BIOLOGICAL BASIS OF

MEMORY

Dr. Karrar
Husain
Moderator : Dr. Piyush
P. Singh

INTRODUCTION

Memory is fundamental to the discipline of psychiatry.

Memory connects the present moment to what came before and is

the basis for the formation of one's life story.

Personality is, in part, a set of acquired habits that have been

learned, many early in life, that create dispositions and determine
how people behave.

Neuroses can be products of learninganxieties, phobias, and

maladaptive behaviors that result largely from experience.

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

acquired through the accumulation of new experiences.

Memory is also of clinical interest because disorders of memory

and complaints about memory are common in psychiatric illness.

Memory problems occur in association with certain treatments,

notably electroconvulsive therapy (ECT).

Our memory stores:

Our personal experiences

Emotions

Preferences/dislikes

Motor skills

World knowledge

Language

Fundamentally, we as a person are derived from experiences that have

been stored in our nervous system.

 Definition

Memory is the ability to store, retain and retrieve information .

word memory comes to us from the Anglo-French memoire or

memorie, and ultimately from the Latin memoria and memor,
meaning "mindful" or "remembering.

Learning vs memory

Squire (1987)

Learning - process of acquiring new information

Memory - persistence of learning in a state that can be revealed at
a later time.

Learning has an outcome - memory - which itself has a further

outcome - a change in future behaviour.

Learning need not imply any conscious attempt to learn. Simple

repeated exposure can, and indeed usually does, lead to learning,
and this is evinced by memory.

Basic Memory Processes

Encoding

Storage

Retrieval

(Code and put

into memory)

(Maintain in
memory)

(Recover from
memory)

Historical Foundations: The

Golden Age
About 30 years ago Paul Rozin described the last
decade of the 19th Century as the Golden Age of
Memory because during that era many of the basic
phenomena and ideas that still occupy researchers
emerged.

Paul Rozin

Historical Foundations: The

Golden
Age
Thodule Ribot proposed that during
disease of the brain, memories disappear
in an orderly fashion.

The Dissolution of Memory

First

Last

Ribots Law: Ribot also proposed that old memories are more resistant to
disease/disruption than new memories.

Historical Foundations: The

Golden
Age
Serge
Korsakoff
Described the syndrome produced by alcohol now called
Korsakoffs Syndrome.
The syndrome is characterized by what we would now
call anterograde amnesiathe inability to acquire new
memories.
During the late stages there is also retrograde amnesia
the loss of memories acquired before the onset of the
disease.
He also proposed that amnesia could be due to either
storage failure or retrieval failure.

Historical Foundations: The

GoldenWilliam
Age
James proposed that memories emerge in stages.
An after image is supported by a very short-lasting trace,
then replaced by the primary trace that also decays.
Secondary memory is viewed as the reservoir of
enduring memory trace that with an appropriate retrieval
cue can be recalled.

Historical Foundations: The

Santiago Ramn y Cajal
Golden
Age
The Neuron Doctrine: The idea that the
brain is made up of discrete cells
called nerve cells, each delimited by an
external membrane.
The Synaptic Plasticity hypothesis:
The idea that the strength of a synaptic
connection can be modified by
experience.

Historical Foundations: The

Golden Age
Ivan P. Pavlov
Developed the fundamental
methodology for studying
associative learning in
animals.

In the Pavlovian conditioning method, two events called the CS and US are
presented together. Subsequently, the CS evokes the response called the CR.
Psychologists assume that the CS evokes the CR because the CS gets associated
with the US. Psychologists and neurobiologists continue to use this method to
study associative learning in animals.

Figure 1.8 Pavlovian conditioning is widely used to study learning and

memory in animals

TYPES OF MEMORY
Sensory
Memory

Shortterm
(Secondary,
Working)

Longterm
(Primary)

Declarative
(knowingwhat)

Episodic

semantic

Nondeclarative

Time base of memory

Memory model of Atkinson & Shiffrin
(1986).
Sensory memory is sub-second to
seconds, as when we can recover what
was said when we werent paying
attention.
Short term is seconds to minutes, as with
retaining a phone number.
Long-term is longerdays, weeks, going
up to years, or even a lifetime.

