LEARNING AND MEMORY I:

TYPES OF MEMORY
 Summary of last lecture

• Emotions
– Expression in humans, animals
• Human: faces, eyes important
• Body also involved in expression (autonomic)
– Experience
• Subjective feeling
– Which comes first?
• Amygdala activation, autonomic response without perception
– Different regions active with different emotions
• Temporal lobes required for fear/aggression perception, generation
– The amygdala activity associated with enhanced emotional memory
– Both sham and predatory aggression controlled by hypothalamus (different regions)

• Sleep
– Biological benefits: energy conservation, avoid predators, restore body, consolidate memories
– EEG monitors synchrony in cortex
• Different rhythms in wake, sleep stages; conserved across animals
• Generated in thalamus
– Stages of sleep (REM/non-REM)
– Dreaming: replay of experience, memory consolidation
– Narcolepsy: hypothalamic deficit in orexin-producing neurons
– SCN sets circadian rhythms, driven by cyclic expression/degradation of clock genes
 Outline for today
What is memory?

Types of memory and where it is stored

Declarative memory: working memory, short-term memory,

consolidation
• Episodic (experience) or semantic (facts)
• Role of medial temporal lobe (H.M.)

Nondeclarative (implicit) memory

• Associative (reinforcement learning)
– classical/Pavlovian (fear conditioning)
– instrumental/operant
– Procedural (motor skills), role of cerebellum
• Non-associative (habituation, sensitization)
 Outline for today
What is memory?

Types of memory and where it is stored

Declarative memory: working memory, short-term memory,

consolidation
• Episodic (experience) or semantic (facts)
• Role of medial temporal lobe (H.M.)

Nondeclarative (implicit) memory

• Associative (reinforcement learning)
– classical/Pavlovian (fear conditioning)
– instrumental/operant
– Procedural (motor skills), role of cerebellum
• Non-associative (habituation, sensitization)
 What are learning and memory?

Learning = acquisition of memories

• modify behavior with experience
• build new knowledge / skills

Consolidation = solidification of new memory

Memory = retention of learned information

• Allows adaptation to environment much faster than evolution
• Major element of individuality

Engram = the memory trace in the brain

Recall = retrieval of memory

Amnesia = memory failure

 Amnesia
Causes: concussion, alcoholism, brain injury, encephalitis, tumor, stroke…
Dissociated amnesia: no other deficits

Anterograde amnesia: no new memories (consolidation impaired)

Retrograde amnesia: forget existing memories (recall impaired)
rarely absolute: oldest memories are strongest

Transient global amnesia (changes in cerebral blood flow, concussion)

brief anterograde amnesia (minutes-days)
 Getting hit on the head can cause amnesia.
Clickers:
(A) True
(B) False
True
Traumatic brain injuries, including sports injuries, can
cause retrograde amnesia over time.
 Types of memory
• Working, short term

• Declarative (explicit): conscious recall of names, facts, events; formed & forgotten easily
• Episodic: autobiographical life experiences
• Semantic: facts
• Spatial: maps

• Non-declarative (implicit): unconscious recall; take longer to form & forget

• Procedural: skills, habits, behaviors (e.g. riding a bike)
• Non-associative: change in response to a single stimulus
• Habituation (repeated)
• Sensitization (in presence of other, strong stimulus)
• Associative / reinforcement: association between two events
• Classical (Pavlovian) conditioning – involuntary (emotional learning)
• Instrumental (Operant) conditioning – motivated (learning about
consequences)
 Different parts of the brain contribute to
different types of learning, on different timescales

Cortex:
Basal ganglia: Many types of learning.
Reinforcement and habit learning Learns relatively slowly.

Hippocampus:
Humans- acquisition of declarative memories.
Rodents- contextual conditioning (e.g.
contextual fear conditioning). Cerebellum:
Learns relatively quickly. motor skill learning.
Types of memory and where they are stored
 Outline for today
What is memory?

Types of memory and where it is stored

Declarative memory: working memory, short-term memory,

consolidation
• Episodic (experience) or semantic (facts)
• Role of medial temporal lobe (H.M.)

Nondeclarative (implicit) memory

• Associative (reinforcement learning)
– classical/Pavlovian (fear conditioning)
– instrumental/operant
– Procedural (motor skills), role of cerebellum
• Non-associative (habituation, sensitization)
 Declarative memory

• Explicit, conscious; names, facts, events

• Duration varies:
• Working memory (seconds)
• Short-term memory (seconds to hours)
• Long-term memory (up to a lifetime)

Consolidation: STM (short term)  LTM (long term)

Ultimately stored in cerebral cortex (?)

