Memory

Overview.

Neural circuits.

Molecular signalling.

Ionotropic and metabotropic receptors.

Memory and molecules.

Implicit memory.

Explicit memory.

Mind, Memory and molecules.

Overview.

Scientists are beginning to understand, the functioning of memory,

quiet recently.

In general, synapses and neural circuits, play a central role, in memory.

Memory works in slightly different way, for different types of memory.

Memory can be considered to have two basic types.

Implicit memory.

Explicit memory.

Within each type of memory, there is a short term component,

and a long term component.

Implicit memory.

This comprises of motor and perceptual skills.

When a baby learns to walk, it goes into its implicit memory.

After it has learnt the motor skill, it becomes automatic.

There is no conscious effort made, to recall the skill required to walk.

This is true for other motor skills, we acquire later in life.

Some examples are :

learning to cycle.

learning to swim.

learning to dance.

learning to play the piano, etc.

These skills become unconscious, and we can recall them without effort.

Many reflex actions, are the result of implicit memory.

The eyelid response, of closing, to protect the eyes, is built into neural circuits.

When we touch something hot, a reflex action, acts to withdraw our hand.

The amygdala, and the cerebrum are involved in implicit memory.

Learning.

Memory is involved, in the learning process.

In implicit memory, the learning is unconscious.

Learning typically involves repetition.

Acquiring skills, involves repetition and refinement.

Some types of learning are:

Sensitisation.

If we experience something unpleasant, our neural circuits,

try to remember it, and avoid it, in the future.

If we have experienced an unpleasant electric shock,

even a mild sensation, caused by a mild voltage,

will cause us to recoil from it.

Our experience has sensitised us.

Habituation.

When we are exposed, to a repeated stimulus,

and we discover, that it is non threatening,

we get habituated to it.

If we suddenly hear, the sound of crackers bursting,

we would get startled.

When we discover, that it is only crackers, for a celebration,

we will get habituated, to the noise.

Future noise from the crackers, will no longer startle us.

Classical conditioning.

Here two unrelated stimuli are associated artificially.

A classical experiment was conducted, with a dog.

A bell was rung, and then food was offered to the dog.

This was repeated many times, till the dog got conditioned,

to associate to the sound of the bell, with food.

Now the bell was rung, but no food was offered.

The dog started to salivate, even without food.

Some habits that we form, are due to classical conditioning.

Operant conditioning.

This is learning which comes with behaviour,

and a response to the behaviour.

When the response is positive, we tend to repeat the behaviour.

When the response is negative, we tend to avoid the behaviour.

When the behaviour of a child, invites a scolding, it tends to avoid that behaviour.

When a behaviour is appreciated, it tends to repeat it.

Many cultural conditioning, is due to operant conditioning.

Explicit memory.

Explicit memory involves remembering facts and events.

When we do some actions, we remember them with explicit memory.

Who we met, when, where, and what they wore,

is a function of explicit memory.

This is also called as episodic memory.

Remembering words and their meanings, are a function of explicit memory.

This is called semantic memory.

Many other things that we learn, are also explicit memory.

What we learn in school, college, and many things in life, is part of explicit memory.

The hippocampus plays a central role,

in storage and retrieval of explicit memory.

Many areas of the cortex, are involved in storing a memory.

For example, a tune might be stored in the audio cortex.

An image might be stored in the visual cortex.

Typically the hippocampus would be involved in the process of encoding storage,

and retrieval of these memories.

Explicit memory process.

Explicit memory processing, involves four distinct stages.

Encoding.

Storage.

Consolidation.

Retrieval.

Encoding.

When the brain receives new information,

it links it to existing information in memory.

This linking is critical, in the process of learning.

For a memory to persist, and be remembered, it needs to be encoded.

This is accomplished, by associating it, with existing knowledge,

that is already established in memory.

Memory encoding is influenced, by the amount of attention directed,

to the incoming information.

The motivation to learn, is also important, in the encoding of memory.

When we are more attentive, and more interested, we tend to remember better.

Storage.

Memory is typically stored in neural circuits.

One of the fascinating aspect, of long term memory,

is that there no known limit, to the amount of memory storage.

We seem to have boundless, unlimited memory capacity.