17

Information-Processing Model of Memory

(Atkinson-Shiffrinmodel)

Retrieval

Stimulus

Sensory
memory

Attention

Forgetting

Short-term
memory

Encoding

Forgetting

Long-term
memory
Forgetting

Ultrashort-term (sensory)
memory
Ability

to retain impressions of sensory information

after the original stimuli have ended.
System via which perception enters memory system
Iconic memory-200 milliseconds
Echoic memory 2000 milliseconds
Memory of olfaction

Short-term memory,

Lasts seconds to hours, during which processing in the

hippocampus and elsewhere lays down long-term changes in
synaptic strength

Limited capacity system (7 +2 chunks of information).

Lost on distraction.

Long-term memory

which stores memories for years and sometimes for life.

Capacity is unlimited.

Depend upon change in neuronal structure.

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.

It consists of a central executive located in the prefrontal cortex,

and two "rehearsal systems," a verbal system for retaining verbal
memories, and a parallel visuospatial system for retaining visual
and spatial aspects of objects (Baddeley , 2001) .

The executive steers information into these rehearsal systems

24

Working memory is modulated by dopamine.

Working memory at bedside can be tested by digit span backwards.

(harrison)

FROM SYNAPSES TO MEMORY

Memory is a special case of the general biological phenomenon of

neural plasticity.

Neurons can show history-dependent behavior by responding

differently as a function of prior input, and this plasticity of nerve
cells and synapses is the basis of memory

Neuro-Plasticity

Neurobiological evidence supports two basic conclusions.

First, short-lasting plasticity, which may last for seconds or

minutes, depends on specific synaptic events, including an increase
in neurotransmitter release.

Second, long-lasting memory depends on new protein synthesis,

physical growth of neural processes, and an increase in the number
of synaptic connections

Short- and long-lasting plasticity are based on enhanced transmitter

release, although the long-lasting change uniquely requires the
expression of genes and the synthesis of proteins.

the long-term change is also accompanied by growth of neural

processes of neurons within the reflex circuit

In vertebrates, behavioral manipulations can also result in

measurable changes in the brain's architecture.

For example, rats reared in enriched environments show an increase

in the number of synapses, small increases in cortical thickness, inc.
in the diameter of neuronal cell bodies, and inc. in the number and
length of dendritic branches.

Behavioral experience thus exerts powerful effects on the wiring of

the brain.

Long-Term Potentiation

LTP is observed when a postsynaptic neuron is persistently

depolarized after a brief burst of high-frequency presynaptic
stimulation.

LTP has a number of properties that make it suitable as a

physiological substrate of memory.
First, it is established quickly and then lasts for a long time.
Second, it is associative in that it depends on the cooccurrence of
presynaptic activity and postsynaptic depolarization.

Third, it occurs only at the potentiated synapses, not at all the

synapses terminating on the postsynaptic cell.
Finally, LTP occurs prominently in the hippocampus, a structure
with important memory functions

The induction of LTP is mediated postsynaptically and involve

activation of the N-methyl-D-aspartate (NMDA) receptor, which
permits the influx of calcium into the postsynaptic cell.

Associative Learning

Additional insights into memory have come from the study of the
neural circuitry underlying the classical conditioning of the eye
blinknictitating membrane response in rabbits.

Repeated pairings of a tone (conditioned stimulus) and an air puff

to the eye (unconditioned stimulus) lead to a conditioned eye blink
in response to the tone.

Reversible lesions of the deep nuclei of the cerebellum eliminate

the conditioned response without affecting the unconditioned
response. These lesions also prevent initial learning from occurring,
and, when the lesion is reversed, rabbits learn normally.

Thus, the cerebellum contains essential circuitry for the learned

association.

Molecular basis of memory

LTP (long term potentiation)

induction of LTP requires an influx of Ca through NMDA into the

postsynaptic cell.

