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Learning and memory. The effects of genes and drugs. Synaptic Self. Joseph LeDoux. Penguin, 2002, New York. Excellent, enjoyable introduction to neurons, brain, memory and behavior. Types of memory.

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learning and memory

Learning and memory

The effects of genes and drugs

slide2
Synaptic Self. Joseph LeDoux. Penguin, 2002, New York.
    • Excellent, enjoyable introduction to neurons, brain, memory and behavior
types of memory
Types of memory
  • There is general agreement that there are several different types of memory, each of which is predominantly in a different part of the brain.
declarative vs procedural memory
Declarative vs. procedural memory
  • Declarative memory
    • explicit memory
    • facts, dates, events
    • Hippocampus is critical
  • Procedural memory
    • non-declarative/implicit
    • how to perform an action (ride a bicycle)
    • Basal ganglia is critical
slide5
Hippocampus is often first region to show damage in Alzheimer's disease
  • Patients with Alzheimer's disease are unable to learn or remember ordinary facts (declarative memory) but are normal or nearly normal at learning and remembering how to do things (procedural memory).
memory experiment
Memory experiment
  • Alzheimer's patients learned and remembered how to read complex words in a mirror as well as normal control subjects
  • Were unable to recall the training session or the fact that they had acquired this skill.
neurons
Neurons
  • Neurons are the cells that transmit information rapidly in the body.
  • Provide mechanism for faster responses to the environment
three main parts of neurons
Three main parts of neurons
  • Dendrites:
    • receive signals from sensors and/or other neurons
  • Cell body:
    • maintains cell
  • Axon:
    • sends signals to other neurons or muscles
synapse
Synapse
  • Neurons communicate with each other at synapses using chemical neurotransmitters.
slide13
Information usually flows across the synapse from the axon terminal (presynaptic) to the receiving neuron (postsynaptic)
  • Neurotransmitter released from the pre-synaptic neuron is detected by receptors on the post-synaptic neuron
how drugs act on synapses
How drugs act on synapses
  • Neurons communicate with each other at synapses using chemical neurotransmitters.
  • This provides the basis for drugs (and poisons) to affect synaptic transmission.
  • Drugs that have chemical properties similar in some way to those of neurotransmitters can act on synapses to alter behavior and thoughts (psychotropic or psychoactive drugs)
slide15
Drugs that increase synaptic transmission are "agonists".
  • Drugs that block or reduce synaptic transmission are "antagonists".
slide17
One type of neurotransmitter receptor present in synapse is the NMDA receptor
  • Involved in learning
  • Consists of subunit 1 (NR1) and one of various NR2 subunits.
slide19
NMDA receptors present in synapse of neurons involved in learning
  • Consist of subunit 1 (NR1) and one of various NR2 subunits.
  • Hypothesis: Increased expression of the NR2B subunit in mice will increase synaptic plasticity and improve memory
methods
Methods
  • Created several strains of transgenic mice that overexpressed NR2B subunit in the forebrain.
  • The transgenic mice have normal growth, body weight, mating behavior, and no obvious neurologic deficits.
  • Assays showed about twice as much NR2B protein in the cortex and hippocampus as in the wild type mice, and elevated levels in the amygdala.
performed several tests of learning
Performed several tests of learning
  • NR2B transgenic mice remembered previously-seen objects better than control mice (spent less time inspecting previously-seen object).
  • In water maze, NR2B mice learned significantly faster than wild-type.
slide22
Did same experiment with transgenic mice from two different genetic strains. Got same results for each strain.
  • Did similar experiments using contextual and cued conditioning (Pavlovian conditioning). NR2B animals had significantly better memory at 1 hour, 1 day, and 10 days.
slide24

Reversal of Age-related Learning Deficits and Brain Oxidative Stress in Mice with Superoxide Dismutase/catalase Mimetics

Liu, Liu, Bi, Thompson

background
Background
  • Loss of learning and memory function in aging mice is associated with increases in markers of brain oxidative stress.
  • Learning ability and levels of protein oxidation in brain are negatively correlation.
hypothesis
Hypothesis
  • Synthetic drugs (Superoxide Dismutase mimetics) that remove reactive oxygen species (ROS) are beneficial in reversing age-related learning deficits.
treat mice with sod mimetics
Treat mice with SOD mimetics
  • Assign female mice at 8 months old to 6 groups (16-18 per group)
    • control
    • untreated control
    • low dose EUK-189
    • high dose EUK-189
    • low dose EUK-207
    • high doseEUK-207
slide29
Minipumps implanted in anesthetized mice.
  • drug delivered for 28 days
  • low rate ~9 nmol/day
  • high rate ~ 90 nmol/day
  • Pumps replaced twice of over 3 months of treatment.
behavioral testing after 3 months
Behavioral testing after 3 months
  • Plexiglass cages.
  • Videocam to record freezing behaviour (indcates of fear conditioning).
  • Computer to control events.
  • Mice placed alone in clean chamber.
learning test
Learning test
  • Generate tone (e.g., 800 Hz), or context (particular cage)
  • Give mild electric footshock
  • Next day, generate same tone, or put mouse in context cage
  • Measure fear conditioning as % of time mice exhibit a freezing response (absence of all movement except breathing)
effects of sod catalase mimetic on fear conditioning learning
Effects of SOD/catalase mimetic on fear conditioning learning
  • control mice
    • 11 month old control mice show impaired learning and memory: low levels of freezing for both tone and context
  • mice treated with SOD mimetic
    • 11 month old mice treated with SOD mimetic show superior memory: increased tone and context freezing at both doses
slide34
Compared memory performance
    • 11 month old mice treated with SOD mimetic versus control mice at 8 months old
    • Similar performance in memory tests
    • Drug appears to reverse impairment of older mice
effects of sod catalase mimetic on brain oxidative stress
Effects of SOD/catalase mimetic on brain oxidative stress
  • Mimetics decreased age-related free-radical damage:
    • decreased lipid peroxidation
    • decreased protein oxidation
donepezil and flight simulator performance effects on retention of complex skills

