Memory

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Memory the Medial Temporal Lobe

• Lecture 25

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Short-term Memory - STM

• Info currently in consciousness
• Limited capacity
• Limited duration

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Long-term - LTM

• Info from STM
• Large capacity
• Relatively permanent
• Info retrieved into STM

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Memory Model
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Long-Term Memory

• Hebb - structural change in brain
• relatively permanent
• Hebb Synapse -
• use strengthens synaptic efficiency

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Short-term Memory

• Hebb -
• Change in neural activity
• not structural
• temporary
• Reverberatory Circuits -
• cortical loops of activity
• Maintains neural activity for a period

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Reverberating loops

• Activity decays
• maintained for only a short period of time

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Long-Term Memory

• Hebb - structural change in brain
• relatively permanent
• Hebb Synapse -
• use strengthens synaptic efficiency

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Long-term Potentiation

• Hebb rule
• use strengthens synaptic connection
• Synaptic facilitation
• Structural changes
• Simultaneous activity
• Experimentally produced
• hippocampal slices
• associative learning also

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Inducing LTP
Stimulating electrode
Record
Perforant Pathway
DG
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Postsynaptic Potential
Single elec. stimulation
100 stim. burst

Single stim.
-70mv
-
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Pattern Of Stimulation

• Strong stim.
• High frequency
• Minimum stimulation
• 1 burst of 4
• 4-7 Hz
• Theta
• HC Arousal REM

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LTP Duration

• Intact animals
• seconds - months
• HC slice
• 40 hrs

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LTP Molecular Mechanisms

• Presynaptic Postsynaptic changes
• HC ---gt Glutamate
• excitatory
• 2 postsynaptic receptor subtypes
• AMPA ---gt Na
• NMDA ---gt Ca
• Glu ligand for both

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NMDA Receptor

• N-methyl-D-aspartate
• Glu binding opens channel?
• NO
• Membrane must be depolarized

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Single Action Potential

• Glu ---gt AMPA
• depolarization
• Glu ---gt NMDA
• does not open
• Mg blocks channel
• no Ca into postsynaptic cell
• Followed by more APs

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Long-Term Memory

• Hebb - structural change in brain
• relatively permanent
• Hebb Synapse -
• use strengthens synaptic efficiency

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Ca
Na
G
G
AMPA
NMDA
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Activation of NMDA-R

• Ca channel
• chemically-gated
• voltage-gated
• Mg blocks channel
• Ca influx ---gtpost-synaptic changes
• strengthens synapse

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LTP Postsynaptic Changes

• Receptor synthesis
• More synapses
• Shape of dendritic spines
• Nitric Oxide synthesis

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Before LTP
Presynaptic Axon Terminal
Dendritic Spine
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After LTP
Presynaptic Axon Terminal

• less Fodrin
• Less resistance

Dendritic Spine
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Nitric Oxide - NO

• Hi conc. ---gt poisonous gas
• Hi lipid solubility
• storage?
• Synthesis on demand
• Ca ---gt NO synthase ---gt NO
• Retrograde messenger
• Increases NT synthesis in presynaptic neuron
• more released during AP

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Ca
G
G
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Memory Model
Amnesia Syndromes

• Short-term memory
• Long-term memory
• Declarative - Explicit
• Episodic autobiographical
• Semantic generic
• Nondeclarative
• Procedural motor skills, etc.

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H.M.

• Greatest contribution to study of memory
• cant remember any of it
• Bilateral medial temporal lobectomy
• to control seizures
• hippocampus amygdala
• midline structures

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Some Abilities Intact

• Personality
• Intelligence
• LTM
• Verbal STM memory OK
• Motor skills

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Retrograde vs. Anterograde Amnesia
Retrograde
Anterograde
time
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Evidence of deficits

• Block tapping memory span
• Matching to sample
• verbal OK - rehearsal
• nonverbal impaired - ellipses

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Initial Conclusions

• Removal of hippocampus (HC) ---gt deficits
• STM not stored in HC
• LTM not stored in HC
• able to retrieve old memories
• HC transfer from STM to LTM
• H. M. - global anterograde amnesia

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Conclusions
Evidence of Spared Memory

• Mirror drawing
• Tower of Hanoi

• Performance improved w/ practice
• no memory of performing tasks
• What type of memory tasks
• procedural
• Procedural memory OK

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Revised Conclusions

• Procedural memory OK
• normal acquisition
• Priming
• motor skills
• conditioning
• Deficits limited to episodic semantic
• HC ---gt declarative memories

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Korsakoffs Syndrome

• Deficits similar to H.M.
• anterograde
• retrograde more severe
• Long-term alcohol abuse
• Thiamine deficiency
• vitamin B1
• required for glucose utilization

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Damage to Diencephalon

• Hypothalamus
• Mammilary bodies mammilothalamic tract
• Anterior Nucleus Thalamus
• Dorsomedial nucleus
• reciprocal inputs w/ prefrontal cortex
• temporal sequence

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Alzheimers Disease

• Moderately common in old age
• 1/4 of all 85 yr olds
• 4 million in U.S.
• Senility not due to age
• Dementia slow death
• 100,000 yr

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• Cause unknown
• Aluminum, Zinc?
• Inherited?
• Effects on memory
• Procedural O.K.
• Declarative deficits
• Diagnosis confirmed at autopsy
• brain atrophy
• plaques and tangles

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Neurofibril Tangles

• Inside neuron
• Abnormal proteins
• Forebrain cortex

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Amyloid Plaques

• Extracellular
• Beta Amyloid protein
• Degenerating neurons
• Found in everyone
• Abundant in Alzheimers patients

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Alternate Enzymatic Splicing?

• Beta amyloid precursor protein
• BAPP
• Cleaved by enzyme
• normal protein
• beta amyloid

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Alternate splicing model BAPP
Protease regulating region
amyloid Beta region
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Alternate splicing model BAPP
Normal splicing
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Alternate splicing model BAPP
Alternative splicing
Beta amyloid
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Genetic Model

• Very old - mild nonfamilial form
• Genetic form
• chromosome 21
• BAPP gene encoding amyloid Trisomy

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• Downs Syndorme
• Adults ---gt Alzheimers
• not same origin
• Correlation age of onset variant of gene
• Apolipoprotein E - APOE
• gene test for AD
• Also chromo 17 19 role

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Cholinergic Degeneration

• Decreased Cholinergic activity
• Receptors?
• NO
• ACh neurons - YES
• Nucleus Basalis of Meynert

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Treatment?

• Choline?
• not effective
• ACh agonists?
• AChesterase inhibitors
• Tacrine
• effective in 33
• Tissue transplants

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Chronic Inflammation Model

• indomethacin slowed progression
• Anti-inflammatory (NSAID)
• Arthritic patients treated with NSAIDs
• less likely to have Alzheimers
• Microglia
• phagocytosis
• inflammatory response

48
New Developments

• Role of beta amyloid Tau
• cause or effect?
• Abnormal beta amyloid is causal
• successfully blocked
• triggers changes in Tau
• Tau
• neurofibrillary tangles are toxic
• Detected beta amyloid in CSF