The Ca activates directly or indirectly at least three protein kinases:

(1) calcium/calmodulin protein kinase II,

(2) protein kinase C and
(3) the tyrosine kinase

Ca2+/calmodulin kinases, protein kinase c and tyrosine kinases

promoting phosphorylation of neurotransmitter receptors

LTP is associated with a selective increase in the AMPA-type

receptor component of the EPSP

the increase in response of the AMPA-type receptors is due to a

rapid insertion of new clusters of receptors in the postsynaptic
membrane from a pool of intracellular AMPA type receptors stored
in recycling endosomes

The activation of the molecules involved in these signalling

pathways can last for minutes and thereby represent a sort of shortterm molecular memory

Short term to long term memory

Consolidation of memory requires protein synthesis

repeated exposure PK-A recruits MAPK

Both PKA and MAPK moves from the synapse to the nucleus of the
cell where

MAPK phosphorylates and inactivates the transcriptional repressor

CREB2

PKA activates the transcription factor, CREB-1 (the cAMP response

element-binding protein).
CREB-1 acts on downstream genes to activate the synthesis of protein
and the growth of new synaptic connections.

Structures involved in memory

Hippocampal formation (the dentate gyrus, the hippocampus, and

the subicular complex) and linked regions of medial temporal lobe
with prefrontal cortex play a critical role in encoding and retrieval
of episodic memory.

diencephalon structures : medial thalamus, mammilary body and

fornix

Interaction b/w HF and amygdala are important for emotional

memories.

Fear conditioning and extinction interaction b/w amygdala and

cingulate gyrus

basal ganglia and cerebellum is important for procedural memory

Priming neocortex

DLPFC(dorsolateral prefrontal cortex) working memory.

Neocortex is the ultimate store of memory.

CORTICAL ORGANIZATION OF
MEMORY

In the 1920s, Karl Lashley carried out a series of experiments.

Lashley recorded the number of trials that rats needed to relearn a

preoperatively learned maze problem after removal of different
amounts of cerebral cortex.

The deficit was proportional to the amount of cortex removed, and,

furthermore, it seemed to be qualitatively similar regardless of the
region of cortex that was removed.

Lashley concluded that memory for the maze habit was not
localized in any one part of the brain but instead was distributed
equivalently over the entire cortex.

Subsequent work has led to a revision of this idea. Maze learning in

rats depends on many forms of information, including visual,
tactual, spatial, and olfactory information.

These various forms of information are processed and stored in

different areas.

Thus, the correlation between retention score and lesion size that
Lashley observed reflected the progressive encroachment of the
lesion on specialized cortical areas serving the many components of
cognition important to maze learning.

Memory is distributed and localized in the nervous system.

Memory is distributed in the sense that, as Lashley concluded, there

is no single cortical center dedicated solely to the storage of
memories.

Yet, memory is localized in the sense that different aspects or

dimensions of events are stored at specific cortical sitesthe same
regions that are specialized to analyze and process those particular
aspects or dimensions of information.

Acetylcholine and Memory.

Two sets of acetylcholine projections are ,

Arising from the brainstem neurotransmitter center.

Arising from the basal forebrain.

Basal nucleus, or nucleus basalis (of Meynert), as well as the

medial septal nucleus

These cholinergic fibers a prominent role in memory

(S. Stahl textbook of
psychoparmacology)

Both animal and human studies Nucleus Basalis of Meynert in

the basal forebrain is the major brain center for cholinergic neurons
that project throughout the cortex .

Have the principal role in mediating memory formation.

Short-term memory disturbance of Alzheimer patients is due to
degeneration of these cholinergic neurons.

Other cholinergic neurons, such as those in the striatum and those

projecting from the lateral tegmental area , are not involved in the
memory disorder of Alzheimers disease.
harrisons principle of internal medicine.

Cholinergic deficiency degeneration limited to the nucleus

basalis of the basal forebrain mild cognitive impairment.

Cholinergic deficiency may also be a part of vascular dementia or

of alcoholic dementia.

This may be why some patients with vascular dementia or alcoholrelated dementias respond to cholinesterase inhibitors.

Lewy bodies damage cholinergic neurons in DLB.

Cholinergic deficiency may also become part of these dementias.

May respond to cholinesterase inhibitors.

When tau pathology affects the frontal and temporal lobe in

frontotemporal dementia, the memory disturbance, personality
changes, disinhibition, of this dementia are not generally improved by
cholinesterase inhibitors, because the pathology and these symptoms
do not arise from cholinergic neurons.
S.Sthal textbook of psychopharmacology

Insights from AMNESIA

the ability to learn new information or the inability to recall

previously learned information

The idea that the functional specialization of cortical regions

determines the locus of information processing as well as the locus
of information storage is important, but it does not provide a
complete account of the organization of memory in the brain.

