Biological basis of memory

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 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

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.

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.

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.

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.

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.
17

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

 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 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 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 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 (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

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, 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 –
12756
 New Oxford Textbook of Psychiatry (2 ed.)

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