 Memory operates on different timescales

• Working memory
consolidation

• Seconds (e.g., arithmetic, phone number)

• Limited capacity, requires rehearsal
• Different modalities stored in different areas

• Short-term
• Seconds to minutes, vulnerable to disruption

• Long-term
• Hours to years

• Mechanistically distinct (next lecture)

 The briefest memories: working memory

• Different from short-term: very transient, tiny capacity, requires rehearsal

• Replay circuit kept active: no lasting storage
• Can read stimulus from firing rates, in absence of stimulus
• Phone number, credit card number (chunked), wifi password…

• Capability of many regions of neocortex, including prefrontal cortex

• delayed-response tasks, Wisconsin card-sorting task, tracing mazes all use working memory
• All need PFC
 Testing working memory:
the delayed match / non-match-to-sample task

Bilateral medial temporal lobe lesions (hippocampus,

amygdala, entorhinal cortex)

• Impair declarative memory (anterograde amnesia)

• consolidation impaired (not modality specific)

• Working memory (seconds delay),

procedural memory intact
 Neural correlates of memory in primate PFC:
which cell might encode working memory?

Cell A: fires when animal sees food

in delayed-response task

Cell B: fires during delay period

Sees food Chooses

 Honeybees can perform
a delayed match-to-sample task (working memory)
Activity in human PFC during working memory tasks

Activity during the delay in many parts of

prefrontal cortex

Different areas for identity, location of face

Cortical areas outside frontal lobe also fire

during working memory (e.g., lateral
intraparietal cortex, or LIP); modality-specific
 Outline for today
What is memory?

Types of memory and where it is stored

Declarative memory: working memory, short-term memory,

consolidation
• Episodic (experience) or semantic (facts)
• Role of medial temporal lobe (H.M.)

Nondeclarative (implicit) memory

• Associative (reinforcement learning)
– classical/Pavlovian (fear conditioning)
– instrumental/operant
– Procedural (motor skills), role of cerebellum
• Non-associative (habituation, sensitization)
 Long-term declarative memory:
what we usually mean when we talk about memory

Semantic (facts, concepts)

Episodic (events, experiences)

Long-term memory of these = the “engram”. Where is it?

Donald Hebb’s model of
declarative memory

• Internal representation of object = all cortical cells it activates

(cell assembly, reciprocally interconnected)
• Involves neurons of sensation, perception
• Activity in assembly = working memory
• With time, connections get stronger:
fire together, wire together

• Distributed engram
• Less vulnerable to disruption
• Basis of computer neural nets

• Lashley (Hebb’s mentor):

• information must pass through medial temporal lobe en
route to cortex
 The medial temporal lobe (includes hippocampus):
gateway to long-term declarative memory

Medial temporal lobe =

Hippocampus + entorhinal, perirhinal, parahippocampal cortex

Inputs: association areas of cortex (e.g., IT)

Major output: fornix thalamus, hypothalamus

 Evidence for role of human medial temporal lobe
in episodic memory
• Stimulation can trigger recollections?
• Temporal lobe epilepsy: feelings of familiarity / infamiliarity, recollections / flashbacks
• Electrical stimulation in patients recollections of autobiographical (episodic) memory

• Recordings show neurons with preferential responses to categories of objects, or specific

people/places

• Lesions disrupt memory (Lonnie Sue Johnson, H.M.)

Lonnie Sue Johnson

• Grew up in Princeton; accomplished graphic

artist, musician, pilot, dairy farmer…

• In 2007, viral encephalitis completely destroyed

her hippocampus

• Severe retrograde and anterograde amnesia

• Procedural memory (viola) intact
• Can’t remember she played
• Can learn to play new music

• Nick Turk-Browne, Princeton: statistical learning

impaired (can’t detect patterns in sounds,
shapes, scenes)
 H.M. (Henry Molaison): patient whose experience led to
important insights about neural basis of learning and memory

Increasingly severe seizures:

unable to work / drive, frequent
falls / accidents /
unconsciousness
HM had experimental surgery (last-ditch treatment for severe
epilepsy, 1950s): bilateral medial temporal lobe excision

• Removed ¾ of hippocampus, surrounding regions

• Seizures improved; perception, intelligence, personality intact
• Severe memory impairment
 Surgery helped his epilepsy,
but could not form a new explicit memory
• Complete anterograde amnesia (never learned
caretaker’s names)

• Partial retrograde amnesia (could still access some

memories from >3 years before surgery)

• Working memory & procedural memory intact

• Improved at task—but couldn’t remember doing it before

Explicit memory requires conscious thought

(e.g. remembering what you had for dinner last night, where you met someone)
 Role for areas beyond medial temporal lobe in
memory formation: patients N.A., R.B.