If it did, then particular cortical injuries would disrupt only

particular domains of learning and memory (i.e., visual memory or
spatial memory). In other words, a global disruption of memory
would never occur.

The hallmark of neurological memory impairment is a profound

loss of new learning ability, or anterograde amnesia, that extends
across all sensory modalities.

Typically, this occurs together with retrograde amnesia, a memory

loss of some knowledge acquired before the onset of amnesia.

The retrograde deficit often has a temporal gradient, such that

memory for recent events is impaired, but memory for remote
events is intact.

Other cognitive functions are preserved, including linguistic

abilities, attention, immediate memory, personality, and social skills

This selectivity of the memory deficit in amnesia implies that the

brain has, to some extent, separated its intellectual and perceptual
functions from the capacity to lay down in memory the records that
ordinarily result from intellectual and perceptual work.

The fact that impaired new learning (anterograde amnesia) can

occur together with intact remote memory indicates that retrieval
mechanisms are intact and that the brain structures damaged in
amnesia are not the ultimate repositories of memory.

Common causes of amnesia

Traumatic Brain Injury (TBI)

Surgery

Infarctions

Alcohol and Illicit Drugs

Vitamin Deficiencies

Neurotoxins

Anoxia and hypoxia

Electroconvulsive Therapy

Limbic Encephalitis

The temporal lobe and memory

1940s and 50s: neurosurgical treatments for epilepsy.

Removal of medial temporal lobe, including the hippocampal

formation resulted in dramatic memory impairments, only if bilateral.

Patient HM - Increasing frequency of his temporal lobe epilepsy led to

bilateral surgery 1953 when he was 27 years old.

He remained of normal intelligence and had no psychological illness.

However, the surgery resulted in intense anterograde amnesia

54

Patient HM

Severe anterograde amnesia

normal STM

Normal LTM (for events prior to surgery)

Problem: transfer from STM to LTM

Could not consolidate new declarative
knowledge
Capable of acquiring implicit
knowledge
amygdala, uncus,
hippocampal gyrus, and
anterior two thirds of the
hippocampus were removed.

hippocampus is not a permanent storage area for explicit

knowledge.

hippocampus is involved [with other cortical areas] in

consolidation, a longer term process taking months to years (note
retrograde amnesia in hippocampus lesion patients for up to 3 yrs).

Consolidation is understood to involve biological changes taking

place in those other areas of cortex, and involving strengthening of
the associations between multiple stimulus inputs and previously
stored information.

Once this has fully taken place, the hippocampus is not required for
retrieval.

56

Frontal lobe and Memory

Although amnesia does not occur after limited frontal damage, the
frontal lobes are fundamentally important for declarative memory.

Patients with frontal lesions have poor memory for the context in
which information was acquired, they have difficulty in free recall,
and they may even have some mild difficulty on tests of item
recognition.

Patient B. G. suffered an infarction restricted to the right frontal

lobe, resulting in substantial false remembering.

He had an abnormal tendency to claim that some stimuli were

familiar, even though they had not been presented for study.

His false responses probably arose because he relied on a general

feeling of familiarity for the kind of stimuli that had been presented,
rather than on specific memories for the stimuli.

Korsakoff's syndrome

diencephalic amnesia

Korsakoff's syndrome is characterized by a pronounced anterograde

and retrograde amnesia and potential impairment in visuospatial,
abstract, and other types of learning.

result of a relatively severe deficiency in the vitamin B thiamine

Degeneration of the mammillary bodies is the neuropathological

hallmark of a Korsakoff's psychosis

regions likely include the mammillary nuclei, the dorsomedial

nucleus of the thalamus, the anterior nucleus, the internal medullary
lamina, and the mammillothalamic tract

Patients with alcoholic Korsakoff's syndrome typically have frontal

lobe pathology in addition to diencephalic damage

Confabulation and personality change are more common in

diencephalic amnesia (e.g., Korsakoff's syndrome) than in pure
hippocampal amnesia, perhaps reflecting a concomitant
involvement of frontal lobe structures or connections

MEMORY LOSS IN ALZHEIMERS

DISEASE

Degeneration of cholinergic neurons due to deposition of amyloid

plaque may begin early within the nucleus basalis of the basal
forebrain at the time of vague and undiagnosed memory symptoms.

