Neurobiology of Learning and Memory

A bridge to our past and future

―Learning is the process of acquiring new

information, while memory refers to the
persistence of learning in a state that can be
revealed at a later time‖ (Squire, 1987).
Greetings to
the 2014
Nobel
Laureates
Hippocampal Place cells

Hippocampal "place" cells are presumably the

principal cells in each of the layers that fire in
complex bursts when an animal moves through a
specific location in an environment. The region in
which a cell fires the most is that cell's "firing-field" or
"place-field" . Given a sufficient number, place cells
and their fields are able to cover or "map" any given
environment. Thus, evidence from place cells offers
strong support for the hippocampus' involvement
in spatial mapping.
Place cells fire at a high frequency the faster the
animal moves- locomotor cues
Higher the firing frequency of a place cell, the
smaller its place field.
Memory

 Hippocampus
 Essential for acquiring new long-tern
memories, but not for maintaining them.
 Amygdala
 Formation and storage of memories
associated with emotional events.
 Involved in the modulation of memory
consolidation.
 The Brain…

 Not static - churns things around

 Recombines invariant
representations.
 leads to entirely novel
concepts, and these concepts
can lead to action.
 Imagination, therefore, is a
reinvention of that which we
have experienced in new ways.
 Neocortex: A Preliminary Explanation

 Our experiences are

converted to
Memories

 Our memory pays

attention to the
unexpected
 Searching Your Memory Bank:
Neocortical Memory is Hierarchical

Conscious
Awareness: Conceptual
Invariant representation:
Integrating
experience
With situations

Impressions: sight, sound, and touch

are at the lowest level.
 Hippocampus: Helps regulate
emotion and memory
 Processes and
stores unique
sensory inputs

 A damaged
hippocampus
impedes memory

Cajal - ‗‗Principles of connection specificity‘‘

Memory
Changes in the sensitivity of synaptic
transmission between neurons as a result of
previous neural activity- causes new
pathways or facilitated pathways- memory
traces- can be activated by thinking mind to
reproduce memories.
memory traces- can occur at level of NS but
most of memory processes is based on the
memory traces of cerebral cortex.
Habituation- negative memory-ignore
information that is of no consequences
Important consequences- stored-positive
Classification of memories
Short term memory- lasts for seconds or
minutes unless converted to long term
memory
Intermediate long term memory- lasts for
days to weeks but then lost
Long-term memory- once stored can be
recalled up to years or even a lifetime later.
Neuroplasticity

 The process by which neurons create new

connections among themselves.

 We can change the way the brain works by

making a brain area more active through
remedial training

 New connections among neurons preserve

memories and make learning possible, but they
also fortify brain functions.
Neuroplasticity and Dyslexia

 These fMRI scans reveal the vigor of neuroplasticity

 Functional magnetic resonance imaging reveals areas in
the right and left hemispheres that are much more active
in strong readers than in struggling readers.
 With practice there is no discernable difference
Hermann Ebbinghaus developed the
first scientific methods for assessing the
acquisition and retention of a controlled
experience. To study ―pure memory‖
required a methodology that could
separate what the subject already has
learned from what the subject is now
being asked to remember. So he
invented the nonsense syllable.
 Described the syndrome produced by alcohol now
called Korsakoff‘s Syndrome. Characterized by
anterograde amnesia— the inability to acquire
new memories.
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.

Ribot’s Law: Ribot proposed that old memories are more

resistant to disease/disruption than new memories
Santiago 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.
 Ivan P. Pavlov
Developed the fundamental
methodology for studying associative
learning in animals.

Classical conditioning
 Developed the first methodology
for studying how we learn about
the consequences of our actions
= Instrumental conditioning
(Thorndikian conditioning)

The Law of Effect: The correct behavior was

learned because the consequences of successful
outcome (a satisfying state) strengthened
connections between the stimulus (S) and correct
response (R) and the consequence of
unsuccessful responses (annoying state) weaken
the competing and wrong S–R connections
  Declarative memory (explicit)
 Knowledge to which we have conscious access,
including personal and world knowledge
DEFINITIONS
 Nondeclarative memory (implicit)
 Knowledge to which we typically have no
conscious access, such as motor and cognitive
skills
 Episodic memory
 Stored information about events in one‘s life,
including information about when they happened
and what happened
 Semantic memory
 A category of memory that is believed to support
memory for facts and the ability to extract
generalizations across experiences
DEFINITIONS
 Procedural memory
A form of non-declarative memory that
involves the learning of a variety of motor
skills and cognitive skills (e.g., how to ride
a bike or how to read)
 Perceptual representation system
 A courier network that delivers sensory
information to the CNS to control muscles
of the body; anything outside the brain and
spinal cord.
  Amnesia
Deficits in memory as a function of brain damage,
DEFINITIONS
disease, or psychological trauma are known
collectively as amnesia.
 Priming

Priming is the improvement in processing a

stimulus as the result of previously having been
exposed to that stimulus.
 working memory

refers to a limited-capacity store that not only

retains information over the short term
(maintenance) but also permits the performance
of mental operations with the contents of this
store (manipulation).
Three gross stages of learning and memory

