Physiology of memory & learning.

PHYSIOLOGY OF MEMORY AND
LEARNING

➢ Memory is the ability to capture externally or internally
presented information, store it and reconstruct it later.
➢ We are consistently presented with a flow of new information,
which needs to be processed and sometimes acted upon.
➢ For us to adapt and survive, our brain, through the
evolutionary process, developed a well-calibrated mechanism
to capture our experiences, which then shape our actions.
➢ This mechanism enables the species to adapt more quickly
to a changing environment and to respond to a stimulus by
comparing it with past experiences.
Definition of memory

Three temporal stages of memory
i.Immediate memory – seconds
ii.Recent memory – minutes to days
iii.Remote memory – years
Memory systems
▪ Short term memory
Working memory
▪ Long term memory
Declarative memory (explicit)
Non declarative memory (implicit)
Types of memory

➢ Explicit & many forms of implicit memory involve:
short-term memory, which lasts secs to hrs, during which
processing in hippocampus & elsewhere lays down long-term
changes in synaptic strength and long-term memory, which stores
memories for yrs and sometimes for life.
➢ During short-term memory, the memory traces are subject to
disruption by trauma and various drugs, whereas long-term memory
traces are remarkably resistant to disruption.
➢ Working memory is a form of short-term memory that keeps
information available, usually for very short periods, while the
individual plans action based on it.
Types of memory

Explict memory
( non declarative memory )
➢ Factual knowledge of people,
places, things and meaning of
facts.
➢ Conscious process and recall
requires conscious search of
memory.
➢ Expressed mainly in verbal form
1.Episodic - events and personal
experience
2.Semantic - memory for facts
Implict memory
( declarative memory )
➢ Involved in training reflexive
motor or perceptual skills.
➢ Builds up slowly through
repetition over many trails.
➢ Recalled unconsciously.
➢ Expressed mainly in form of
performance.

Classification of memory
Two forms of long term memory
Explicit
(declarative)
Implicit
(Nondeclarative)
Facts
(Semantic)
Events
(Episodic)
•Medial Temporal
Lobe
•Hippocampus
Priming Procedural
(skills &
habits)
Associative
Learning:
Classical &
operant
conditioning
Nonassociative
learning:
Habituation &
sensitization
Emotional
responses
Skeletal
musculature
Neocortex Striatum Amygdala Cerebellum Reflex
pathways

Stages of memory process
➢ How does information get into memory ?
Reception and registration
➢ How is information maintained in memory ?
Storage and retention
➢ How is information pulled back out of memory ?
Recall and retrieval

➢ Episodic memory refers to the explicit and declarative memory
system used to recall personal experiences framed in our own
context, such as a short story or what you had for dinner last night.
➢ This memory system depends on the medial temporal lobes
(including the hippocampus and the entorhinal and perirhinal
cortexes).
➢ Other structures include the basal forebrain with the medial
septum and diagonal band of Broca’s area, the retrosplenial cortex,
the presubiculum, the fornix, mammillary bodies, the
mammillothalamic tract and the anterior nucleus of the thalamus.
Episodic memory

Papez Circuit
Mammillary bodies
Other hypothalamic nuclei
Septal nuclei
Substantia innominata
(Basal nucleus of Meynert)
Hippocampal
Formation
(hippocampus
and dentate gyrus)
Anterior Thalamic
nuclear group
Cortex of Cingulate
Gyrus
Parahippocampal
Gyrus
Neocortex
Fornix
Mammillothalami
c
tract

➢ Memory loss attributable to dysfunction of the episodic
memory system follows a predictable pattern known as
Ribot’s law, which states that events just before an ictus are
most vulnerable to dissolution, whereas remote memories are
most resistant.
➢ Thus, the ability to learn new information is impaired
(anterograde amnesia), recently learned information cannot be
retrieved (retrograde amnesia) and remotely learned
information is usually spared.