N.A.:
• Left dorsomedial thalamus damage (mini fencing foil)
• Severe anterograde amnesia, and retrograde for ~2 years
prior to injury

R.B.: bilateral hippocampal damage: moderate anterograde

amnesia

Current hypothesis
Required for normal formation of new memories (damage 
anterograde amnesia) includes:
• Hippocampus
• Entorhinal, perirhinal cortex
• Thalamus / mammillary body
 Evidence for role of hypothalamus in memory:
Korsakoff’s syndrome
• Chronic alcoholism thiamine deficiency
• Damage to dorsomedial thalamus, mammillary bodies
• Can be severe anterograde (consolidation impaired) AND / OR
retrograde (recall impaired) amnesia
• OR suggests consolidation & recall have separable mechanisms
 What we learned from H.M.

Medial temporal lobe:

• Critical for consolidation (formation) of explicit / declarative memories

• Not required for working memory
• Not required for formation or retention of procedural memory
• Not required for retrieval of older existing memories

Where are older declarative memories stored? Neocortex.

Relevant for Alzheimer’s? Medial temporal encephalitis

 Memory storage in neocortex:
different types in different regions
Working memory: cortical lesions can sometimes only
affect memory of seen or spoken numbers

Long-term explicit memory: Does remembering involve

reactivating sensory and motor components of event
that lead to forming memory?

Word (DOG) paired with either a picture or sound (bark)

Instruction: vividly recall dog
- Remembering picture? Visual areas active
- Remembering sound? Auditory areas active
Systems consolidation: memories may migrate from
hippocampus to cortex over time
Standard model:
• Hippocampus forms & stores new episodic memories
• Hippocampus “trains” cortex, where remote memories are
stored

(HM: lost hippocampus: anterograde amnesia, but also some

years-long retrograde…not consolidated yet?!)

Multiple trace model:

• Engrams continue to involve BOTH
hippocampus and cortex

Helps explain extended retrograde amnesia

with hippocampal damage

Each time memory retrieved (new context),

new trace, so old memories have most
traces, are most robust
 Modifying existing memories: reconsolidation
(consistent with multiple trace model?)
• Reactivating memories may make them vulnerable to modification or erasure

• Of concern in witness testimony?

• Of use in treating PTSD?

 Creating false memories?
False memories might be created by directly activating hippocampal neurons during aversive stimuli

Cells active when in Box A: In Box B, turn on the Animal freezes

make an “on switch” protein “Box A” cells, in Box A Animal doesn’t
(ChR2) give shock (created fear memory?) freeze in novel Box
STRETCHING AND QUESTION BREAK
Declarative memory functions of the hippocampal system
Roles in:
• Linking sensory information (facts / events people / objects)
• Spatial memory (where objects are)
• Memory consolidation / storage (duration under debate; includes working memory?)

Testing memory in rodents: radial arm maze and Morris water maze

Hippocampal lesions: re-visit

same arms (working memory
deficit, procedural OK)
Hippocampal lesions:
fail to remember platform location
 Spatial memory: hippocampal place cells
Human place cells?
Hippocampal place cells fire at given location in environment
Activity in hippocampus
(“place field”); remap when learning new environment
while navigating in a video game
(but not if following arrows!)

Loss could impair memory of arms visited in radial arm maze, London taxi drivers:
platform location in water maze larger posterior hippocampus

TT: 40 years London taxi driver,

then bilateral hippocampal
damage
OK on main roads, not side
streets
 Place cells + grid cells: the brain’s “inner GPS”
• Place cells = in hippocampus

• Grid cells: upstream of hippocampus, in entorhinal

May-Britt Moser, Edvard Moser, and
cortex John O’Keefe: Nobel prize, 2014

• Respond when animal is at multiple locations that

form a hexagonal grid

• Different grid cells: different grid spacings

• all tile the environment (at different resolutions)

Place cell Grid cell

 Are place cells in hippocampus the result of
convergent inputs from grid cells in entorhinal cortex?
Grid cells fire at multiple locations
Place cells fire at a given location
arrayed on a grid
= location where specific set of grid cells all fire?
Different cells: different grid sizes
 Brain training software can improve
cognition and memory
Clickers:
(A) True
(B) False False
Exaggerated and misleading claims of the brain training industry
exploit anxiety about impending cognitive decline.