Acquisition
Storage
Retrieval
THE ATKINSON AND SHRIFFIN MODAL MODEL OF MEMORY
Taxonomy of Long-term Memory Systems
Hippocampal connections
 LTP and LTD
synaptic plasticity are generally viewed as a plausible
neural basis for learning and memory.
The phenomena of long term potentiation (LTP) and
depression (LTD), as commonly studied in the CA1
region of hippocampus, are important in part because
of the potential relationship between their longterm
expression and the persistence of memories.
Bliss & Lomo (1973) discovered that high-frequency
stimulation of neurons in the hippocampus results in
increase in synapse strength (known as long-term
potentiation, or LTP)
LTP: a sustained increase in synaptic strength
that is elicited by brief high frequency stimulation
of excitatory afferents.
LTP and LTD are activity dependent and mutually reversing and both lead to the induction
of plasticity and present the unwanted plasticity and the potential loss of memories.
hippocampus is a critical component of a neural
system that is required for the initial storage of certain
forms of long-term memory.
LTP can be generated rapidly and is strengthened
with repetition. It exhibits
Input specificity: LTP occurs only at synapses
stimulated by afferent activity but not at adjacent
synapses on the same postsynaptic cell.
associativity (Hebbian): LTP is readily elicited in in
vitro preparations of the hippocampus, and this
makes it amenable to rigorous experimental
manipulations.
Cooperativity: The probability of LTP increases with
the number of afferent fibers tetanically stimulated.
Persistence: Li lasts for many minutes (in brain
slices) to months when induced in vivo.
 Two phases of LTP: early (E-type) which
does not require protein synthesis, and late
(L-type) which does.

LTD is seen in hippocampus and cerebral cortex

where it can occur alongside LTP and in the
cerebellum (in which it is never seen).
Model for the Induction of LTP in the CA1 Region of the Hippocampus.
During normal synaptic transmission, glutamate (GLU) acts on both NMDA and AMPA
receptors. Na+ flows through the AMPA receptor channel but not through the NMDA
receptor channel because of the Mg++ block of this channel. Depolarization of the
postsynaptic cell relieves the Mg++ block of the NMDA receptor channel, allowing Na+
and Ca++ to flow through this channel. The resultant rise in Ca++ in the dendritic spine
is a necessary trigger for subsequent events leading to LTP.
 A Model for the
Signaling Cascades
Mediating LTD and
LTP

During prolonged 1 Hz stimulation (shown as traces below the LTD spine), Ca++ enters the dendritic
spine via the NMDA receptor channel and causes a small rise in Ca++. Ca++ binds to CaM, which
preferentially activates calcineurin (PP2B). Calcineurin then dephosphorylates inhibitor 1 (II), which
therefore no longer inhibits PPl. Active PPl may act upon any number of substrates, including
CaMKII, AMPA receptor subunits, or some unknown process that influences the production of
putative retrograde messengers. During high frequency stimulation (shown as traces below the LTP
spine), a large amount of Ca++ enters the dendritic spine via the NMDA receptor channel. Ca++
again binds to CaM and preferentially activates CaMKII. Active CaMKll may act on the same
substrates as those modified during LTD. The 60 mV cAMP-dependent protein kinase-(PKA) also
may be activated by high Ca++ and phosphorytate inhibitor 1.
NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
First messengers carry information between neurons; second messengers
carry the signal into the neuron
 What Can Promote our Learning and
Memory ?
 Intellectual stimulation and maternal behavior
enhance memory and increase both the strength and
number of hippocampal neurons as well as increasing
brain weight
 Oxytocin plays central role in social bonding and
maternal behavior but also facilitates positive social
memories (Guastella Biol Psychiat 2008)
 Sleep consolidates memory through simultaneously
reviewing the days events through the hippocampus
and visual cortex (Ji, Nature Neuroscience, 2007)
 Lack of sleep suppresses neurogenesis (Gould, Nat Rev
Neurosci. 2007)
 Deep brain stimulation (Herrera, 2006, 2008)
 Reflex Action
Relatively simple, stereotyped, reaction to peripheral stimulation
Impt. In clinical neurology
Neural circuitry- reflex arc (arc like anatomy of reflex circuits in
spinal cord)
Five neural elements:
1. receptor organ
2. an afferent neuron
3. interneurons in the cord or brain
4. efferent neurons
5. an effector organ (skeletal muscle, smooth muscle, gland)
Spinal reflexes:
 Flexion (withdrawal) reflex- toe pinch
 Crossed extensor reflex- steping on a tack or piece of glass
 Myotatic reflex (stretch reflex)- sudden stretching of muscle
 Inverse myotatic reflex- Golgi tendon organ mediates
 Scratch reflex
 Micturition reflex etc.
 Extensor muscle
Stretch reflex contraction Flexion reflex

Extensor stretch Extensor

receptor
Interneuron motor neuron
Interneuron
Flexor stretch Renshaw cells
receptor Interneuron
Pain receptor

Flexor motor
neuron

Flexor muscle
contraction
 Pain physiology
Fast pain Slow pain
Synonyms sharp pain, pricking pain, acute Slow burning pain, aching pain,
pain, electrical pain thrombing pain, nauseous pain and
chroninc pain
Example Needle stuck into skin, skin cut Tissue distruction
with knife, acute skin burn
Pain receptors Free nerve endings Free nerve endings
Stimuli Mechanical, thermal chemical
Chemicals Bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine,
eliciting pain and proteolytic enzymes
Prostaglandins and substance P enhance sensitivity but not directly elicit
pain
Pain fibers Fast: Aδ, 6-30 m/sec Slow: C fibers, 0.5-2 m/sec
transmitter glutamate Substance P
Tract Neospinothalamic tract Paleospinothalamic tract
Termination of Lamina I of dorsal horn (lamina Lamina II and III of dorsal horn
fibers marginalis) (substantia gelatinosa)
also Lamina V
Pain localization yes Very poor
Referred pain
When a person feels pain in a part of body that is
considerably remote from his body.
Gen. initiated in visceral organ and felt over the body
surface
Branches of visceral pain fibers synapse in the spinal
cord with second order neuron that receive pain signals
from skin.
Visceral pain
Pain from different viscera from abdomen and chest.
Diffused pain nerve endings