➢ Frontal lobes are involved in the registration, acquisition, or
encoding of information, the retrieval of information without
contextual and other cues, the recollection of the source of
information and the assessment of the temporal sequence and
recency of events.
➢ They permit the person to focus on the information to be
remembered and to engage the medial temporal lobes.
➢ Dysfunction of the frontal lobes may cause distortions of
episodic memory as well as false memories, such as
information that is associated with the wrong context or with
incorrect specific details.

➢These differences between deficits in episodic memory that occur
because of damage to the medial temporal lobes (and the Papez
circuit) and those that occur because of damage to the frontal lobes
can be conceptualized in a clinically useful analogy.
➢The frontal lobes are analogous to the “file clerk” of the episodic
memory system, the medial temporal lobes to the “recent memory
file cabinet,” and other cortical regions to the “remote memory file
cabinet.” Thus, if the frontal lobes are impaired, it is difficult — but
not impossible — to get information in and out of storage.
➢However, the information may be distorted owing to “improper
filing” that leads to an inaccurate source, context, or sequence.
➢

➢If, however, the medial temporal lobes are rendered completely
dysfunctional, it will be impossible for recent information to be
retained.
➢ Older information that has been consolidated over a period of
months or years is thought to be stored in other cortical regions and
will therefore be available even when medial temporal lobes and the
Papez circuit are damaged.
➢ For example, although patients with depression and those with
Alzheimer’s disease may exhibit episodic memory dysfunction, the
former have a dysfunctional “file clerk” and the latter have a
dysfunctional “recent memory file cabinet.

➢ Semantic memory refers to our general store of conceptual
and factual knowledge, such as the color of a lion or the first
president of the United States. This is a declarative and
explicit memory system.
➢ There is evidence, for example, that visual images are
stored in nearby visual-association areas. However, a more
restrictive view of semantic memory, one that is justified in
light of the naming and categorization tasks by which it is
usually measured, localizes semantic memory to the
inferolateral temporal lobes.
Semantic memory

➢ Disorders of semantic memory should be suspected when
patients have difficulty naming items whose names they previously
knew.
➢ Patients with mild dysfunction of semantic memory may show
only reduced generation of words for semantic categories (e.g., the
number of names of animals that can be generated in one minute).
➢ Patients with a more severe impairment of semantic memory
typically show a two-way naming deficit (i.e., they are unable to
name an item when it is described and are also unable to describe
an item when they are given its name).
➢ These more severely affected patients also show impoverished
general knowledge.

Memory processing
➢ Information is first acquired through unimodal and
polymodal association areas – prefrontal, limbic and
parieto-occipito-temporal cortex – which synthesize visual
and somatic information.

• Look at some face
•Processed in visual ass. area in inferotemporal cortex
• Parahippocampal cortex, perirhinal cortex , entorhinal cortex.
•Hippocampus
• Via entorhinal cortex
•Neocortex storage system
Association areas are the ‘ultimate
repositories’

➢ Therefore entorhinal cortex have dual functions – both input
and output.
➢ Damage causes severe memory loss and all sensory
modalities involved.
➢ Earliest pathological change in AD – entorhinal cortex
involvement and so explict memory lost early.
➢ Hippocampus
Right side – spatial memories stored (lesions cause defect
in spatial orientation)
Left side – memories for words, objects and people (lesions
cause defect in verbal memory)

➢ Hippocampus is only a temporary way station for LTM.
➢ Unimodal and polymodal association areas of cortex are
concerned with LTM storage.
➢ Amygdyla – stores component of memory concerned with
emotion. It doesn't store factual information. (damage has no
effect on explict memory)
➢ In hippocampus , it takes days-wks to facilitate storage of
information about the face initially processed by ass. areas.
➢ There is relatively slow addition of information to neocortex,
which permits new data to get stored without disrupting
information.

➢ A long-term increase in the excitability of a neuron to a
particular synaptic input caused by repeated high-frequency
activity of that input.
➢ It occurs in many parts of the nervous system but has been
studied in greatest detail in the hippocampus.
Long term potentiation

▶ 3 major pathways
Perforant pathway
Mossy fiber pathway
Schaffer collateral pathway
• Long term potentiation - physiological mechanism.

