Neurobiology of Memory
Dr Ravi Soni
Dept. of Geriatric Mental Health
• Anatomical and Functional organization of memory
• Hippocampus formation
• Afferents and efferents from hippocampus formation
• Learning and memory
• Types of memory
• Cellular and molecular process in Short term and Long term
• Molecular mechanisms in Implicit memory
• Molecular mechanisms in Explicit Memory
• Long term Potentiation in Hippocampus
ANATOMICAL AND FUNCTIONAL
ORGANIZATION OF MEMORY
Introduction to the Limbic System
• Anatomically refers to areas surrounding the
diencephalon (limbus = border) and bordering the
• The “C”-shaped hippocampal formation and includes the
amygdala, cingulate and parahippocampal cortices.
The key to learning, memory, and behavior (including
emotional behavior) – of paramount importance in
Posterior section: Hippocampus, Fornix
Divisions or nuclei of
Note the hippocampal formation, fornix, and amygdala
I. Anatomical Location and Overview.
A. Limbic association cortex – surrounding
-medial + inferior (orbital) surface
cingulate gyrus, parahippocampal gyrus,
orbital gyrus, temporal pole.
B. the Hippocampal Formation and Amygdala.
Note the “C” shape, along with the major output paths for the
hippocampus: the fornix.
II. Hippocampal Formation:
A subcortical structure composed of allocortex.
A central function: Consolidation of STMs into
LTMs (+ many other limbic functions through
Note the 3 components
Neocortex and Allocortex
A.Components and structure –
a banana-shaped structure with its
components (dentate, hipp,
subiculum) folded upon one
another like a “jelly roll”.
Inputs are from entorhinal
cortex, which collects info
from other association areas
hipp formation + subculum
output to fornix and
also back to entorhinal cortex
Input and Output
Serial and Parallel Processing of Hippocampal Circuits
• Korsokoff’s Syndrome: thiamine deficiency (i.e.,
from alcoholism) degeneration of mammillary
• Other output: via entorhinal cortex to a number
of association areas, involve the prefrontal cortex
(control of mood and behaviours).
C. Anatomy and Information Flow in Greater
Cytoarchitechture dimensions of hippocampus
(Ammon’s horn): CA1, CA2, CA3, CA4 (hilus)
[CA = coronus ammonis].
A) Lateral Ventricle, B) ependymal glia (ventricular surface), C) Alvear Layer, (pyramidal axons)
3 layers of hippocampus (archicortex):
1. Polymorph Layer (pyramidal axons & basket cells (-))
2. Hippocampal pyramidal layer (pyramidal cell bodies)
3. Molecular Layer (pyramidal dendrites)
A) Lateral ventricle
B) Ependymal glia
C) Alvear layer
1. Polymorph Layer
2. Pyramidal Layer
3. Molecular Layer(pyramidal dendrite)
(pyramidal cell body)
(Corkin, Amaral, Gonzalez, Johnson and Hyman J. Neuro, 1997)
(Scoville and Milner, 1957)
Patient H.M. and the Human MTL
• Suffered head injury @age 9
– Developed severe epilepsy
• Surgeon surgically removed the medial
temporal lobe bilaterally
• HM suffered severe anterograde and
temporally graded retrograde amnesia
• Spared skill learning
Different regions of brain involved in specific
• Learning: relatively permanent change in an
individual's behavior or behavior potential (or
capability) as a result of experience or practice.
1. Change in behavior
2. Change takes place due to practice or experience
3. Change is relatively permanent
• Memory: is complex cognitive or mental process that
involves encoding, storage and retrieval of the
I. Encoding: is process of receiving input and
transforming it into a form or code, which can be
II. Storage: is process of actually putting coded
information into memory.
III.Retrieval: is process of gaining access to stored,
coded information when it is needed.
• Factual knowledge of people, places, things, and events, along with
concepts derived from this knowledge
• Well developed in vertebrate brain
• Explicit (declarative) memory is recalled by conscious effort, and can
involve assembly and association of many pieces of information in
• Dependent on the structures like medial temporal lobe of the cerebral
cortex and hippocampus formation
• Declarative memory can be further classified as episodic or
autobiographic memory and semantic memory.
