Neuro Learning Memory Burrell 4/23/10 Ssom

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There are several types of learning and memory that can be divided in terms of _ and _

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content (what is learned)

temporal parameters (how much detail can be retained after seconds, hours, days, etc.)

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Non-associative learning
3 types

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Habituation
Dishabituation
Sensitization

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Non-associative learning
Habituation

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decrease in response to repetitive stimuli that is not the result of fatigue or sensory adaptation (learning to ignore irrelevant stimuli)

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Non-associative learning
Dishabituation

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increase in a habituated response due to the presentation of a very strong or salient stimulus

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Non-associative learning
Sensitization

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increase in response due to the presentation of a strong or salient stimulus

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Associative learning
(what)

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involves forming an internal, cognitive connection (association) b/w two environmental stimuli
2 basic forms

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Associative learning
2 basic forms

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Classical conditioning
Operant conditioning

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Associative learning
Classical Conditioning
(definition)

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learning that one stimulus acts as cue that predicts arrival of second stimulus (outcome)

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Associative learning
Classical Conditioning
(cue is also called _,
outcome stimulus called _,
2 things required for conditioning to occur)

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cue = conditioned stimulus (CS)
outcome stimulus = unconditioned stimulus (US)

For conditioning to occur:
(1) the CS and US must occur close together in time
(2) CS must occur before the US

Most of the time multiple CS-US pairings are required to learn the association

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Associative learning
Classical Conditioning
Pavlovian conditioning

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bell is neutral (wouldn't normally get response) and is the CS
Present steak shortly after bell rung, dog associates bell with steak
response elicited by steak is *unconditioned response* or UR b/c its a salient stimulus that produces a response by itself
This new response to the bell is the *conditioned response* or CR

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Associative learning
Classical Conditioning
unconditioned response (UR)

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dogs response to steak
(would normally respond to it)

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Associative learning
Classical Conditioning
conditioned response (CR)

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dogs response to bell
(wouldn't normally respond to it)

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Associative learning
Classical Conditioning
stimulus generation

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stimulus other than a CS to elicit CR
only works if second stimulus is sufficiently similar to CS
(responds to different pitched bell but not a horn)

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Associative learning
Operant Conditioning
(definition)

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behavior paired with reinforcing stimulus in such a way that anytime the behavior is expressed, the reinforcement is delivered
No specific stimulus that elicits the behavioral response to be reinforced and in initial stages the behavior to be modified is expressed randomly
reinforcing stimulus (delivered only after the behavior of interest is performed) rewards the performance of that behavior
(Skinner box experiments)

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Associative learning
Operant Conditioning
Skinner Box experiments

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rat in cage with lever, food dispenser
pressing the lever has no special meaning to rat, so probability of behavior is low
if food delivered every time the lever pushed, the lever-pressing increases as rat associates the two

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LTP: cellular-level process that may contribute to learning and memory

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LTP due to increase in synaptic transmission
thought that LTP initiated by co-activation of pre- and postsynaptic neurons acting as correlate of CS and US pairing
convergence of glutamate release presynaptically and depolarization due to postsyn activity activates NMDA receptors that initiate LTP

coincidence of signals:
CS with US leads to associative learning
pre- and postsyn activity leads to LTP
glutamate binding and depolarization leads to NMDA receptor activation and ultimately LTP

LTP early stages (hours) due to AMPA insertion
LTP later stages (days) due to growth of new (additional) synaptic connections

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Clinical Correlation
Deficits in LTP associated with animal models of Down syndrome

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many studies observed dysfunction in LTP and/or LTD in animal models that mimic cognitive disorders like Alzheimer's and mental retardation associated with Down or Fragile X syndrome
deficits in LTP observed in mice with Downs-like symptoms (deficits in learning and memory)
reversed the LTP and cognitive deficits by using antagonist for GABA receptors
No Tx anytime soon though b/c LTP/LTD not well understood and developing Tx extremely difficult

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Stages of Memory Formation

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Acquisition (actual learning of new stimuli) > Consolidation (storage of learned events into memory) > Retrieval (process of recalling what was learned)

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Declarative Memory
(memory for _ and _,
structures involved are _ and _)

