HIGHER FUNCTIONS OF

THE BRAIN: LEARNING

AND MEMORY
BY
ADEJARE, A. A.
DEPT. OF PHYSIOLOGY, CMUL.
TECHNIQUES OF ASSESSING THESE FUNCTIONS

• 1. Positron emission tomographic

(PET) scanning: for glucose
metabolism which is proportional to
neural activity.

PET scan in males (left) and females (right) for speech presentation
• 2. Functional magnetic resonance imaging (fMRI): to measure local oxygenated blood.
• The techniques can be used to study complex aspects of learning, memory, and perception.
• 3. Direct stimulation of the cerebral cortex in conscious humans undergoing neurosurgical procedures
or using chronically implanted electrodes:
• 4. Use of laboratory primates like chimpanzee
 LEARNING AND MEMORY

• Learning is the acquisition of information that makes alteration of behaviour on the basis of experience possible.

• Memory is the retention and storage of that information.

• A thought results from a pattern of stimulation of many parts of the nervous system at the same time in definite
sequence, probably involving the cerebral cortex, thalamus, limbic system etc.

• Memories are stored in the brain by changing the basic sensitivity of synaptic transmission between neurons as a result
of previous neural activity.

• The new or facilitated pathways are called memory traces. They are important because once the traces are established,
they can be selectively activated by the thinking mind to reproduce the memories.

• Most memory that we associate with intellectual processes is based on memory traces in the cerebral cortex.
MEMORY
FORMS OF MEMORY / CLASSIFICATION BASED ON THE TYPE OF MEMORY THAT IS
STORED
 EXPLICIT OR DECLARATIVE MEMORY

• It is the memory of the various details of an integrated thought, such as memory of an important experience that includes
(1) memory of the surroundings, (2) memory of time relationships, (3) memory of causes of the experience,
• (4) memory of the meaning of the experience, and (5) memory of one’s deductions that were left in the person’s mind.

• It is associated with consciousness—or at least awareness—and is dependent on the hippocampus and other parts of the
medial temporal lobes of the brain for its retention.
• Explicit memory is divided into episodic memory for events and semantic memory for facts (eg, words, rules, and
language).

• Explicit memories initially required for activities such as riding a bicycle can become implicit once the task is thoroughly
learned.
 IMPLICIT OR NON-DECLARATIVE MEMORY

• Does not involve awareness, and its retention does not usually involve processing in the hippocampus.

• It is frequently associated with motor activities of the person’s body, such as all the skills developed for hitting a tennis ball,
including automatic memories to (1) sight the ball, (2) calculate the relationship and speed of the ball to the racquet, and (3)
deduce rapidly the motions of the body, the arms, and the racquet required to hit the ball as desired,

• All of these activated instantly based on previous learning of the game of tennis—then moving on to the next stroke of the
game while forgetting the details of the previous stroke.
• Implicit memory is subdivided into four types.

• Procedural memory includes skills and habits, which, once acquired, become unconscious and automatic.

• Priming is facilitation of recognition of words or objects by prior exposure to them. An example is improved recall of a
word when presented with the first few letters of it.

• In non-associative learning, the organism learns about a single stimulus.

• In associative learning, the organism learns about the relation of one stimulus to another.
• In terms of the duration of the storage of the information

• (1) short-term memory, which lasts seconds to hours, during which processing in the hippocampus and lays down long-
term changes in synaptic strength.

• During short-term memory, the memory traces are subject to disruption by trauma and various drugs.

• Short-term memory is believed to be caused by continual neural activity resulting from nerve signals that travel around and
around a temporary memory trace in a circuit of reverberating neurons.
• 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 is that form of memory which permits us, for example, to look up a telephone number, then remember the number while
we pick up the telephone and dial the number.

• It consists of what has been called 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. The executive steers information into these rehearsal systems.

• Working memory areas are connected to the hippocampus and the adjacent parahippocampal portions of the medial
temporal cortex.
• Areas concerned with encoding explicit memories.

• The prefrontal cortex and the parahippocampal cortex of the brain are
active during the encoding of memories

• Note: In humans, bilateral destruction of the ventral hippocampus, or

Alzheimer disease and similar disease processes that destroy its CA1
neurons, cause striking defects in short-term memory, as do bilateral
lesions of the same area in monkeys.
 SYNAPTIC PLASTICITY AND LEARNING

• In post-tetanic potentiation (following stimulation in the presynaptic neurone), there is the production of
enhanced postsynaptic potentials in response to stimulation.

• This enhancement lasts up to 60 seconds and occurs after a brief (tetanizing) train of stimuli in the presynaptic neuron.

• The tetanizing stimulation causes Ca2+ to accumulate in the presynaptic neuron to such a degree that the intracellular
binding sites that keep cytoplasmic Ca 2+ low are overwhelmed.