Types of Explicit Memory
• allows us to remember
personal events and
experience and, being a link
between what we are and
what we have been, gives
us the sense of our
• is a sort of public memory
for facts and notions, be
they general or
• Over time, autobiographical
memory shades into
semantic memory so that
the experience of an event
is remembered as the
simple occurrence of such
• It refers to information storage to perform various reflexive or perceptual tasks is also
referred to as non-declarative memory because it is recalled unconsciously.
• When we use implicit memory, we act automatically and we are not aware of being
recalling memory traces.
• Implicit memory is a heterogeneous collection of memory functions and types of
learned behaviors such as
– reflexive learning (sensitization, habituation),
– classical conditioning,
– fear conditioning,
– Procedural memory (for skills and habits) and
– priming (the recall of words or objects from a previous unconscious exposure to them).
• Here simple associative form of memory are classical conditioning etc.
• Non associative forms such as sensitization and habituation
• It involves the cerebellum, the striatum, the amygdala, the neocortex and in the
simplest cases, the motor and sensory pathways recruited for particular perceptual or
motor skills utilized during the learning process
• Implicit memory, such as
learning to ride a bike, takes
time and many attempts to
• Implicit memory is much
more robust and may last
for all our life even in the
absence of further practice
• Explicit memory, such as
learning a page of history
or a telephone number, is
more immediate and
implies a smaller effort.
• explicit memory fades
relatively rapidly in the
absence of recall and
From short- to long-term memories: memory consolidation,
forgetfulness and recall
• Learning induces cellular and molecular changes that facilitate or impair
communication among neurons and are fundamental for memory
• If learning brings about changes in “synaptic strength” within neuronal
circuits, the persistence of these changes represents the way memories
• Short-term memory is believed to involve only functional changes in pre-
existing neuronal networks mediated by a fine tuning of multiple
intracellular signal transductions systems.
• These short-lived changes can undergo either of two processes:
– either fade out with time (forgetfulness) or
– be reinforced and transformed into long-term memory by a process called memory
• Forgetfulness is at least as important as consolidation.
• To be consolidated, functional changes have to be followed by gene
transcription and protein synthesis that produce permanent phenotypic
changes in the neuron associated with structural rearrangements in
• Thus, consolidation of memories is abolished by mRNA and protein
Cellular and Molecular processes in STM
1. changes in the excitation-secretion
coupling at the presynaptic level
promoted by changes in channel
conductances due to phosphorylation
and Ca2+ influx;
2. Ca2+ influx at the postsynaptic level
through NMDA glutamate receptors by
Ca2+/calmodulin kinases, protein
kinase C and tyrosine kinases
promoting phosphorylation of
neurotransmitter receptors and
generation of retrograde messengers
(such as nitric oxide and arachidonic
acid) that reach the presynaptic
terminal and increase
neurotransmitter release in response
to action potentials.
• The activation of the molecules
involved in these signaling pathways
can last for minutes and thereby
represent a sort of short-term
Role of CaMKII and PP1
• A very important role in the establishment of short-term memories is
played by the balance between Ca2+/calmodulin-dependent protein
kinase II (CaMKII) and protein phosphatase 1 (PP1).
• Upon Ca2+ influx during training, CaMKII undergoes an
autophosphorylation reaction that transforms it into a constitutively
activated kinase. The “switched-on” CaMKII, however, is returned to the
resting state by PP1 that thereby has an inhibitory effect on learning
• Thus, the antagonistic interactions between CaMKII and PP1 represent a
push-pull system that plays a fundamental role during learning as well as
in the delicate balance between maintaining and forgetting stored
Consolidation into Long Term Memory
• The sustained activation of the same pathways promotes memory consolidation by
affecting the gene transcription and translation.
• Sustained stimulation leads to persistent activation of the protein kinase A (PKA) and
MAP kinase Erk (MAPK) pathways.
• PKA phosphorylates and activates the transcriptional activator CREB1a, whereas MAPK
phosphorylates and inactivates the transcriptional repressor CREB2.