In contrast short term working memory, is limited.

Studies have found, that we can store about 7 chunks of information,

in short term working memory.

Memory is stored, in different associated locations, and linked to each other,

through neural circuits.

Consolidation.

Consolidation is the process of transforming,

relatively short term memory, to long term memory.

Consolidation involves expression of genes, protein synthesis,

and building of new connections, and synapses with other neurons.

Retrieval.

Retrieval is the process by which stored memories are recalled.

It involves bringing back to mind, different kinds of information from different sites.

Memory is literally assembled and reconstructed from different storage sites.

One or more cues, can be used to retrieve a memory.

A single cue, can sometimes retrieve, a strong memory.

Many cues might be required, to retrieve a weaker memory.

A stronger memory typically involves building more number of connections,

between the neurons.

Associating what we want to remember, with many other facts, events or locations,

results in formation of stronger memories.

Neural circuits.

A neuron can connect to hundreds and thousands of other neurons.

This is specially true in the brain.

In the peripheral nervous system, the number of connections,

between neurons, is relatively less.

We all have experienced some reflex actions.

When we touch something hot, we instinctively withdraw our hand.

Our eyelids close, to avoid an intruding object.

These are unconscious reflex actions.

The memory and learning to do this,

is built into reflexive neural circuits.

Scientists have extensively studied,

reflex circuits, in simple animals.

Using the latest, imaging technology,

they have studied this circuits, at the individual neuron level.

Latest technology, also helped to study the biological processes involved,

at the molecular level.

In a simple reflex circuit, sensory neurons are connected to motor neurons.

In the peripheral nervous system, these connections, can be in the spinal cord.

When a stimuli is applied, it is sensed by the sensory neurons.

These in turn stimulate, the motor neurons to act.

This is the basic process involved in a neural circuit.

There are other neurons, which also connect to the sensory and motor neurons.

They are called inter neurons.

The inter neurons, modulate the signals, between the motor neurons,

and the sensory neurons.

The modulation can be excitatory.

The modulating neurons, can amplify these signal, received by the motor neuron.

This is what happens, in the process of sensitisation.

When a circuit has experienced an unpleasant electric shock,

the neural circuit remembers this experience.

When a milder current is experienced, the signal is amplified,

to stimulate the protective action, of the motor neuron.

The modulation can be inhibitory.

Here the modulating neuron inhibits the signal received by the motor neuron.

This is what happens, in the process of habituation.

When we hear a sudden loud noise, we get startled.

When we hear the sound of more harmless crackers bursting,

we get habituated.

We no longer get startled.

The modulatory neuron, by giving an inhibitory signal,

suppress or reduce the response of the motor neuron.

Neural circuits specially, the synapses between the neurons,

play a central role, in memory and learning.

It would be interesting to learn, the processes at the molecular level.

This will help us understand, the biology of memory, at the very basic level.

This will lay the foundation, of our understanding, of memory and learning.

Molecular signalling.

Extracellular signalling.

Neurons use electrical and chemical signalling mechanisms.

Most of the signalling mechanisms, at the synapse, is chemical.

The sending neuron, releases neurotransmitter molecules, at the synapse.

These molecules diffuse, across the synaptic cleft.

They bind to a receptor, in the post synaptic membrane.

In many cases, this leads to an opening, of an ion channel.

The chemical signal gets transduced to electrical signal.

Intracellular molecular signalling.

Neurons also use intracellular molecular signalling.

The neurotransmitter binds to the receptor.

This binding activates the receptor.

It then stimulates, a cascade of intracellular reactions.

Typically they use a second messenger molecule, to trigger a chain reaction.

These reactions result in a physiological state, of the receiving neuron.

They modulate the behaviour of the neuron.

The intracellular signal transduction, can also cause longer lasting changes.

These changes involve altering the transcription of genes,

and synthesis of new proteins.

The intracellular signalling pathways involve a long chain of chemical reactions.

This allows for a very fine precise control, of the behaviour of target neurons.

The coordination of electrical and chemical activity, in related neurons,

influence the behaviour of neural circuits.

Memory and learning involve the behaviour of neural circuits.

Molecular signalling process.

Molecular signalling mediates, and modulates all brain functions.

The chemical signal has three components.