Donepezil and flight simulator performance: Effects on retention of complex skills

J.A. Yesavage et al.

slide38
Donepezil is an FDA-approved drug used to treat Alzheimer’s disease.
  • Can donepezil improve memory in healthy adults?
slide39
Yesavage and colleagues performed a randomized, double-blind, parallel group, placebo controlled study to test the effects of the donepezil (5 mg/d for 30 days),
  • Memory test: Ability to remember a sequence of complex tasks in flight simulator
  • 18 licensed aircraft pilots, mean age of 52 years.
results
Results
  • After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p <0.05.
  • Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.
  • See also letter critiquing methodology and result.
slide41

The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function

Egan et al.

Cell, Vol. 112, 257–269, January 24, 2003,

background42
Background
  • Episodic memory – the ability to store and recall experiences and events – depends on the hippocampus.
slide43
BDNF
  • Brain-derived neurotrophic factor (BDNF) appears to play an important role in memory formation.
slide44
BDNF enhances synaptic transmission by facilitating synaptic vesicle docking.
  • Inhibition of BDNF signaling in rodents by gene knockout or infusion of antisense BDNF impairs spatial learning and memory.
slide46
A polymorphism in the human BDNF gene has been identified.
  • The polymorphism changes the amino acid at codon 66 from valine to methionine
  • Refer to as val66met
slide47
This polymorphism located in the 5' pro-BDNF-sequence, and thus is unlikely to alter the intrinsic biological activity of the mature protein.
  • However, the authors hypothesized that this polymorphism would affect intracellular processing and secretion of BDNF, leading to impairments in hippocampal function in humans.
  • They also hypothesized that BDNF genotype might be associated with genetic risk of schizophrenia.
methods48
Methods
  • To test these hypotheses, the authors examined the effects of the BDNF val66met substitution in a cohort of normal controls, patients with schizophrenia and their unaffected siblings.
effects of bdnf genotype on episodic memory
Effects of BDNF genotype on episodic memory
  • Examined the effects of BDNF genotype on measures of episodic memory in a cohort of 621 subjects, including
    • normal controls
    • patients with schizophrenia, and
    • their unaffected siblings
slide50
Evaluated memory using the Wechsler Memory Scale (WMS), a test of verbal episodic memory.
  • Delayed recall scores on WMS reflect the amount of information from two stories with 50 total elements that subjects are able to recall following a 0.5 hour delay.
results52
Results
  • Patients with schizophrenia had substantially lower scores compared to controls
results53
Results
  • Looking at all three groups (normal, patients, siblings)
    • BDNF genotype had a significant effects on memory scores (p=0.02).
  • Looking just at the 133 controls alone,
    • BDNF genotype had a significant effects on memory scores (p=0.008).
val and met bdnf expression in cultured hippocampal neurons
Val- and Met-BDNF expression in cultured hippocampal neurons
  • Egan examined the expression, processing, biological activity, and release of the two BDNF isoforms.
  • Expressed constructs containing either valBDNF or met BDNF attached to green fluorescent protein (GFP)
slide55
valBDNF-GFP
    • distributed throughout the cell body and extending to processes.
  • metBDNF-GFP
    • mainly in cell bodies
slide57
valBDNF-GFP
    • Neuronal activity-dependent secretion was normal.
  • metBDNF-GFP
    • Neuronal activity-dependent secretion was severely reduced and sometimes not detectable.
slide58
valBDNF-GFP-containing particles were often superimposed with punctuate staining for the synapse marker protein synaptophysin.
  • metBDNF-GFP showed no colocalization with synaptophysin.
slide59
metBDNF’s failure to localize at synapses may contribute to memory impairment and to schizophrenia.
clinical caveats
Clinical caveats
  • The authors point out several caveats with regard to this work.
  • 1. The magnitude of the effects of BDNF genotype on in vivo measures of hippocampal function is small. This is expected, given the likely polygenic aspects of these traits.
slide61
2. Spurious results can arise when ethnic groups are mixed ("population stratification").
  • Because the effects are found in a single ethnic group (European Americans) and because similar effects are seen in both normal controls in patients, the authors believe that stratification is unlikely to explain their results.
slide62
3. Genetic association per se cannot exclude a potential effect of another nearby SNP in linkage disequilibrium with val66met.
  • The authors re-sequenced the BDNF coding region in 16 subjects (32 chromosomes) and scanned for polymorphisms in 66 subjects.
  • Only one rare synonymous change was observed, suggesting that linkage disequilibrium to a nearby locus does not account for these results.
slide63
The authors argue that their demonstration that the met allele is both associated with relatively poorer hippocampal function in vivo and with impaired trafficking and regulated secretion in vitro indicates strongly that the effects in humans are due specifically to the met allele.
what determines intelligence
What determines intelligence?
  • Likely the cumulative effect of variations in large numbers of genes, plus environmental factors.
  • Exposure to chemicals and drugs during fetal development can adversely affect neuron growth, formation of synapses.
  • Future treatments may involve gene therapy to replace poorly-functioning genes.