• There is increased release of neurotransmitters from the presynaptic terminal because of increased intracellular Ca2+.
 SYNAPTIC PLASTICITY AND LEARNING

• Habituation (as seen in non-associative learning) is a simple form of learning in which a neutral stimulus is
repeated many times.

• The first time it is applied it is novel and evokes a reaction (the orienting reflex or “what is it?” response).

• However, it evokes less and less electrical response as it is repeated.

• Eventually, the subject becomes habituated to the stimulus and ignores it.

• There is reduced release of neurotransmitters from the presynaptic terminal because of reduced intracellular Ca2+
caused by progressive closure of calcium channels.
• Sensitization (caused by presynaptic stimulation/facilitation): is the
prolonged occurrence of augmented postsynaptic responses after a stimulus to
which one has become habituated is paired once or several times with a
noxious stimulus.
• Sensitization is in a sense the opposite of habituation.

• The short-term prolongation of sensitization is due to a Ca2+-mediated change

in adenylyl cyclase that leads to a greater production of cAMP.
• The long-term potentiation also involves protein synthesis and growth of the
presynaptic and postsynaptic neurons and their connections.
• In the figure above, there are two synaptic terminals. One terminal is from a sensory input neuron and terminates directly on the surface of the neuron
that is to be stimulated; this is called the sensory terminal.

• The other terminal is a presynaptic ending that lies on the surface of the sensory terminal, and it is called the facilitator terminal.

• When the sensory terminal is stimulated repeatedly but without stimulation of the facilitator terminal, signal transmission at first is great, but it
becomes less and less intense with repeated stimulation until transmission almost ceases. This phenomenon is habituation, as was explained
previously. It is a type of negative memory that causes the neuronal circuit to lose its response to repeated events that are insignificant.

• Conversely, if a noxious stimulus excites the facilitator terminal at the same time that the sensory terminal is stimulated, then instead of the
transmitted signal into the postsynaptic neuron becoming progressively weaker, the ease of transmission becomes stronger and stronger; and it will
remain strong for minutes, hours, days, or, with more intense training, up to about 3 weeks even without further stimulation of the facilitator
terminal.

• Thus, the noxious stimulus causes the memory pathway through the sensory terminal to become facilitated for days or weeks thereafter.

• It is especially interesting that even after habituation has occurred, this pathway can be converted back to a facilitated pathway with only a few
noxious stimuli.
• Our brain is inundated with sensory information from all our senses. If our minds attempted to remember all this
information, the memory capacity of the brain would be rapidly exceeded.
• Fortunately, the brain has the capability to learn to ignore information that is of no consequence.

• This results from inhibition of the synaptic pathways for this type of information; the resulting effect is called
habituation.
• Conversely, for incoming information that causes important consequences such as pain or pleasure, the brain has a
different automatic capability of enhancing and storing the memory traces.
• This is positive memory. It results from facilitation of the synaptic pathways, and the process is called memory
sensitization.
• Long-term potentiation (LTP): is a rapidly developing persistent enhancement of the postsynaptic potential response to
presynaptic stimulation after a brief period of rapidly repeated stimulation of the presynaptic neuron. It resembles
posttetanic potentiation but is much more prolonged and can last for days.

• Unlike posttetanic potentiation, it is initiated by an increase in intracellular Ca2+ in the postsynaptic rather than the
presynaptic neuron.

• There are two forms in the hippocampus: mossy fiber LTP, which is presynaptic and independent of N -methyl-D-
aspartate (NMDA) receptors; and Schaffer collateral LTP, which is postsynaptic and NMDA receptor-dependent.
Production of LTP in Schaffer collaterals in the hippocampus.
Glutamate (Glu) released from the presynaptic neuron binds to AMPA and
NMDA receptors in the membrane of the postsynaptic neuron.
The depolarization triggered by activation of the AMPA receptors relieves the
Mg 2+ block in the NMDA receptor channel, and Ca2+ enters the neuron with
Na + .
The increase in cytoplasmic Ca 2+ activates calmodulin (CaM), which in turn
activates Ca 2+ /calmodulin kinase II (CaM kII). The kinase phosphorylates
the AMPA receptors (P), increasing their conductance, and moves more
AMPA receptors into the synaptic cell membrane from cytoplasmic storage
sites. In addition, a chemical signal (PS) may pass to the presynaptic neuron,
producing a long-term increase in the quantal release of glutamate.
• (2) Intermediate long-term memory: which last for
days to weeks but then fade away;

• Experiments in primitive animals have demonstrated

that memories of the intermediate long-term type can
result from temporary chemical or physical changes,
or both, in either the synapse presynaptic terminals or
the synapse postsynaptic membrane, changes that can
persist for a few minutes up to several weeks.
• (3) long-term memory,
which stores memories for
years and sometimes for
life. Long-term memory
traces are remarkably
resistant to disruption.
• While the encoding process for short-term explicit memory involves the hippocampus, long-term memories are
stored in various parts of the neocortex.