• The CREB family of transcription regulators is highly conserved across evolution and
represents the major switch involved in the transformation of short-term memory into
• The CREB target genes, whose transcription is regulated during consolidation, include a
set of immediate- early genes (such as C/EBP or zif268) that affect transcription of
• This results in changes, both increase and decreases, in the expression of an array of
proteins involved in protein synthesis, axon growth, synaptic structure and function
Molecular mechanisms of short- and long-term memory.
From Synapses to memory
• Memory is a special case of the general biological phenomenon of neural plasticity.
• Neurons can show history-dependent activity by responding differently as a function
of prior input, and this plasticity of nerve cells and synapses is the basis of memory.
• Experience can lead to structural change at the synapse, including alterations in the
strength of existing synapses and alterations in the number of synaptic contacts along
• Neurobiological evidence supports two basic conclusions.
1. Short-lasting memory: which may last for seconds or
minutes, depending on specific synaptic events, including an
increase in neurotransmitter release.
2. long-lasting memory: depends on new protein synthesis, the
physical growth of neural processes, and an increase in the
number of synaptic connections
• implicit memory can also be studied in a variety of simple
reflex systems, including those of higher invertebrates,
whereas explicit forms can best (and perhaps only) be studied
• Implicit memory can be studied through the gill- and siphon withdrawal reflex of the marine
invertebrate Aplysia californica (sea snail)
• Aplysia is capable of associative learning (including classic conditioning and operant conditioning) and
nonassociative learning (habituation and sensitization).
• Aplysia is able to learn very peculiar behaviors that, upon practice, can be consolidated into long-term
• The animal learns to respond progressively more weakly to repeated innocuous stimuli (e.g.
a light tactile stimulus), a behavior called habituation, and to reinforce the response to
repeated noxious stimuli (e.g. a painful electrical shock), a behavior known as sensitization.
• THESE IMPLICIT MEMORIES ARE STORED IN SPINAL REFLEX PATHWAYS
Nonassociative Learning in Aplysia
• Sensitization had been studied using the gill-withdrawal reflex, a
defensive reaction in which tactile stimulation causes the gill and siphon
• When tactile stimulation is preceded by sensory stimulation to the head
or tail, gill withdrawal is facilitated.
• The cellular changes underlying this sensitization begin when a sensory
neuron activates a modulatory interneuron, which enhances the strength
of synapses within the circuitry responsible for the reflex.
• This modulation depends on a second-messenger system in which
intracellular molecules (including cyclic adenosine monophosphate
[cAMP] and cAMP-dependent protein kinase) lead to enhanced
transmitter release that lasts for minutes in the reflex pathway.
Habituation in Aplysia
• If the siphon of the animal is
stimulated mechanically the
animal withdraws the gill,
presumably for protection.
• With repeated activation, the
stimulus leads to a decrease in
the number of dopamine-
containing vesicles that release
their contents onto the
Long-term storage of implicit memory for sensitization involves changes
shown in last slide plus changes in protein synthesis that result in formation
of new synaptic connections.
• With only short-term tail stimulation,
the sensitization will fairly quickly
disappear when tail stimulation ceases.
• However, the sensitization can be
made relatively permanent by
repeated tail stimulation.
• This long-term sensitization (and also
long-term habituation) occurs because
there are structural changes that occur
in the presynaptic terminals (sensory
neuron 1, for example).
• With sensitization, there is an up to 2-
fold increase in the number of synaptic
terminals in both sensory and
• Alternatively, with habituation, there is
a one-third reduction in the number of
synaptic terminals. Both of these
changes require altered protein
synthesis by mechanisms shown in Fig.
Associative learning in Aplysia
The molecular basis for classical conditioning in Aplysia
Long term Potentiation
• A large amount of studies demonstrated that LTP is indeed a valid model
of “memory storage”:
• LTP is observed when a postsynaptic neuron is persistently depolarized
after a high-frequency burst of presynaptic neural firing.
• LTP has a number of properties that make it suitable as a physiological
substrate of memory.
• It is associative, in that it depends on the co-occurrence of presynaptic
activity and postsynaptic depolarization.