Associativity: LTP will not occur unless the presynaptic fiber
and the postsynaptic cell are coincidentally active.
Cooperativity: More than one presynaptic fiber needs to be
active.
Input specificity: LTP that is produced at a given synapse is
specific for a given site.
➢ In other words, fibers that produce LTP at a certain synaptic
location will not produce LTP at another.
Properties of LTP at the CA3-CA1 Synapse

“When an axon of cell A… excites cell B and repeatedly or
persistently takes part in firing it, some growth process or
metabolic change takes place in one or both cells so that A's
efficiency as one of the cells firing B is increased.”
“Cells that fire together, wire together”
Hebb's rule (1949- Donald Hebb)

▶ There are 2 forms in the hippocampus: mossy fiber LTP,
which is presynaptic and independent of NMDA receptors;
and Schaffer collateral LTP, which is postsynaptic and
NMDA receptor-dependent.

▶ LTP can be demonstrated in CA1 cells by stimulating the
afferent pathways to the cells and recording EPSPs.
▶ After stimulation, there was increased EPSP activity in CA1
cells, which lasted several wks.
▶ This may be regarded as a form of neuronal memory within a
single nerve cell.
LTP in Hippocampus

▶ From granule cells of the dentate gyrus, NT- glutamate.
▶ Binds to both NMDA & non-NMDA receptors on the target
pyramidal cells.
▶ Activates Ca/calmodulin dependent
adenylyl cyclase cAMP activates PKA
enhances NT release.
Mossy fiber pathway (LTP)

▶ Schaffer pathway- CA3 to CA1
▶ Perforant pathway- entorhinal cortex to dentate gyrus
▶ In both, NT- glutamate.
▶ NMDA type receptors.
▶ Subsequently- Ca influx- activation of PKC & PKA.
LTP in other pathways

▶ Retrograde messenger
▶ Induction of LTP- requires events in postsynaptic cell
▶ Expression of LTP- presynaptic (NT release)
▶ Presynaptic cell must receive information that LTP is induced
▶ Nitric oxide- candidate
LTP

Early LTP
▶ lasts 1-3 hours.
▶ Represents only functional changes
▶ No change in the number of active zones, synapses.
Late LTP
➢ requires new protein synthesis.
➢ Involves-
- activation & growth of additional presynaptic NT vesicles
- insertion of new clusters of postsynaptic receptors.
➢ Involves cAMP-PKA-MAPK-CREB pathway.
Early & Late LTP

▶ Mutant mice.
▶ NMDA & AMPA receptors gene knock out.
▶ Loss of LTP.
▶ Impaired memory formation.
Gene disruption & LTP

➢ Procedural memory refers to the ability to learn behavioral and
cognitive skills and algorithms that are used at an automatic,
unconscious level.
➢ It is nondeclarative but during acquisition may be either explicit
(such as learning to drive a car with a standard transmission) or
implicit (such as learning the sequence of numbers on a touch-tone
phone without conscious effort).
➢ Research with the use of functional imaging has shown that brain
regions involved in procedural memory, including the supplementary
motor area, basal ganglia, and cerebellum, become active as a new
task is being learned.
Implicit memory (procedural memory)

Types of learning (Implicit memory)
Simple
(Non associative)
Associative Complex
Habituation Classic conditioning Observational learning
Sensitisation Operant conditioning Latent learning
Aversion learning

➢ The subject learns about the properties of a single stimulus
when exposed to it once or repeatedly.
➢ Two forms- Habituation & Sensitization.
➢ Habituation is a decrease in response to a benign stimulus
when that stimulus is presented repeatedly.
➢ Sensitization is an enhanced response to a wide variety of
stimuli after an intense or noxious stimulus.
➢ A sensitizing stimulus can also override the effects of
habituation, a process called dishabituation.
Simple (Non associative)

Defensive reflexes- can be used to study sensitization &
conditioning
Habituation and sensitization in Aplysia (marine snail)

Physiological basis - habituation
➢ Decrease in the EPSP- due to decrease in the number of quanta
released.
➢ Calcium is the mediator of quanta release at neuromuscular junction.
➢ Action potential (AP)- initial part mediated by Na channels & later by
calcium .

