NEUROBIOLOGY OF

MEMORY

Namita JR III
INTRODUCTION
 Memory is not just an ability to store information, but is the essence of
our beings, the basis of our individuality and our consciousness. Each
individual knows that he/she is unique, not merely because of his/her
external appearance, but for his/her personal history, Behaviour and
ability to face daily life.

 In the same sense, the neuroses are often products of learning—

anxieties, phobias, and maladaptive behaviours that result from
particular experiences.

 Psychotherapy itself is a process by which new habits and skills are

acquired through the accumulation of new experiences.

 Webster’s New World College Dictionary… defines memory as what is

learned and retained through non conscious associative mechanisms.
However, neuroscientists and experimental psychologists distinguish
several types of memory, each of which is served by different
combinations of brain regions
INTRODUCTION
• A characteristic of animals and humans is the ability to alter
behavior on the basis of experience.
• LEARNING ----- acquisition of the information that makes this
possible.
• MEMORY ------- is the retention & storage of that
information…
THE TWO ARE OBVIOUSLY RELATED & SHOULD BE
CONSIDERED TOGETHER
 COMPONENTS

ENCODING STORAGE RETRIEVAL

• how information • retention of • bringing memory
gets into memory information over out of memory
time storage
MEMORY STORAGE
Memory Storage
A time-dependent process underlies the creation of different stages of
memory.
(Modified from McGaugh JL.Memory: a century of consolidation. Science 2000;287:248-51.)
Sensory memory

A brief trace that results from visual , auditory & other

sensory events, lasting no longer than a quarter of second

Visual memory stored in primary visual cortex

Auditory memory stored in primary auditary cortex

FACTS

• There is evidence, however, that the brain does

not really store whole memories, but rather stores
pieces of information that later can be used to
create memories. We often recall facts incorrectly,
suggesting that memory is not simply replayed as
from a tape recorder

• Memory can be considered a place where we

store and process information, where we update
existing knowledge as new information is
acquired, and where we compare one experience
to another.
Short term memory (STM)/
Active memory
• Lasts several seconds to minutes depending on rehearsing or
concentrating
• STM LTM by rehearsal & by use in context
• Working memory is a type of STM that keeps information for very
short periods
• Mechanism  changes in synaptic strength by release of
neurotransmitter leading presynaptic inhibition or facilitation
• LATERAL PREFRONTAL AREA
LONG TERM MEMORY(LTM)

classical
conditioning
TYPES OF LONG TERM MEMORY
Explicit memory
• Declarative or Conscious or recognition
memory
• Memory consciously recalled or declared
• Can use explicit memory to directly respond
to a question
• Two subtypes of explicit memory-
• Episodic and semantic
 Episodic memory
• Memory tied to our own personal
experiences(when’s ,where’s)
• Examples: birthday, movie seen yesterday?
• These are called explicit memory because we can
actively declare our answers to these questions
• It is context & time specific(visual image of me sitting
& watching movie)
Semantic memory
 Memory not tied to personal events
 General facts and definitions about the world
 General academic knowledge, meaning of words,
important places/dates
 These are also explicit memory because we can
actively declare our answers to these questions
 Examples:
 How many tires on a car? and What is a cloud?
Important note: Though we may have personal
experience with these items, our ability to answer Q’s
does NOT depend on tying the item to our past
• i.e. Do not have to recall the time last week when you ate a banana to say
that bananas are yellow
Implicit memory
• Non declarative/ reflexive memory
• Influences our thoughts or behavior, but does
not enter consciousness
• Includes skills, habits & conditioned reflexes
Implicit memory (cont..)
• This memory is affected by prior experiences without that
experience being consciously recalled
• Can not be verbally recalled
• We know how to ride a bicycle but may not remember when & how
we learned it
(explicit memory initially required for activities such as riding a
bicycle ..Becomes implicit once the task is thoroughly learned)
• Does not involve awareness of ‘when n where’
• Three subtypes…..
Subtypes of Implicit Memory

