BIOLOGICAL BASIS OF

MEMORY

Dr. Karrar Husain

Moderator : Dr. Piyush P.

Singh

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 learning—anxieties, 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.

INTRODUCTION

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.

Storage

(Maintain in

memory)

Retrieval

(Recover from

memory)

Encoding

(Code and put into

memory)

Basic Memory Processes

Historical Foundations: The

Golden AgeAbout 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 AgeThéodule Ribot proposed that during

disease of the brain, memories disappear

in an orderly fashion.

The Dissolution of Memory

First Last

Ribot’s Law: Ribot also proposed that old memories are more resistant to

disease/disruption than new memories.

Historical Foundations: The

Golden AgeSerge Korsakoff

Described the syndrome produced by alcohol now called

Korsakoff’s Syndrome.

The syndrome is characterized by what we would now

call anterograde amnesia—the 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

Golden AgeWilliam 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

Golden AgeSantiago Ramón y Cajal

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

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.

Ivan P. Pavlov

Developed the fundamental

methodology for studying

associative learning in

animals.

Figure 1.8 Pavlovian conditioning is widely used to study learning and memory in

animals

TYPES OF MEMORY

Sensory

Memory

Short-term

(Secondary,

Working)

Long-term

(Primary)

Declarative

(knowing what)Non declarative

Episodic semantic

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 weren’t paying attention.

Short term is seconds to minutes, as with retaining a phone number.

Long-term is longer—days, weeks, going up to years, or even a lifetime.

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Information-Processing Model of Memory(Atkinson-Shiffrin model)

Short-term

memoryStimulus

Sensory

memory

Long-term

memory

Attention Encoding

Retrieval

Forgetting ForgettingForgetting

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

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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

blink–nictitating 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 short-

term “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 sites—the 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 fibersa 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 Alzheimer’s disease.

harrison’s 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 alcohol-

related 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 hippocampalformation 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

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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.

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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 (yes–no 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 one-season 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-thirdEdition

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, 445–468.

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 –

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New Oxford Textbook of Psychiatry (2 ed.)