Attributed to structural changes.
1. Reduction in active zones,
2. Active zones- smaller & flatter.
3. Changes in inter-neurons.
Long term habituation – Physiological basis

Sensitization
Intense stimuli
Enhanced response
Periodic touching
Consistent response

Activation of nociceptor pathway (serotonin).
Activates specific receptors on sensory
neurons.
Coupling of receptors to produce cAMP.
Activation of cAMP dependent protein
kinase,Phosphorylation of K channels to
reduce K currents.
Increased Ca influx, increase quanta release.
Sensitization – Physiological basis

➢ Increase in the active zones.
➢ Sprouting of axonal branches.
➢ Indicate that cAMP- mediated
new protein synthesis.
➢ increased gene transcription-
the products of which mediate
positive feed back.
Sensitization – long term changes

➢ The subject learns about the relationship between two stimuli
or between a stimulus and a behavior.
➢ Three forms- Aversion learning, Classical & operant
conditioning.
➢ Classical conditioning involves learning a relationship
between two stimuli, whereas operant conditioning involves
learning a relationship between the organism's behavior and
the consequences of that behavior.
Associative learning

➢ The essence of classical conditioning is the pairing of two
stimuli.
➢ Conditioned stimulus (CS) & unconditioned stimulus (US)
(reinforcement).
➢ Unconditioned response- innate; produced without learning.
➢ When a CS is followed by a US, the CS will begin to elicit a
new or different response called the conditioned response.
Classical conditioning

➢Under normal circumstances
Conditioned stimulus (CS) No response
Unconditioned stimulus (UCS) UR
➢During conditioning
Conditioned stimulus (CS)
Unconditioned stimulus (UCS) UR
➢After conditioning
Conditioned stimulus (CS) Conditioned response

Reward Punishment
➢ Also called trial-and-error learning.
➢ Learning in which behaviors are emitted to obtain rewards
or avoid punishment.
Operant conditioning

➢ When experiences are aversive, the type of learning that
encodes memories of such events is called `aversive
learning.’
➢ 1960- Garcia J & Koelling R
➢ Rats- taste & sickness
➢ Rats- irradiated with strong X rays to damage the GI tract &
it was paired with tasty solutions to drink
➢ After recovery- rats refused to drink tasty water
➢ Similar to classic conditioning with respect to pairing of US
& CS
Aversion learning

▶ Include
Latent learning
Observational learning
Complex learning

➢ A form of learning that is not immediately expressed in an
overt response & occurs without obvious reinforcement to be
applied later.
➢ An organism learns something in its life, but the knowledge is
not immediately expressed.
➢ Remains dormant, and may not be available to
consciousness, until specific events/experiences might need
this knowledge to be demonstrated.
➢ For instance a child may observe a parent setting the table or
tightening a screw, but does not act on this learning for a year;
then he finds he knows how to do these.
Latent learning

➢ A type of learning that occurs as a function of observing,
retaining and replicating novel behavior executed by others.
➢ Although observational learning can take place at any stage in
life, it is thought to be of greater important during childhood,
particularly as authority becomes important.
Observational learning

➢ Practice makes perfect.
➢ Repeated experiences consolidates memory by converting
short term to long term form.
➢ Best studied for sensitization in Aplysia.
➢ Short term- doesn't require new protein synthesis.
➢ Long term memory involves 3 major processes-
Gene expression
New protein synthesis
Growth of synaptic connection.
Long term storage of implicit memory

Long term habituation &
sensitization

➢ Studies of long-term sensitization of the gill-withdrawal reflex indicate that:
➢ Serotonin- along with PKA (protein kinase A) recruits another second
messenger, Mitogen activated protein kinase (MAPK)
➢ These 2 kinase act on the nucleus of sensory neuron- activate the genetic
switch.
➢ Activates transcription factor- CREB1 (cAMP response element binding
protein). Also inhibit action of CREB2 – repressor of transcription.
➢ Activation CREB1 induces Activation of ubiquitin carboxyterminal
hydrolase- makes PKA persistently active.
➢ Activates transcription factor C/EBP- necessary for the growth of new
synaptic connections.
Role of gene & protein

Persistent synaptic
enhancement with
long-term sensitization.