Im plicit M em ory

C lassical P rocedural P rim ing

C onditioning M em ory
CLASSICAL CONDITIONING
Natural reflex

Conditioned reflex
 Procedural memory
• Memory that enable us to perform specific learned skills or habitual
responses
• Examples:
• Riding a bike
• Tying your shoe laces
• Q: Why are these procedural memories implicit?
• A: Don’t have to consciously remember the steps involved in these
actions to perform them
• Try to explain to someone how to tie a shoelace
 Priming
• Its facilitation of recognition of words and concept by prior exposure to them
e.g… improved recall of a word or picture when presented with first few
of it
….HI…… HISTORY
REPRESENTATION OF LTM
• DECLARATIVE / EXPLICIT MEMORY—
• THIS IS TYPE OF MEMORY LOST IN “AMNESIA”
• IT DEPENDS ON
MEDIAL TEMPORAL LOBE
+
MEDIAL DIENCEPHALON
+
EXTENSIVE PORTION OF NEOCORTEX
MTL [ hippocampus proper ( CA1, CA2, CA3 fields, dentate gyrus &
subiculum ) and adjacent regions of entorhinal , peri rhinal &
parahippocampal cortex
 Temporal lobe
• Includes:
• hippocampus
• amygdala
Non declarative / implicit

Several brain system-CORPUS STRIATUM, CEREBELLUM etc..

Habits depend on both neocortex and neostriatum

Conditioning of skeletal muscle depends on cerebellum

Priming is done in neocortex

Emotional learning is by AMYGDALA

Taxonomy of Long-term Memory Systems

Squire L, Zola S PNAS 1996;93:13515-13522

Adapted from Squire, Knowlton 1994
 ENCODING & CORTICAL
CONSOLIDATION OF MEMORY

• Consolidation – process by which enduring DECLARATIVE memories are

stored in cerebral cortex. This is required because the elements of DM
are not easily held together due to their anatomical isolation.
Brain regions believed to be critical for the formation
and storage of declarative memory……

CEREBRAL CORTEX

MEDIAN DIENCEPHALON
MEDIAL TEMPORAL LOBE (medial thalamic nuclei,
(Hippocampal region anterior thalamus, dorso-
including perirhinal cortex medial thalamus,
and entorhinal cortex) mammillary nuclei
STAGE 1
• A fact or event is encoded in representation that involve multiple cortical
regions (NEURONAL ENSEMBLES) that represent different high level
perceptual , cognitive and emotional attributes processed in functioning
distinct cortical zones

• The experiences of a fact or event in present moment can be ( as in

working memory) achieved when one such set of distributed neuronal
ensembles is activated under control of prefrontal cortex
Progression to stage 2
• These NE begin to make contact with neurons in MTL region and medial
Diencephalon.
• HIPPOCAMPAL connections rapidly become part of a newly formed
network so that the dispersed cortical fragments can remain connected
beyond span of working memory……. But
ITS STILL TEMPORARY
• Inputs from NE relayed to Parahippocampal gyrus (PG), Perirhinal cortex
(PR) , & Entorhinal cortex ( EC)
• From NE  hippocampus
• Processed in dentate gyrus (DG) & in the CA3 and CA1 regions of
hippocampus
• It then leaves via Subiculum to return to EC, PR , PC and neocortical
association areas from which it arose
 Stage 3
• This temporary linking function is ultimately replaced by new NEOCORTICAL
representations called “COHERENCE ENSEMBLES”, which located in the
temporal region near the hippocampus (PR, EC, PG)
• The central function of these newly formed coherence ensembles is to
provide coherence to dispersed neocortical representation which can take
part in reactivation of dispersed neocortical memory without any necessary
contribution from Hippocampal region
• Enduring declarative memories are by this account characteristically
composed of a set of distributed neocortical ensembles ( i e NEURONAL)
plus associated coherence ensembles
Plasticity of synapses
• Specific synaptic events including an increase in neurotransmitter
release are responsible for short term memory which may last
seconds or minutes
• Long lasting memory depends on new protein synthesis, physical
growth of neural processes and an increase in number of synaptic
connections
• A major source of information has been extended study of marine
mollusc Aplysia California
• Both STM and LTM are based on increased neurotransmitter release
but LTM uniquely requires genes and protein synthesis
• The synaptic events that are responsible for such changes are
described next
Synaptic plasticity and memory
• Long term changes in synaptic function can occur as a result
of the history of discharge at the synapse i.e. synaptic
conduction can be strengthened or weakened on the basis of
past experience
Post-tetanic potentiation
• The production of enhanced post synaptic potentials in
response to stimulation
• May last up to 60 sec and occurs after a brief (tetanizing) train
of stimuli in the presynaptic neuron.
• The tetanizing stimulation causes calcium to accumulate in the
presynaptic neuron to such a degree that the intracellular
binding sites that keep cytoplasmic calcium low are
overwhelmed.
Long term potentiation
• It is rapidly developing persistent enhancement of the post synaptic
potential response to presynaptic stimulation after a brief period of
rapidly repeated stimulation of the presynaptic neuron