A molecular signal, that transmits information from one cell to another.

A receptor that transduces, the information received.

A target molecule, mediates the cellular response.

The part of this process, that takes place within the cell,

is called intracellular signal transduction.

An advantage of chemical signalling, is signal amplification.

Amplification occurs because,

the reactions can generate a much larger number of molecular products,

than the number of molecules, that initiates the reaction.

A single neurotransmitter molecule, that binds to its receptor,

can generate many thousands of second messenger molecules, like cyclic AMP.

This can impact an even larger number, of target proteins.

This in effect produces an amplification of tens of thousands.

This amplification, ensures a physiological response in the neuron.

The complex signal transduction pathways, has another advantage.

It facilitates precise control of cell behaviour.

Some molecular interactions, transfer information rapidly.

Some molecular interactions, transfer information slowly,

and are longer lasting.

Having multiple levels of molecular interactions,

facilitates intricate timing, of desired response.

An example of amplification:

The signalling molecule is norepinephrine.

This leads to the activation of numerous G proteins.

The activated proteins, bind to other signalling molecules,

like the enzyme adenylyl cyclase.

Each activated enzyme generates a large number of cyclic AMP molecules.

Cyclic AMP binds to and activates the enzyme, protein kinases.

The protein kinases, phosphorylates many more target proteins.

The net result is a large increase, in the potency, of the original signal.

Receptor types.

There are many types of receptors for molecular signalling:

Ligand gated ion channels.

Enzyme linked receptors .

G protein coupled receptors.

Intra cellular receptors.

These receptors bind to specific signalling molecules.

This binding causes a conformational change, in the receptor.

This triggers the subsequent signalling cascade.

Ligand gated ion channels.

These receptors are proteins, embedded in the membrane.

Here the neurotransmitter, binds to the extracellular side of the molecule.

This causes, another part of the same molecule, to open an ion channel.

Typically, these receptors are ionotropic receptors.

G protein coupled receptors.

These receptors involve an intermediate transducing molecule.

These types of receptors, are typical of, what is called as metabotropic receptors.

These molecules are called GTP binding proteins, or G proteins.

They regulate intracellular reactions.

G proteins serve a important function, as the molecular transducing element,

that couples membrane receptors, to their molecular effectors, within the cell.

When a transmitter binds to a receptor, the G proteins get activated.

They trigger a cascade of other reactions.

Activated G proteins alter the function of many down stream effectors.

Most of these effectors, are enzymes that produce, intracellular second messengers.

Example of an effector enzyme, is adenylyl cyclase.

The second messengers produced, initiate a complex biochemical signalling cascade.

A specific G protein, typically activates, a specific pathway.

There are many types of G proteins.

Each of them can initiate distinct pathways.

G proteins can also bind to, and activate ion channels.

Some neurons, and heart muscle, have G protein receptors, which bind acetylcholine.

They open up potassium channels.

This inhibits the rate at which neurons fire action potentials.

This slows down the beating of cardiac muscle.

Second messenger.

Neurons use many different second messenger, as intracellular signals.

Each second messenger, can activate its own pathways.

Calcium.

Calcium is a common intracellular messenger.

It influences many different neuron functions.

Calcium binds to a large number of calcium binding proteins,

that serve as molecular targets.

Cyclic AMP.

Another important group of second messenger, are cyclic nucleotides.

Cyclic AMP is one of the more common, cyclic nucleotide second messenger.

Cyclic AMP, is cyclic adenosine monophosphate.

It is a derivative of the common cellular energy storage molecule, ATP.

Adenylyl cyclase converts ATP, to cyclic AMP, by removing,

two phosphate groups, from ATP.

A common target of cyclic AMP, is cyclic AMP dependent protein kinase A.

This is known as PKA.

Second messenger target.

Second messengers typically regulate neuron functions,

by phosphorylation of proteins.

Phosphorylation is the addition of phosphate groups to a protein.

Phosphorylation changes the function of the protein.

Typically dephosphorylation, will reverse this change.

Phosphorylation is frequently used to switch on and off,

the function of a protein.

Proteins of phosphorylated, by a wide variety of protein kinases.

The activity of protein kinases, can be regulated,

by second messengers, like calcium or cyclic AMP.