▶ Working memory is typically defined as a storage system that
holds a limited amount of information for a brief time, where that
information is in a rapidly accessible state and can be changed from
moment to moment.
▶ It is a combination of the traditional fields of attention,
concentration, and short-term memory.
▶ Because it requires active and conscious participation, working
memory is an explicit and declarative memory system.
▶ traditionally been divided into components that process phonologic
information (e.g., keeping a phone number “in your head”) or spatial
information (e.g., mentally following a route) and an executive
system that allocates attentional resources.
Working memory

➢ Numerous studies have shown that working memory uses a
network of cortical and subcortical areas, depending on the
particular task. However, virtually all tasks involving working
memory require participation of the prefrontal cortex.
➢ Typically, the network of cortical and subcortical areas includes
posterior brain regions (e.g., visual-association areas) that are
linked with prefrontal regions to form a circuit.
➢ Studies have shown that phonologic working memory tends to
involve more regions on the left side of the brain, whereas spatial
working memory tends to involve more regions on the right side.
➢ More difficult tasks involving working memory require bilateral
brain activation, regardless of the nature of the material being
manipulated.

▶ Furthermore, there is an increase in the number of activated
brain regions in the prefrontal cortex as the complexity of the
task increases.
▶ Almost any disease process that disrupts the frontal lobes or
their connections to posterior cortical regions and subcortical
structures can interfere with working memory.
▶ Such processes include strokes, tumors, head injury, and
multiple sclerosis, among others.
▶ Because phonologic working memory involves the silent
rehearsal of verbal information, almost any kind of aphasia can
also impair it.
▶.

▶ Disorders that diminish attentional
resources, such as attention deficit–
hyperactivity disorder, OCD,
schizophrenia, and depression, also
impair working memory.
▶ Most commonly, the patient will
show an inability to concentrate or
pay attention. Difficulty performing a
new task involving multistep
instructions may be seen.

Evaluation of memory
▶ Assess type of memory deficit.
▶ Degree of memory loss.
▶ Impact of memory loss on patients functional ability
▶ Accurate assessment of memory requires that any question
asked by examiner be verifiable from a source, other than pt.

➢ Most valid and sensitive test for recent memory –
learning new material and
recalling it over time.
➢ Hinders to the test are –
> inattention .
> disturbances of basic sensory, motor and language
functions.
➢ Any evidence of aphasia impairs both verbal STM and LTM.
Caution to be taken while examining these pts.

Immediate recall / stm
Tested by digit repetition.
▶ Repeat digits at rate of one per
second.
▶ Normal person repeats
five to seven digits.
*< five digits – impaired repitition
3-7
2-4-9
8-5-2-7
2-9-6-8-3
5-7-1-9-4-6
8-1-5-9-3-6-2

Recent memory (orientation)
▶ Ask the Q. in sequence.
1. PERSON
Name
Age
Birth date
2. PLACE
Location
City
Home address
3. TIME
Date
Day of the week.
Time of the day
Season of the year
Duration of time with
the examiner.

➢ Normal people usually perform well , some time with less
scores in ‘time orientation’
➢ Failed items are usually date of month and day of week .(
mainly illiterates)
➢ Orientation to time and place are actually measures of
recent memory, as they test the pts ability to learn these
changing facts

Remote memory
➢ Evaluated by pts ability to
recall personal events and
historic events.
➢ Normal and those with mild
nonspecific brain damage do
with same accuracy.
➢Impaired performance is
pathologic.
PERSONAL INFORMATION
Where were you born?
School information
Vocational history
Family information

➢ Normal person tells with out difficulty
➢ If pt has no memory of these events, this implies deficient
memory. ( some Q. depend on literacy level of pts )
HISTORIC FACTS
Four CM s during your lifetime
Last elections

New learning ability
➢This is to assess pts ability to actively learn new material ( to
acquire new memories)
➢ All stages of memory process are necessary for adequate
performance.
➢ Any defect at any stage l/t loss of this ability.