Lumosity was forced to pay a settlement for false advertising.

 Can you do anything to improve your
declarative memory?
Besides sleeping enough, eating well, and exercising?

Maybe.

Focus, don’t multitask

Engaging spatial memory may improve learning

• Mnemonics: the method of loci / mental walk / “mind palace”

• Greek poet Simonides of Ceos, 477 BC
• Solomon Shereshevsky (studied by Luria, 1920s; The Mind of a
Mnenonist)

• Winners of World Memory Championships:

• Use mnemonics when memorizing
• Spatial memory areas activated during memorization, recall
 Extraordinary memory

Artist Stephen Wiltshire:

Detailed cityscapes from memory

Jill Price: first person identified Violinist Louise Owen: can

with Highly Superior remember details of every day
Autobiographical Memory since age 11
(HSAM) (“I see it on a calendar”)
“Like living with a split screen”
Actress Marilu Henner: explicit
autobiographical memory for
almost every day of her life
• HSAM: about 60 known

• MRI: in some, significantly larger temporal

lobes and caudate nuclei

• Cause or effect?
 Outline for today
What is memory?

Types of memory and where it is stored

Declarative memory: working memory, short-term memory,

consolidation
• Episodic (experience) or semantic (facts)
• Role of medial temporal lobe (H.M.)

Nondeclarative (implicit) memory

• Associative (reinforcement learning)
– classical/Pavlovian (fear conditioning)
– instrumental/operant
– Procedural (motor skills), role of cerebellum
• Non-associative (habituation, sensitization)
 Nondeclarative memory:
procedures, associations, habits and sensitivities
 Different parts of the brain contribute to
different types of learning, on different
timescales
Cortex:
Basal ganglia: Many types of learning.
Reinforcement and habit learning Learns relatively slowly.

Hippocampus:
Humans- acquisition of declarative memories.
Rodents- contextual conditioning (e.g.
contextual fear conditioning). Cerebellum:
Learns relatively quickly. motor skill learning.
Two types of trial-and-error associative learning
Reinforcement and habit learning (basal ganglia)

Hmmm, where should

I throw to get a
big reward?

$100!
Goal learned
Wrong guesses don’t suggest correction
Guess right: DA reinforcement signal!
Includes Pavlovian and Operant

Supervised Learning (cerebellum)

Whoops!
I missed to the right.
Next time I should throw
more left

Goal known
Mistakes  correction
When you hit target, no error signal
 Categories of nondeclarative memory
• Associative: connecting multiple events
• Classical (Pavlovian) conditioning – involuntary
• Instrumental (Operant) conditioning - voluntary

• Non-associative: change in response to a single stimulus

• Habituation (ignore the irrelevant)
• Sensitization (pay more attention to the important)
 Pavlovian (aka classical) conditioning:
associating neutral stimulus (conditioned stimulus, CS) with
reward or punishment (unconditioned stimulus, US)

Also:
• Cued fear conditioning
(amygdala)

• Contextual fear conditioning

(hippocampus)
 Operant (aka instrumental) conditioning:
associating an action
with reward or punishment (unconditioned stimulus, US)

Involves motivation, includes animal models of addiction

(Press lever to receive dopamine, stimulation of DA neurons, cocaine…)
Requires striatum / basal ganglia
 Nondeclarative memory:
Pavlovian vs operant conditioning

Classical / Pavlovian conditioning

Produce new response (drool) to neutral stimulus (CS; bell)
after repeatedly pairing with stimulus that induces a response
(US; food)

Instrumental / Operant conditioning

Goal-directed; learning through consequences of behavior
(role of reward prediction error)
Timing is crucial (close is best)
Used in many experiments (testing visual perception, etc)

Shared between both: extinction

(stop reinforcing, behavior diminishes)
 Reinforcement learning is
associative learning

Change in behavior
based on experience with rewards / punishments

Reinforcement learning is ubiquitous, and shapes

our everyday decisions
Addiction: pathological reinforcement learning
in the brain’s reward circuits

, opiates

alcohol
 Nondeclarative memory: Habit / procedural learning
HM could still learn new habits

In mice, Hippocampal lesions disrupt formation of new declarative memories (“already checked that arm”)

Striatum fires during, required for habit learning (“go to maze arm with light”)
firing pattern changes as habit develops