Spreading to projection areas such as hippocampus, amygdala, and

entorrhinal cortex by the time of early diagnosis.

Then diffusely throughout neocortex by the time of nursing home

placement and loss of functional independence.

Eventually involving the loss of a great many neurons and

neurotransmitter systems by the time of death.

Episodic memory is impaired first;

Then short-term memory

Then semantic memory

Finally procedural memory

However, as the disease advances, parts of memory which were

previously intact also become impaired, and eventually all
reasoning, attention, and language abilities are disrupted.

Electroconvulsive Therapy

ECT produces a transient amnesia, manifested by a diminished

ability to form new memories during the period of treatment.

The amnesia remits within days or, at most, a few weeks after
completion of treatment.

The patient is left with a retrograde amnesia for many events during
the days or weeks of treatment.

Psychogenic amnesia

Also k/a dissociative amnesia/ functional amnesia

characterized by abnormal memory functioning in the absence of

structural brain damage or a known neurobiological cause.

It results from the effects of severe stress or psychological trauma

on the brain,

Psychogenic amnesias typically do not affect new learning capacity

The main positive symptom in psychogenic amnesia is extensive

and severe retrograde amnesia

Patients may be unable to recall their own name or to recollect

pertinent information from childhood or from some part of their
past

By contrast, patients with neurological amnesia never forget their

names, and their remote memories for the events of childhood and
adolescence are typically normal

Some patients with psychogenic amnesia have circumscribed

retrograde memory loss that covers a particular time period or that
covers only autobiographical memories

Assessment of memory

A complete assessment of memory usually involves assesment of

intellectual functions,
new learning capacity,
remote memory,
and memory self-report.

New Learning Capacity

two important principles

First, tests are sensitive to memory impairment when more

information is presented than can be held in immediate memory.
e.g. paired-associate task

Second, tests are sensitive to memory impairment when a delay,

filled with distraction, is interposed between the learning phase and
the test phase. Memory can be tested by unaided recall of
previously studied material (free recall), by presenting a cue for the
material to be remembered (cued recall), or by testing recognition
memory (yesno recognition tests, multiple-choice tests)

Remote Memory

Autobiographical memory tests : word-probe task-patients are

asked to recollect specific episodes from their past in response to
single word cues (for example, bird and ticket) and to date the
episodes. normal subjects Most of the memories come from
recent time periods (the past one or two months).
Patients with amnesia few episodic memories from the recent
past, but producing as many remote autobiographical memories as
normal subjects.

Test about material in the public domain e.g. about former oneseason television programs, news events, or photographs of famous
persons.

Memory Self-Reports

Patients can often supply descriptions of their memory problems

Tests used are called tests of metamemory

Depressed patients rate their memory as poor in a rather

undifferentiated way, endorsing equally all the items on a self-rating
form.

amnesic patients endorse some items more than others; that is,
there is a pattern to their memory complaints.

Amnesic patients do not report difficulty in remembering very remote

events or in following what is being said to them, but they do report
having difficulty remembering an event a few minutes after it happens

THANK YOU

References

Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 9th

Edition

Review of Medical Physiology, William F. Ganong, Twenty-third

Edition

Biology of memory, Larry r. Squire, ph.D., And kena. Paller, ph.D.

Stahl essential psychopharmacology

Harrison textbook of internal medicine,18th edition.

Cognitive Neuroscience and the Study of Memory Brenda Milner,

March, 1998 Neuron, Vol. 20, 445468.

The molecular biology of memory: cAMP, PKA, CRE, CREB-1,

CREB-2, and CPEB, Eric R Kandel, Molecular Brain 2012, 5:14

The Biology of Memory: A Forty-Year Perspective, Eric R. Kandel,

The Journal of Neuroscience, October 14, 2009 29(41):12748
12756

New Oxford Textbook of Psychiatry (2 ed.)