• DIFFERENCE WITH POST TETANIC POTENTIATION

• Resembles post-tetanic potentiation but is much more prolonged
and can last for days
• Initiated by increase in intracellular calcium in the post-synaptic
neuron
• Occurs in various parts of nervous system but has been studied in
greatest detail in hippocampus
• Mossy fiber LTP- Presynaptic and independent of NMDA Receptor
• Schaffer collateral LTP- Post synaptic and NMDA Receptor dependent
Long-term Potentiation (LTP) and Depression
(LTD)
• LTP: a burst of stimulation from axons, e.g., 100 excitations per second for 1-4
seconds onto dendrites results in potentiated synapses for minutes, days or
weeks
• specificity: only active synapses become strengthened
• cooperativity: nearly simultaneous stimulation by two or more
axons results in LTP
• associativity: pairing a weak input with a strong input enhances
later response to the weak input
• LTD: prolonged decrease in response to a synaptic input where two or more
axons have been active together at 1-4 times per second
Biochemical Mechanisms of
LTP in Hippocampus
• AMPA and NMDA receptors are involved in LTP
• glutamate receptors that open channels in postsynaptic neurons
to let in one or more kinds of ions (ionotropic)
• AMPA receptors: glutamate opens sodium channels
• similar to before
Biochemical Mechanisms of LTP in
Hippocampus cont.
• NMDA receptors: normally blocked by magnesium but responds to glutamate
when depolarized by AMPA receptors
• calcium enters and activates protein CaMKII, which is necessary for
LTP, and sets several processes in motion:
• structure of AMPA receptors change, becoming more responsive to
glutamate
• some NMDA receptors change to AMPA receptors and increase their
responsiveness to glutamate
• dendrites may build more AMPA receptors and make more branches
• Once established, LTP no longer depends on NMDA synapses
The AMPA and NMDA receptors during LTP.
CREB- cAMP
response element
binding protein
Biochemical Mechanisms of LTP in
Hippocampus cont.
• Presynaptic changes
• stimulation of the postsynaptic cell releases a retrograde transmitter that
feeds back to presynaptic cell
• increases presynaptic release of neurotransmitter and production of
GAP-43, facilitating growth of axons
• Consolidation of LTP
• following training, LTP seen in hippocampus quickly and in cerebral cortex
90-180 minutes later
• drugs that block NMDA receptors within 2 weeks of training also block
consolidation of long-term memory
• but, other studies found blocking NMDA for first week prolonged LTP
and increased dendritic branching
LTP and Behavior

• Neurons change early in training, a preliminary step before behavioral

change
• Research with mice
• abnormal NMDA receptors impair learning
• more than normal NMDA receptors enhances learning
• drugs that block LTP block learning while drugs that facilitate LTP
facilitate learning
• a lack of AMPA receptors creates deficits in LTP and memory
• over production of GAP-43 enhances learning and problem solving
Gene expression- New synaptic
connections

• APOE gene = more recently, it has been studied for its role in
Alzheimer's disease(AD), and cognition .
• WWC1 encodes KIBRA protein which appears to be associated
with the rate at which material is forgotten over a delay
period.
• Long term changes in memory are blocked by inhibitors of
RNA and protein synthesis
• Synaptogenesis is involved
• Exact pathways in human being isn’t clear till now
Biology and Memory
• Hippocampus and hippocampal region
• Hippocampal region
• A part of the limbic system which includes the hippocampus itself and its
underlying cortical areas
• Research has established that the hippocampus is critically important
for storing and using mental maps to navigate in the environment
 Biology and Memory
• Hormones and memory
• Mc Gaugh and Cahill (2000)
• Suggest that there may be two pathways for forming memories – one for
ordinary information and another for memories that are fired by emotion
• When a person is emotionally aroused, the adrenal glands release the
hormones adrenalin and noradrenaline into the bloodstream
• Excessive levels of the stress hormone cortisol have been shown to
interfere with memory in patients who suffer from diseases of the
adrenal glands
• Estrogen, the female sex hormone, appears to improve working
memory efficiency
HOW SOME MEMORY DRUGS WOULD WORK

• Some drugs under investigation aim to speed memory storage by

amplifying the AMPA receptors response to glutamate & thus
facilitating depolarization
• Other compounds aim to increase a cell’s supply of active CREB–
such as by inhibiting an enzyme ( phosphodiesterase) that normally
degrades the C AMP needed for CREB activation
Factors Influencing Retrieval
Serial • Primacy effect- The tendency to recall the first items on
position a list more readily than the middle items
• Recency effect - The tendency to recall the last items
on a list more readily than the middle items
effect
Environme • Any elements of the physical setting in which a person

ntal
learns information are encoded along with the
information and become part of the memory trace
• Memories are better recalled in the environment they

context were learned

State- The tendency to recall information better if one is in

•
the same psychological (mood) state as when the
information was encoded
dependent • Evidence does suggest that anxiety and fear influence
memory
• Adults who are clinically depressed tend to recall
effect more negative life experiences and are likely to
recall their parents as unloving and rejecting
Retrieval can be