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memory for facts (semantic memory) and events (episodic memory like personal recollections)
involves hippocampus and association cortices

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Declarative Memory
(input from _ carried to _ through _,
_ processes the info and sends thru _ back to _,
_ areas act to retain info over short term, and in these areas memories will ultimately be stored)

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association cortex to hippocampus thru entorhinal cortex
hippocampus processes and sends thru entorhinal cortex back to cortical regions that provided the original inputs
neocortical

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Declarative Memory
(what is consolidation, lesion to hippocampus effects)

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hippocampus acts as temporary buffer during formation of new declarative memories until the information is finally encoded in the neocortex

lesion to hippocampus can prevent encoding of long-term memory, but if interval b/w learned event and lesion is delayed by days or weeks, then long-term memory of event is spared

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Clinical Correlation
Henry Molaison

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bilateral resection of entire (piriform-amygdaloid-hippocampal) complex including hippocampal gyrus
produced severe anterograde amnesia (can't store new memories)
little retrograde amnesia
other cognitive skills intact
everyday is a new day for HM
restricted to declarative memory

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Procedural Memory
(memory of _,
large role in _)

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memory of how to perform motor skills
large role in sensorimotor adaptations that accompany our planned movements
we are largely unconscious of their contribution
ex: pressing numbers on keypad; first time very deliberate, repeated performance become faster

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Procedural Memory
(structures involved and their roles)

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striatum:
mediates procedural memory that enhances performance of motor skills (unconscious improvement)
cerebellum:
mediates procedural memory that alters reflexes in response to new learned stimuli
(ex. is eye-blink conditioning - air puff causes eye to blink

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Emotional Memory
(memory that _)

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stores info on preferences and aversion to events
we are unconscious of its contribution
may be concerned with facts or events, but independent of declarative memory

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Emotional Memory
(structure involved and role)

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amygdala:
necessary for fear conditioning - Pavlovian association b/w neutral stimuli and aversive stimuli that produces startle response

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Emotional Memory
(can have _ role on other types of memory)

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modulatory effect (especially on declarative)
we tend to remember events that have an emotional component better whether good or bad (9/11 vs. baby birth)

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Temporal Categories of Memory
(name)

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Immediate memory
Short term/working memory
long-term memory (LTM)

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Temporal Categories of Memory
Immediate memory
(duration, structures, ability to _, aka)

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< 1 second
brainstem, frontal cortex, other association areas
ability to hold ongoing events in the mind, a necessary process for normal attention
aka immediate recall

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Temporal Categories of Memory
Short-term/Working memory
(duration, structures)

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seconds to minutes
frontal cortex and other association areas

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Temporal Categories of Memory
Short-term/Working memory
(storage of info for _,
refers to capacity to _,
requires _
how test in clinical setting)

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storage of info for short period of time after event has passed
capacity to hold info long enough to carry out sequence of actions
requires intact frontal lobe
can be tested by asking patient to remember string of numbers presented in random order
normal digit span is 7-9 #s

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Temporal Categories of Memory
LTM
(duration, structures)

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hours to days to years
hippocampus and association cortex

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Temporal Categories of Memory
LTM
(_ encoding of info
requires _ and _ that produce changes in _ and _)

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relatively permanent encoding
requires modification of gene expression and new protein synthesis that produces changes in synaptic signaling (LTP & LTD) and neuronal excitability
may include growth of new synaptic connections

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For declarative memories, an inability to form new long term memories (anterograde amnesia) may indicate damage to either _ or _
inability to recall already established long term memories (retrograde amnesia) indicates _ damage

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hippocampus or association cortical regions

cortical damage

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Role of repetition and rest in long-term memory

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repetition can improve retention
benefit best when spread over time
"spacing out" of learning improves cellular processes that mediate consolidation and storage and
is a fundamental property of learning

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Dementia
(definition)

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a decline in memory and other cognitive functions (language, object recognition)

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Dementia
(types)

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Alzheimer's Disease (AD)
Vascular Dementia (Multi-infarct dementia)
Frontotemporal Dementia
Huntington's Disease
Lewy Body Dementia
Korsakoff's Syndrome
Creutzfeldt-Jacob