Lesions of striatum disrupt formation of new procedural memories without affecting declarative memory

Changes in recordings from rat striatum:

trace of habit formation?
 Nondeclarative / procedural memory impairments
In Huntington’s and Parkinson’s
(damage to basal ganglia)
Huntington’s
• Kills neurons in striatum
• Uncontrollable movements

Parkinson’s
• Kills inputs to striatum (substantia nigra)
• Difficulty initiating movements

Both:
• Impaired nondeclarative / procedural memory formation
– Intact nondeclarative recall
• Intact declarative memory formation
 Different parts of the brain contribute to
different types of learning, on different
timescales
Cortex:
Basal ganglia: Many types of learning.
Reinforcement and habit learning Learns relatively slowly.

Hippocampus:
Humans- acquisition of declarative memories.
Rodents- contextual conditioning (e.g.
contextual fear conditioning). Cerebellum:
Learns relatively quickly. motor skill learning.
Two types of trial-and-error associative learning
Reinforcement and habit learning (basal ganglia)

Hmmm, where should

I throw to get a
big reward?

$100!
Goal learned
Wrong guesses don’t suggest correction
Guess right: DA reinforcement signal!
Includes Pavlovian and Operant

Supervised Learning (cerebellum)

Whoops!
I missed to the right.
Next time I should throw
more left

Goal known
Mistakes -> correction
When you hit target, no error signal
 Supervised motor learning

• Cerebellum, striatum, basal ganglia

• According to consolidated theories, motor learning consists of three main
phases:
– Cognitive (involves attention; duration depends on complexity of task): frontal/parietal
– Associative (consolidation) (PD: trouble here and beyond)
– Autonomous (automatic): cortical and subcortical motor areas, less attentional areas
 Cerebellum is involved in calibration and fine tuning
of all movements
For ballistic movements, based on predictions from past experience
(too fast for sensory feedback)

Error correction-> motor learning

 “Muscle memory”: complex movement
consolidated into memory with repetition

Correlates with reduced M1 – cerebellar connection (less error correction needed)

 Categories of nondeclarative memory
• Associative: connecting multiple events
• Classical (Pavlovian) conditioning – involuntary
• Instrumental (Operant) conditioning - voluntary

• Non-associative: change in response to a single stimulus

• Habituation (ignore the irrelevant)
• Sensitization (pay more attention to the important)
 Non-associative learning:
habituation and sensitization
Habituation
Simplest form of learning
Decrease in magnitude of response to repeated stimuli (“getting used to it”)

Sensitization
Increase in magnitude of response with repeated exposure, or when a new stimulus (often noxious)
occurs: non-associative!
Example: walking in dark, sensitized to sounds

(contrast to classical conditioning, where repeated temporal pairing creates a new associative stimulus-
response relationship)
 The sea slug Aplysia:
model for studying habituation & sensitization
Touch  withdraw gill
Touch repeatedly  stops withdrawing (habituation)
Pair touch with shock  withdraw faster and more completely (sensitization)

Model for studying cellular & molecular basis of learning and memory
(next lecture)
A simple sensory-motor circuit
controls gill withdrawal

• Siphon stimulation activates sensory neurons

• Motor neurons cause gill withdrawal

Analogous to the knee-jerk reflex: monosynaptic

stimulus-response arc
How could repeated touch habituate
the gill withdrawal reflex?

• Sensory neuron adaptation

• Reduced efficacy of synaptic transmission
• sensory-motor synapse
• neuromuscular synapse
• Muscle fatigue

• Sensitization: same synapse gets stronger

• Amnesia = anterograde (no new learning) or retrograde (forget old)

• Declarative (explicit) memory = conscious recall

– episodic (experience), semantic (facts), spatial
– Working memory requires sustained activity (transient); cortex, including PFC
– Short-term-> (consolidation)-> long-term memory
• Medial temporal lobe required, particularly hippocampus
– H.M. lost hippocampus, anterograde amnesia
– Place cells in hippocampus
• Other regions also involved (e.g., entorhinal cortex grid cells, thalamus / diencephalon)
• Reconsolidation may make memories vulnerable to modification

• Nondeclarative (implicit) memory = unconscious skills, habits

– Associative (reinforcement) = Pavlovian (involuntary) or operant (motivated)
• Skills and habits: reinforcement via basal ganglia
• Supervised motor learning: includes error correction by cerebellum
• Emotional learning: includes amygdala
– non-associative = habituation, sensitization
 NEXT
PLASTICITY II: NEURAL SUBSTRATES