Recall  Recognition 
• a memory measures • a memory measure in
in which the individual which the individual
must retrieve only has to identify
previously learned ( recognize) learned
information. e g.. items. e g.. MULTIPLE
ESSAY TEST CHOICE QUESTIONS
Amnesia
• Results from damage to either of two brain regions
• MTL  Medial temporal lobe &
• MD  Medial diencephalon

• Amnesia is forgetting produced by brain injury or trauma

• Retrograde amnesia refers to problems with recall of information
prior to a trauma
• Anterograde amnesia refers to problems with recall of information
after a trauma

Retrograde amnesia Anterograde amnesia

Point of Trauma
Hippocampal Temporal lobe
damage damage
• Deficits in •Impaired performance
on task that tests
forming new explicit memory
•Not impaired on similar
explicit task that taps habit-
based (implicit)
memories memory
Improving Memory
• Overlearning
• Practicing or studying material beyond the point where it can be
repeated once without error
• Research suggests that people remember material better and longer
if they overlearn it
• Krueger--Showed very substantial long-term gains for participants
who engaged in 50% and 100% overlearning
• physical exercise
• aerobic exercises such as running, cycling and swimming
• increases neurotransmitter levels, improved oxygen and nutrient
delivery, and increased neurogenesis in the hippocampus.
• Improves children's academic performance, maintaining mental
abilities in old age.
Improving Memory
• Massed practice Vs Distributed Practice with rest periods

• Massed practice occurs when one skill is continuously practiced in a

session with only brief rest periods or none at all.
• Long periods of memorizing make material particularly subject to
interference and often result in fatigue and lowered concentration
 Why do we forget?
• The major reasons why are:
• Retrieval failure
• why retrieval fails is known as decay theory. Decay theory suggests that over
time, these memory traces begin to fade and disappear. If information is not
retrieved and rehearsed, it will eventually be lost.
• Interference
• suggests that some memories compete and interfere with other memories.
When information is very similar to other information that was previously
stored in memory, interference is more likely to occur.
• Failure to store
• information failed to store because it never actually made it into long-term
memory. Encoding failures sometimes prevent information from entering long-
term memory.
• Motivated forgetting
• Sometimes, we actively work to forget memories, especially those of traumatic
or disturbing events or experiences. The two basic forms of motivated
forgetting are: suppression, a conscious form of forgetting, and repression, an
unconscious form of forgetting.
False memory
• Human memory is created and highly suggestible.
• can be falsely created through the use of different techniques,
including guided imagery, hypnosis and suggestion by others.
• After receipt of new information that is misleading in some
way, people make errors when they report past memory. The
new, post-event information often becomes incorporated into
the recollection, supplementing or altering it, sometimes in
dramatic ways.
• Understanding how we become tricked by revised data about
a witnessed event is a matter of research.
• Experimental researchers have demonstrated that memory
cells in the hippocampus of mice can be modified to artificially
create false memories.[
 ALZHEIMER’S DISEASE/ ALCOHOLISM

• In human being bilateral destruction of the ventral hippocampus or AD or

Alcoholism & similar disease process that destroy its CA1 neuron cause
striking defect in SHORT TERM MEMORY

• They have intact working memory, intact remote memory and intact
implicit memory…i.e they can not form long term memories

• They perform adequately in terms of conscious memory as long as they

concentrate on a task on what they are doing. If distracted even for a very
short period , all memory of what they are doing is lost

• Confabulation….is still poorly understood, caused by lesion of ventero-

medial portion of frontal lobe.
Schizophrenia
• memory impairment in schizophrenia is wide ranging
• perceptual implicit memory is preserved in schizophrenia
independently of the intellectual functioning level of the
patients
• conceptual priming is deteriorated even in intellectually
preserved patients
• it is not possible to establish the cause or underlying
mechanism of the memory impairment in schizophrenia.
• Impairments in encoding and consolidation have been
associated with hippocampal and temporal lobe dysfunction

Intellectual functioning and memory deficits in schizophrenia, Juan Carlos Ruiz at al;
Comprehensive Psychiatry 48 (2007).
 Bipolar disorder
• Several domains of cognitive function were examined in 30 depressed
bipolar patients (DSM-IV criteria for major depression, Hamilton Depression
Rating Scale score ≥17), 34 manic or hypomanic bipolar patients (DSM-IV
criteria for manic or hypomanic episode, YMRS≥12), and 44 euthymic
bipolar patients, Results compared with healthy individual.
• The three groups showed cognitive dysfunction in verbal memory and
frontal executive tasks in relation to the comparison group.
• Low neuropsychological performance was associated with poor functional
outcome.
• Impairment of verbal memory was related to the duration of illness and the
numbers of previous manic episodes, hospitalizations, and suicide attempts.