• LTP occurs prominently in the hippocampus, a structure that is important
• The induction of LTP is known to be mediated postsynaptically and to
involve activation of the N-methyl-D-aspartate (NMDA) receptor, which
permits the influx of calcium into the postsynaptic cell.
• LTP is maintained by an increase in the number of α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionate (AMPA; non-NMDA) receptors in the
postsynaptic cell and also possibly by increased transmitter release.
Experimental setup for LTP
• A. Experimental setup for demon-
strating LTP in the hippocampus.
The Schaffer collateral pathway is
stimulated to cause a response in
pyramidal cells of CA1.
• B. Comparison of EPSP size in early
and late LTP with the early phase
evoked by a single train and the
late phase by 4 trains of pulses.
(Kandel, ER, JH Schwartz and TM
Jessell (2000) Principles of Neural
Science. New York: McGraw-Hill.)
• During normal synaptic transmission glutamate binds to non-NMDA receptors allowing
cations to flow through the channels and the cell membrane to hypopolarize.
• Glutamate also binds to metabotropic receptors, activating PLC, and to NMDA
• NMDA receptor channels can bind glutamate but no current will flow through the
channels unless the Mg++
that binds to the channel lumen is displaced. The latter event
can be effected by hypopolarizing the cell.
• the high-frequency stimulation opens non-NMDA glutamate channels leading to
• This dislodges Mg++
from the NMDA glutamate channels, and Ca++
enters the cells.
• The calcium triggers the activity of Ca-dependent kinases, PKC and Ca-calmodulin, and
tyrosine kinase. Ca-calmodulin kinase phosphorylates non-NMDA channels, increasing their
sensitivity to glutamate and a messenger is sent retrogradely to the presynaptic terminal to
increase the release of transmitter substance.
• In the late phase of LTP, calcium
enters the cell and triggers Ca-
calmodulin, which in turn
activates adenylyl cyclase and
• The latter translates to the
nucleus of the cell and starts
processes that lead to protein
synthesis and to structural
changes, i.e., the formation of
new synapses. Many scientists
believe that this is the substrate
for long-term memory–the
formation of new synapses.
Facts to be highlighted
• LTP induced by an experience, is inhibited by a novel experience
administered soon (within 1 hour) after the first one, whereas an LTP
established for more than 1 hour is immune to this reversal mechanism.
• Critical event in determining the retention of information may consist in the
stabilization of the potentiated Hippocampal synapses in order to resist to
LTP reversal upon new information.
• Although hippocampus is fundamental to acquire new memories, it appears to
be dispensable after the memory has been fully consolidated.
• Permanent memories are distributed among different cortical regions
according to the various perceptual features and that these various aspects
are linked so that, upon recall, the different components of a memory are
bound together to reproduce the memory in its integrity.
• hippocampus is still necessary to bind together the components of recent
memories, whereas more remote explicit memories can be recalled
independently of the hippocampus as the connections between cortical
• Plasticity by Santiago Ramon y Cajal as “the property by virtue of which
sustained functional changes occur in particular neuronal systems
following the administration of appropriate environmental stimuli or the
combination of different stimuli”.
• Most distinctive feature of the nervous system is the astonishing ability to
adapt to the environment and to improve its performance over time and
• Synaptic connections that are scarcely used become weaker and weaker
and eventually disappear
• Synapses that are heavily used become stronger and stronger and
eventually increase in number
• Neural plasticity represents the basis of the higher brain functions such as
learning and memory
• Built-in property of neural plasticity allows experience to shape both
functionally and structurally the nervous system.
• synaptic strength can be finely tuned over
– a short or even a long time scale by a combination of factors including previous activity
of the network, generation of second messengers, functional changes in pre- and post-
synaptic proteins as well as regulation of the expression of genes implicated in growth,
survival and synaptic transmission
• This results in changes in the efficiency of synaptic transmission
– That can last from fraction of seconds to minutes in case of short-term synaptic
plasticity (including paired-pulse facilitation or depression, augmentation, depression,
– That can last to hours, days and months in case of long-term synaptic plasticity (long-
term potentiation, long-term depression).