The primary effector of cyclic AMP,

is cyclic AMP dependent protein kinase A, or PKA.

PKA has two catalytic subunits,

and two regulatory subunits.

The regulatory subunits act as inhibitors.

In normal state, PKA is inactive.

Cyclic AMP, activates PKA by binding to the regulatory subunits.

This causes the catalytic subunits to be released.

The PKA is now said to be activated.

The catalytic subunit of PKA, phosphorylates many different target proteins.

The second messenger calcium, activates calcium dependent protein kinase.

This molecule phosphorylates, a large number of protein,

involved in intracellular signal transduction.

It is involved in phosphorylating ion channels.

Nuclear signalling.

Some second messengers can enter the nucleus,

and promote the transcription of new RNA.

They can act like genetic switches, which can, turn genes on and off.

Once a gene is turned on, it transcribes new RNA.

This in turn can synthesise, new proteins.

This can result in long term changes, in the neuron.

For example, new synapses can be formed.

The first step in RNA synthesis, is the de-condensation of the structure,

of chromatin.

This provides binding sites, for RNA polymerase and transcription factors.

RNA polymerase is an enzyme complex.

Transcriptional activator proteins attach to the binding site,

that are present in the DNA.

These sites are present, near the start of the target gene sequence.

The net result, is to stimulate RNA polymerase, to assemble,

in the promoter region of the DNA.

This triggers RNA transcription.

RNA is then exported to the cytoplasm.

Here it serves as messenger RNA, for translation into protein.

Intra cellular signal transduction, regulate DNA expression.

This has a direct impact on formation of long term memory.

The molecule, cyclic AMP responds element binding protein,

is called CREB.

CREB is normally bound to its binding site, on DNA.

This site is called cyclic AMP response element or CRE.

In unstimulated cells, CREB is not phosphorylated,

and therefore not active.

Phosphorylation of CREB, potentiates transcription.

Multiple signalling pathways converge by activating kinases,

that phosphorylate CREB.

These include calcium and PKA.

CREB is involved in formation of new synapses.

This is called synaptic plasticity.

The wide variety, of molecular signalling pathways,

generate responses, over a wide range of time, and distances.

This greatly augment and refines, the information processing ability,

of neural circuits, and the brain.

Ionotropic and metabotropic receptors.

Ionotropic receptors.

When a neurotransmitter binds to an ionotropic receptor,

it opens an ion channel.

Ionotropic receptors are, ligand gated receptors.

The neurotransmitter, is the ligand or molecule, which binds to the receptor.

The receptor, is a macro molecule, which directly opens up,

and lets ion flow through.

This is the most common form, of communication across the synapse.

These channels produce a fast response.

The response is very brief, and lasts only for a few milliseconds.

Ionotropic receptors mediate behaviours,

from simple reflexes, to complex cognitive processes.

This kind of synaptic transmission,

is used in most motor and sensory processing.

Ionotropic receptors, regulate channels,

that function as simple on-off switches.

Their main job is to excite a neuron, to fire an action potential,

or to inhibit the neuron from firing.

These channels are normally confined, to post synaptic membranes.

There action is local.

Metabotropic receptors.

Metabotropic receptors are also ligand gated.

They respond when a neurotransmitter binds to them.

But a essential difference, is that they do not directly open an ion channel.

They regulate the opening of ion channels, indirectly,

through biochemical signalling pathways.

Metabotropic receptors modulate behaviours.

They modify reflex strength,

help focus attention,

set emotional states.

They also contribute to long lasting changes, in neural circuits,

that underlie learning and memory.

The actions of ionotropic receptors are local.

Metabotropic receptors, can act on channels,

which are located at a distance.

Metabotropic receptors, typically act as modulators.

They modulate the strength and efficacy of synaptic transmission.

The modulator can increase the strength of a signal,

like in sensitisation.

The modulator can decrease, the strength of the signal,

like habituation.

Ionotropic receptors change the balance of charge,

across the neuron’s membrane, very quickly.

When a metabotropic receptor is activated,

the initial action begins locally, but spreads to a wider region, of the cell.

When a neurotransmitter binds to a metabotropic receptor,

it activates a protein.

The protein in turn activates effector enzymes.