• Apparently, the various parts of the memories—visual, olfactory, auditory, etc—are located in the cortical
regions concerned with these functions, and the pieces are tied together by long-term changes in the strength of
transmission at relevant synaptic junctions so that all the components are brought to consciousness when the
memory is recalled.
• Long-term memory is generally believed to result from actual structural changes, instead of only chemical changes, at
the synapses, and these enhance or suppress signal conduction. The most important of the physical structural changes

• that occur are the following:

• 1. Increase in vesicle release sites for secretion of transmitter substance

• 2. Increase in number of transmitter vesicles released

• 3. Increase in number of presynaptic terminals

• 4. Changes in structures of the dendritic spines that permit transmission of stronger signals
• Also note:

• Number of neurons and their connectivities often change significantly during learning: soon after birth, there is a principle
of “use it or lose it” that governs the final number of neurons and their connectivities in respective parts of the human
nervous system.

• For short-term memory to be converted into long-term memory that can be recalled weeks or years later, it must become
“consolidated.” That is, the short-term memory if activated repeatedly will initiate chemical, physical, and anatomical
changes in the synapses that are responsible for the long-term type of memory
• One of the most important features of consolidation is that new memories are codified into different classes of
information.

• During this process, similar types of information are pulled from the memory storage bins and used to help process the
new information.

• The new and old are compared for similarities and differences, and part of the storage process is to store the information
about these similarities and differences, rather than to store the new information unprocessed.

• Thus, during consolidation, the new memories are not stored randomly in the brain but are stored in direct association
with other memories of the same type.

• This is necessary if one is to be able to “search” the memory store at a later date to find the required information.
• Rehearsal enhances the transference of short-term memory into long-term memory neural basis of memory.

• The key to memory is alteration in the strength of selected synaptic connections. This usually involves protein
synthesis and activation of genes.

• In animals, acquisition of long-term learned responses is prevented if, within 5 min after each training session, the
animals are anesthetized, given electroshock, subjected to hypothermia, or given drugs, antibodies, or oligonucleotides
that block the synthesis of proteins.

• In humans, there could be retrograde amnesia ie loss of memory for the events that happened before the shock therapy.
 CONDITIONED REFLEXES

• A conditioned reflex is a reflex response to a stimulus that previously elicited little or no response, acquired by
repeatedly pairing the stimulus with another stimulus that normally does produce the response. A classic example of
associative learning is a conditioned reflex. In Pavlov experiment: the meat placed in the mouth was the unconditioned
stimulus (US),

• The stimulus that normally produces a particular innate response. The conditioned stimulus (CS) was the bell ringing.
After the CS and US had been paired a sufficient number of times, the CS produced the response originally evoked only
by the US.
• Neurogenesis

• New brain cells (neurons) form from stem cells throughout life in two areas: the olfactory bulb and
the hippocampus.

• There is evidence implicating a role of neurogenesis in the hippocampus with learning and memory.

• A reduction in the number of new neurons formed reduces at least one form of hippocampal
memory production.
APPLIED PHYSIOLOGY
• Alzheimer Disease: is the most common age-
related neurodegenerative disorder. Memory
decline initially manifests as a loss of episodic
memory, which impedes recollection of recent
events.

• Loss of short-term memory is followed by

general loss of cognitive and other brain
functions, the need for constant care, and,
eventually, death.
• Mechanism

• The cytopathologic hallmarks of Alzheimer disease are intracellular neurofibrillary tangles, made up in part of
hyperphosphorylated forms of the tau protein that normally binds to microtubules, and extracellular senile plaques, which
have a core of β-amyloid peptides (Aβ) surrounded by altered nerve fibers and reactive glial cells.

• The Aβ peptides are products of a normal protein, amyloid precursor protein (APP), a transmembrane protein that
projects into the extracellular fluid (ECF) from all nerve cells. This protein is hydrolyzed at three different sites by α-
secretase, β-secretase, and γ-secretase, respectively.

• When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced.

• However, when it is hydrolyzed by β-secretase and γ-secretase, polypeptides with 40 to 42 amino acids are produced; the
actual length varies because of variation in the site at which γ-secretase cuts the protein chain. These polypeptides are toxic,
the most toxic being A βσ1–42.

• The polypeptides form extracellular aggregates, which can stick to AMPA receptors and Ca2+ ion channels, increasing
Ca2+ influx. The polypeptides also initiate an inflammatory response, with production of intracellular tangles. The damaged
cells eventually die.
• THA