• Cognitive Function Across Manic or Hypomanic, Depressed, and Euthymic

States in Bipolar Disorder, Anabel Martínez-Arán,et al Am J Psychiatry 2004
Mania
• Some studies have shown that memory and cognition
problems are at their worst during manic episodes.
• Patients operating at high speeds due to mania have a hard
time encoding new information into their memories and also
show difficulty accessing memories.
 Depression
• Being depressed can make it difficult to pay attention and focus, which can
affect memory.
• Depression has been linked to memory impairment, but being depressed
doesn't affect all types of memory uniformly.
• In a meta-analytic study used data from 99 studies on recall and 48 studies
on recognition in clinically depressed and nondepressed samples. A
significant, stable association between depression and memory impairment
was revealed.
• Further analyses indicated, that it is likely that depression is linked to
particular aspects of memory in particular subsets of depressed individuals.
• Aetiology….. inhibition of the connectivity between nerve cells,
• During depression, the researchers also hypothesize that the brain seems to
stop producing new neurons in the hippocampus, in turn affecting pattern
separation abilities.
• Studies support the hypothesis of deficits in hippocampal and anterior
cingulate functioning in depression.
• Depression and memory impairment: A meta-analysis of the association, its pattern, and
specificity. Burt, Diana Byrd; Zembar, Mary Jo;Psychological Bulletin, Vol 117(2), Mar 1995
• Deficits in Hippocampal and Anterior Cingulate Functioning During Verbal Declarative Memory
Encoding in Midlife Major Depression ,J. Douglas Bremner, Am J Psychiatry 2004;
Anxiety disorders and PTSD
• The majority of noradrenergic neurons located in the locus
coeruleus (Pons) with projections throughout the cerebral
cortex, including hippocampus, amygdala, thalamus and
hypothalamus.
• Stress exposure in anxiety, fear, PTSD is associated with
enhanced noradrenergic activity.
• Noradrenergic is also involved in neural mechanisms such as
sensitization and fear conditioning.
• Noradrenergic augmentation during retrieval of fear memories
may contribute to persistence and severity of traumatic
memories in PTSD.
Dissociative amnesia
• Sudden retrograde autobiographical memory loss, said to
occur for a period of time ranging from hours to years
• Access to episodic memory can be impeded, while the degree
of impairment to short term memory, semantic memory and
procedural memory is thought to vary among cases.
• It has been suggested that deficits in episodic memory may be
attributable to dysfunction in the limbic system
• While self-identity deficits have been suggested as attributable
to functional changes related to the posterior parietal cortex.

• Arzy, S et al (2001) "Psychogenic amnesia and self-identity: a multimodal

functional investigation". European Journal of Neurology.
Dissociative identity disorder
 As a whole, research suggests that amnesic barriers between alter
personalities are typically impervious to explicit stimuli, as well as
conceptually driven implicit stimuli.
 Autobiographical memory deficits are also experimentally evident in
DID. Although no experimental studies have addressed the issue of
source amnesia or pseudo memories.
 There is some evidence that pseudo memories are an infrequent but
real phenomenon in DID patients. Finally, potential deficits in
working memory are outlined, including those relating to cognitive
inhibition

• Dissociative identity disorder and memory dysfunction: the current state of

experimental research and its future directions. Dorahy Mj.Clin psychol Rev. 2001
Jul;21(5):771-95.
 CONCLUSION
• All forms of memory from the simplest to the
most complex ones, are encoded as plastic
changes in synaptic connections sharing a
common molecular alphabet and

• Not withstanding the differences between implicit

and explicit memory systems and the distinct
brain areas involved, the cellular and molecular
mechanisms are closely similar and appear to
utilize elements of a common genetic program.
CONCLUSION
• Memory is integral to our sense of self-identity. It is a mental
diary of the events that we experience, which gives us
continuity as individuals across our lifespan. We hold some
memories dear in our hearts; others may be recollected with
less fondness; and yet others may be upsetting or even
traumatic. Collectively, the contents of our mental diary make
us who we are…..!!!!
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