The effector enzymes often produce second messenger molecules.

The second messenger diffuses, within the cell,

and activates other enzymes.

These modify the activity of a variety, of target proteins.

One of the common type of metabotropic receptors,

is called as G protein couple receptor.

Typically these receptors, use a second messenger.

A prominent second messenger, is cyclic AMP.

Cyclic AMP is produced from adenosine triphosphate, or ATP.

Memory and molecules.

Memory is related to the functioning of neural circuits.

These circuits are regulated, and modulated, by molecular signalling.

We have discussed some key molecular signalling mechanisms.

These mechanisms play an central role in memory.

Research to understand memory, at the molecular level, is quite recent.

Scientists have studied, the functioning of memory,

in great detail, in simple animals.

Thanks to imaging and other advanced technologies, now available,

it is possible to study memory, at the neuron level, and the molecular signalling,

that takes place within the neuron.

This has given us, a first level insight,

of how memory works at the molecular level.

The same basic principles of memory,

are involved in higher level animals, including human beings.

We will briefly discuss, the broad concepts, in memory,

and the underlying molecular mechanisms.

At the molecular level,

implicit and explicit memory, work in different ways.

Within it, short term and long term works,

in very significantly different ways.

We will discuss each case separately.

Implicit memory.

Implicit memory is an unconscious process, by which neural circuits,

learn from experience and training.

Implicit short term memory.

Implicit memory is unconscious and automatic.

A reflex action, is a classical case of implicit memory.

Even very simple animals, learn reflex actions, using implicit memory.

We will discuss the specific case, of sensitisation, in implicit memory.

Learning involves memory.

Behaviour is modified by memory.

The functioning of the neuron, before and after learning,

will help us to understand, the molecular level functioning of the neuron.

Scientists studied implicit memory, in a simple animal.

The animal was sensitive to touch.

Its behaviour was modified, when it was given,

an unpleasant electric shock.

The animal learnt to become more sensitive to touch.

Simple neural circuit.

We can construct a simplified model of the neural circuit,

involved in reflex actions.

A sensory neuron, in an organ of the animal,

senses touch, and generates an action potential.

This action potential is communicated to a motor neuron.

The motor neuron triggers a reflexive action, in the muscle.

The muscle contracts, and the animal withdraws the organ.

Some neurons, called interneurons, also connected to the sensory neuron,

and the motor neuron.

These interneurons can perform, regulatory and modulatory functions,

to the sensory neuron, and the motor neuron.

Before learning process.

A stimuli is sensed by the sensory neuron.

This is translated into an action potential.

This action potential travels along the sensory neuron, till it reaches the synapse.

At the synapse, the action potential causes,

voltage gated calcium channels, to open.

Calcium ions flow into the synapse.

The synapse has vesicles containing neurotransmitters, say glutamate.

The calcium ions causes the vesicles to move, and bind with the presynaptic membrane.

The vesicles open, and release the neurotransmitter glutamate.

The neurotransmitter diffuses across the synaptic cleft.

They bind to the glutamate receptors, in the post synaptic membrane.

This causes the ligand gated, sodium ion channels to open.

Sodium floods into the post synaptic membrane, of the motor neuron.

This generates a action potential, in the motor neuron.

The motor neuron, acts on the muscle, causing it to contract.

This results, in the normal, pre-learning reflex action.

After learning process.

The neural circuit, has experienced a strong unpleasant stimuli.

The modulatory interneuron is aware of this.

When the mild stimuli is applied, the modulatory neuron,

releases another neurotransmitter, called serotonin.

The modulatory neuron has a synapse with the sensory neuron.

Serotonin is released at this synapse.

This binds to the post synaptic membrane.

These receptors are G protein coupled receptors.

It engages an enzyme adenyl cyclase.

This causes to convert ATP to cyclic AMP.

Cyclic AMP is the second messenger.

Cyclic AMP carries information to the molecular machinery in the neuron cell.

It activates cyclic AMP dependent protein kinase.

This is called protein kinase A, or PKA.

PKA has two subunits.

A regulatory and a catalytic subunit.

In the normal state, the regulatory unit inhibits the catalytic subunit.

The cyclic AMP binds to the PKA.

This causes a conformation change.

This frees the catalytic subunit.

