s)sensory input to neocortex

stored by association repetition - association partial pattern recall

compulsive use / abuse of a drug despite adverse consequences

addiction - definition

recollections of an addict:recollections of an addict:

Skinner-boxlever-press > rewardrate reward

electrical self-stimulation

“a hungry animal often ignored available food in favor of the pleasure of stimulating itself electrically .... 2000 times per hour for 24 consecutive hours”

(Olds 1956)

“pleasure centers”

where are the pleasure centers?

medial forebrain bundle VTA - Nucleus Accumbens (after Koob 1992)

dopamine

DA neurons and reward

(Schultz et al, 1993)

drug abuse is a form of associative learning

associated cues could trigger “craving” nicotine is continuously

paired with taste and smell of cigarettes

heroin or other drug use may be associated with a specific setting

evidence………….

VTA DA response becomes associated with the sound cue i.e. DA response predicts reward

learning

predicting reward

displacement of [11C]raclopride binding by DA release

“craving”PET scan

(Volkow et al, 1997)

MP = methylphenidate “RITALIN”

what happens to DA in addicts?

associations - summary

synaptic plasticity hippocampus / cortex NMDA receptor - coincidence detector Mg2+ & Ca2+

addiction midbrain - VTA / Nucleus Accumbens Dopamine predictive cues

(from McNaughton & Morris, 1987)

in theory…..