Four unrelated words
➢ Tell that “I am going to tell u 4 words that u have to
remember. In a few minutes, u have to recall these words.
➢ Ask him to repeat the words after they are presented- to
ensure that he understood.
➢ After 5 min , ask him to recall the words
Ex) Fun – carrot – knee – honesty
Red – happiness – brush – grapes
➢ Normal pt < 60 yrs accurately recalls three or four words
after 10 min delay.
➢ pt > 80 yrs recalls two words normally after 5 min delay.

➢ If he cannot recall ,
1. cues – semantic (‘one word is color’)
phonemic (‘hap… for happy’)
2. ask to select from a series of words.
➢ When 2 yeilds better than 1(recall), the problem may be due
to retrieval defect, rather than storage.
➢ This indicates normal implict memory.

Verbal story for immediate recall
➢ Tell the pt “ I am going to read a short story and I want u to
remember, and I want u to tell me what I have told ”
➢ Read the story slowly and correctly without any pauses.
➢ Ask the pt to retell the story as accurately as possible.

It was july / ramu had packed up / their four children / and were
off on vacation .
They were taking / their yearly trip / to the beach / of vizag.
This year / they were making / a one day stop / at araku.
After a long day drive / they came back to hotel / and found
that / they had left / their suit cases / in the garden.
▶ No. of correct memories _________
▶ Describe confabulations , if present.

▶ Of these 20 separate ideas, a normal person of < 70 yrs should
be expected to produce atleast 10 items
▶This is a sensitive method of assessing short term verbal recall.
▶Story recall discriminates b/w
Normal and AD pts
Brain damaged and low IQ pts

VISUAL MEMORY (hidden objects)
➢Tested in all pts, but mainly useful in aphasic pts. and also for
illiterates.
➢Tell the pt that you are going to hide some objects and ask
him to remember where they are.
➢Hide 4 or 5 common objects like – keys, pen, etc in various
areas of pt’s sight.
➢After 5 min , ask pt to find the objects.
➢Ask him to name the objects that he could not find.

Assess by following Q.
▶Number of hidden objects found.
▶Number of hidden objects named, but not found.
▶Number of hidden locations found, but objects not named.
▪ Normal person < 60 yrs finds 4 or 5 objects.
▪ Impaired visual memory – finds < 3 objects.
▪ Aphasic pt should find the objects , but may not be able to
name them.

Paired associate learning
➢ Another highly sensitive measure of new-learning ability.
➢ Tell the pt that you are going to read a list of words – two at a
time.
➢ Pt is expected to remember the two paired words. ( ex. High –
Low )
➢ Read the 1st presentation list and test for recall by saying 1st
recall list .
➢ (Give the first word of pair – ask for other)

▶ Correct the incorrect responses , if any.
▶ After 10 sec, give 2nd presentation and recall lists.
1ST PRESENTATION LIST
Weather - box
High - low
House - income
Book – page
1st RECALL LIST
House - ______
High - ____
Weather - _______
Book - ____
2nd PRESENTATION LIST
House - income
Book – page
Weather - box
High - low
2nd RECALL LIST
High - ____
House - ______
Book - ____
Weather - _______

➢ No. of easy paired associates recalled :
➢ No. of difficult paired associated recalled :
➢ Normal pt < 70yrs – recalls two easily paired associates and
atleast one hard on 1st recall and to recall all on 2nd trail.
➢ Total PAL score is the best measure of verbal learning.

▶ Molecular mechanism involved in implicit & explicit memory-
almost similar. cAMP-PKA-MAPK-CREB pathway.
▶ Long-term memory requires new protein synthesis, whereas
short-term memory does not.
▶ To study specific molecular changes- look for altered gene
expression in normal & diseased states
Take home message

Physiology of memory & learning.

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