This leads to phosphorylation of several proteins.

This includes acting on potassium ion channels .

Some of the potassium ion channels close preventing outflow of potassium ions.

This action prolongs the presynaptic action potential.

This causes more calcium channels, to open.

This results in more calcium flowing in.

More calcium influx, results in more neurotransmitter release.

This results in a stronger chemical signal, at the presynaptic signal membrane.

We note, that before learning calcium influx resulted,

in the release of a certain amount of neurotransmitters.

After learning more calcium influx, is induced by the neurotransmitter serotonin.

This results in more neurotransmitters, glutamate, being released after learning,

from the sensory neuron to the motor neuron.

This enhances synaptic transmission,

between the sensory neuron and the motor neuron.

The modulatory neuron, which released serotonin,

has succeeded in effectively increasing the signal strength, for the same stimuli.

This is a functional change.

This is the basic biological change, involved in short term implicit memory.

Implicit long term memory.

Repeated training, results in formation of long term memory.

This also results from serotonin release, from the modulatory neuron.

More frequent serotonin release, results in more cyclic AMP.

This activates PKA, persistently.

Like in short term memory, this results in increased release,

of glutamate from the pre-synaptic membrane.

In this case however, PKA is involved in another interesting process.

PKA phosphorylates and activates, the transcriptional activator, CREB.

CREB binds to Cyclic AMP Responsive Elements, or CRE.

This acts on regulatory regions, of DNA.

This results in transcription of other genes.

Many downstream processes, are activated.

One of them, is the stimulation of an enzyme, by CREB.

This enzyme is called Ubiquitin hydroxylase.

This stimulates degradation, of the regulatory sub unit, of PKA.

This causes, a persistent increase, in the amount of free catalytic, PKA.

This PKA, is persistently active.

It no longer requires serotonin to be activated.

CREB also stimulates, other genes which results in production of proteins.

These proteins participate in building more synaptic terminals.

This results in the increase, in the synapses of the sensory and motor neurons.

They cause long lasting changes, in the overall strength, of the circuit connections.

This structural change, in the neurons is the basis of long term memory.

Explicit memory.

Explicit memory involves remembering facts and events.

It is a conscious process.

Many areas in the brain are involved, in explicit memory.

Of particular significance and importance, is the hippocampus.

The hippocampus, is located in the medial temporal lobe, under the cerebral cortex.

The hippocampus, is involved in formation and retrieval of memory.

There are some specific areas, in the hippocampus, which are of special significance.

A special circuit, in the hippocampus processes memory related events.

2 distinct areas, have been identified, and named as the CA3, and the CA1 regions.

From the cortex, a pathway leads to granule cells.

Fibres from the granule cells, called mossy fibres, connect to the CA3 neurons.

The axons of the CA3 neurons, called Schaffer collaterals, connect to the CA1 neurons.

Much of the study of explicit memory,

has focused on the synapse between CA3 and CA1 neurons.

AMPA and NMDA receptors.

AMPA and NMDA are two type of receptors, commonly found,

in memory circuits of the hippocampus.

AMPA receptors.

AMPA receptors are ligand gated receptors.

When the neurotransmitter, glutamate binds to an AMPA receptor,

it opens up ion channels.

This allows sodium ions, to flow in.

This generates an EPSP.

This results in depolarisation, of the receiving neuron.

NMDA receptors.

NMDA receptors are also ligand gated.

The neurotransmitter glutamate binds to this receptor.

But, this receptor, works in a different way.

When glutamate binds to it, the channel does not open.

The channel is blocked by a magnesium ion,

when the post synaptic neuron, is at its resting potential.

In this state, in spite of binding to glutamate, the channel remains inactive.

No EPSP is generated.

The magnesium blockade, of the NMDA receptor is voltage sensitive.

When there is a prolonged depolarisation, the blocking magnesium ion,

is expelled.

This allows the ion channel to open, and allow calcium ions to flow in.

The increased calcium ions, are the trigger for long term potentiation, or LTP.

The NMDA receptor, works as a coincidence detector.

Two events have to occur simultaneously.

1. Glutamate has to bind to the receptor.

2. Postsynaptic cell, has to be depolarised, to remove the magnesium blockade.

More than one type of event, can cause the depolarisation,

of the postsynaptic cell.