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Most common form of dementia

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AD

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AD
(fast or gradual progression of disease)

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relatively gradual progression

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Vascular Dementia (Multi-infarct dementia)

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2nd most common form (10-15% of dementia cases)
result of accumulated effects on many mini-strokes
can resemble AD, but more step-like progression

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Frontotemporal Dementia
(compare to AD, traits include _ _, has _ but no _)

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earlier onset than AD and more likely to cause dementia in people < 60
severe apathy and disinhibition (poor impulse control)
has neurofibrillary tangles of tau but
no Abeta plaques

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Huntington's Disease
effects _ memory since HD is disease of _

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procedural memory
disease of striatum

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Lewy Body Dementia
(can accompany _ Disease, especially early-onset forms
level of Dementia can _
another component is _)

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can accompany Parkinson's
level can fluctuate
Visual hallucinations are another element

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Korsakoff's Syndrome
(results from _
involves dysfunctions of _
_ is characteristic of this condition)

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thiamine deficiency
common among alcoholics
memory dysfunction: both retrograde and anterograde amnesia
confabulation (making up stories)

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Creutzfeldt-Jacob
_ progression and _ onset
_ and _ atrophy apparent in CT
caused by _

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rapid progression
early onset (40-50 yrs)
cortical and cerebellar atrophy
caused by prions (protein-like particles that replicate w/o DNA or RNA)

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Memory/cognitive dysfunction can also result from _ _ _ _

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seizure
blow to head
traumatic brain injury
various types of tumors

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AD
(prevalence)

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most common form of dementia in elderly
probability increases with age

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AD
(early stages characterized by _)

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impairment of ability to generate memories of recent events while
ability to recall remote facts is intact

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AD
(*initial impairment specific for _ memory suggesting _ dysfunction)

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*declarative memory*
hippocampal

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AD
progression characterized by continued decline in cognitive abilities including _ _ _ _

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visual agnosia (ability to ID simple objects)
language function (aphasia - can be mute at late stages)
apraxia (ability to carry out purposeful movements)
difficulty in navigation (getting lost)

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AD
eventually memory of _ and _ is affected

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recent and remote

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AD
4 neuropathological features

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(1) Extracellular deposits of amyloid-beta plaques (peptide generated by cleaving amyloid precursor protein)
(2) Intracellular accumulation neurofibrillary tangles (NFT) - these consist of micro-tubule associated protein tau
(3) loss of neurons starting in the hippocampus and progressing to other areas (neurodegeneration) - as much as 40% reduction in brain weight over course of disease
(4) loss of synapses

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Three genes that cause inherited, early-onset AD
(only 5% of all AD cases familial or inherited)

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Presenilin 1
Presenilin 2
Amyloid precursor protein (APP) gene
(may be more genes)

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What is amyloid-beta?

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40-42 aa peptide
synthesized by cleavage of amyloid precursor protein (APP)
transmembrane protein with unknown precise function but appears to be involved in neurodevelopment
normally present in brain at low (picomolar) concentration
could play role in regulating synaptic transmission

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amyloid-beta controversy

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are Abeta plaques the cause of AD
consensus seems to be modified hypothesis:
soluble or pre-plaque forms of Abeta (oligomers) are the toxic form agent in AD
levels correlate better with the level of dementia, and they are seen early in hippocampus, they disrupt synaptic transmission (LTP and LTD) and cause neuroinflammation and neurodegeneration
(the Abeta plaques don't correlate with progression and they develop first in cortex not hippocampus)

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Tau

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role of NFTs that form from tau during AD receiving more attention
matches progression better than Abeta plaques
found in hippocampus first then cortex
tau and Abeta may work together to produce symptoms of AD

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AD
Tx
(see notes for more info)

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Donepezil (Aricept) for mild to moderate AD:
cholinesterase inhibitor
memantine (Namenda): NMDA-receptor antagonist for moderate to severe AD
Abeta peptides and antibodies (Bapineuzumab in clinical trials - Phase III)
CV health appears to reduce AD probability (unknown why)
(see notes for more about all treatments)