A persistent signal, can cause summation of EPSPs, and cause depolarisation.

Many times memories, are formed by association.

If a neighbouring pathway, synapses with the same cell, is activated,

along with the main signal, the summation of the signals, can cause LTP.

This joint activation of synaptic inputs, can be considered,

as the molecular equivalent of associative memory.

It is well known that association, helps in formation of long term memory.

NMDA is a calcium ion channel.

Opening of this channel, results in a calcium influx.

Calcium acts as a second messenger.

Calcium induces LTP, by activating signal transduction cascades.

This typically involves calcium dependent protein kinase.

This is the most abundant protein, in Schaffer collateral synapses.

It plays an important role in inducing long term potential, or LTP.

It is involved in adding new AMPA receptors.

It is also involved, by acting as a second messenger,

in activating gene expression, and creation of new synapses.

Explicit short term memory.

Repeated stimuli causes an increase, in the potentiation of the connection,

between the CA3 and CA1 neurons.

This can last for several hours.

This is called as an early phase of long term potentiation.

Two type of receptors are present in the post synaptic membrane.

They are called as AMPA, and NMDA receptors.

Normally, the glutamate acts only on the AMPA receptors.

The NMDA cells are normally blocked by a magnesium ion.

After training, the glutamate is able to activate the NMDA receptors also.

When there is a strong coincident presynaptic and postsynaptic activity,

the NMDA receptor is activated.

The presynaptic activity releases glutamate.

The coincident postsynaptic activity, releases the magnesium block.

This allows the influx of calcium ions.

Calcium activates a second messenger, called calcium sensitive kinase.

This acts by inserting additional AMPA receptors.

This causes the post synaptic membrane to be more sensitive to glutamate.

The signalling mechanism acquires more persistence.

This results in short term synaptic plasticity.

This is the underlying mechanism for explicit short term memory.

Explicit long term memory.

Long term memory is activated by more than one pathway.

NMDA receptors get activated by appropriate combination of stimuli.

Under specific conditions, this could involve,

gene expression and synthesis of new proteins.

This is called as a late phase of LTP.

It is initiated by protein kinase A.

This goes on to activate transcription factors, like CREB.

This stimulates expression of other proteins.

This results in formation of new synapses.

New synapses, are the foundation of long term memory.

Long term memory can last from weeks to a lifetime.

Mind, memory and molecules.

Every process of the mind, is carried out by the brain.

The brain is somewhat, like the hardware.

It processes the thoughts, in our mind.

Every mental function, of the brain,

is carried out, by separate neural circuits.

Different regions of the brain, have specialised neural circuits.

Each region, typically specialises, in one or a few functions.

We have a good understanding, of the anatomy of the brain.

We have a fairly good understanding, of the broad functional areas, of the brain.

The cortex is the higher level processing centre, of the brain.

Anatomically it is like a crown, on our more primitive brain.

It is our superior cortex, that differentiates us, from other animals.

The cortex has about 50 specialised areas.

All these areas are interrelated in someway.

This is what makes our brain fascinatingly complex.

Interestingly all the neural circuits, are made of the same kind of signalling units.

The basic unit of the brain, is the neuron.

Of special interest, is the synapses of the neuron.

The synapses perform, the communication function.

The synapses are also central, to memory.

The functioning of each individual synapse, influences memory.

A neuron can have thousands of synapses.

The collective functioning of the synapses, form the basis of neural circuits.

These neural circuits are the basis, of memory.

We do not yet know, all the possible connections, that exists, in the brain.

Scientists have undertaken, an ambitious project,

to map all the connections in the human brain.

The project is called as the connectome project.

Molecular mechanisms, are at work at each synapse.

They trigger a cascade of bio chemical reactions, within the neuron cell.

We are beginning to understand, the functioning of these molecules,

and related biochemical processes.

What we have discussed, is the simplest of cases,

in terms of functioning of memory.

These results, have led us to understand, the fundamental basics,

of the functioning of memory, at the molecular level.

This science of memory, is at the nascent stage.

Scientists are carrying out extensive research, into the functioning of memory.

We can expect, many more fascinating discoveries to emerge, in the years to come.