The Making of Neural Networks

Just as any information flow is facilitated by proper connections between the sender and receiver, the flow of information to and from the brain is through a complex network of nerves that connect brain to all body parts. However, a still more complex neuronal network exists in the brain itself by which, billions of nerve cells are connected to each other forming an infinitely complex network of nerve processes that ultimately carry out the innumerable brain functions.

The Neuronal ‘Chit Chat’

In a neuronal network, a single nerve cell could be connected to thousands of neighbouring nerve cells. Communication between cells of such complex biological circuits in the brain takes place through a chemical signal, the proper flow of which is essential for several brain functions. It is basically for their discoveries concerning this signal transmission between nerve cells that Arvid Carlson of the Department of Pharmacology, University of Gothenburg, Sweden: Paul Greengard of the Laboratory of Molecular and Cellular Science, Rockefeller University, New York and Eric Kandel of the Centre for Neurology & Behaviors, Columbia University, New York were jointly awarded the Nobel Prize in Physiology or Medicine for the year 2000. These pioneering discoveries concerning the chemical signaling between nerve cells are crucial for understanding the normal functioning of the brain.

Nerve cells or neurons have a central core or cell body containing a nucleus that carries the genetic material. Synthesis of different proteins is directed by the nucleus, which act as signal molecules or neurotransmitters that travel form the cell body, in the form of an electrochemical signal, passing down the neuron at lightning speed, to a long process called axon which branches into thousands of nerve endings. This signal is then transmitted from the nerve endings to the slender protrusions or tentacle-like structures called dendrites sprouting from the cell body of connecting neurons, thus enabling one neuron to link with thousands of its counterparts.

The site of contact between nerve endings of one neuron and dendrites of another is called the synapse, and it is at these synaptic junctions that several neurotransmitters carrying specific signals coded in their molecular structures are released. On being released at the nerve endings, the neurotransmitters blind to the receptor molecules present on the surface of dendrites of a receiving neuron, thus triggering another electrical impulse that carries on the message. Different neurons, therefore, ‘chit chat’ with each other in a language understood in the form of these chemical transmitters.

The credit for the discovery that the chemical ‘dopamine’ is a neurotransmitter, a key molecule in the brain responsible for controlling body movements goes to Arvid Carlsson. His pioneering work, which he did about five decades ago, conclusively proved that dopamine is not a precursor of another neurotransmitter, as was believed earlier, but is itself a powerful transmitter of electrical signals between neurons. Carlsson actually developed an assay by which tissue levels of dopamine could be measured with high sensitivity. He found that dopamine was particularly present in the cluster of neurons forming a region called ‘basal ganglia’ in the brain. This part of the brain plays a phenomenal role in controlling motor behaviour or body movements.

Needless to say, abnormally low and high levels of dopamine give rise to many diseases. Carlsson showed that experimental animals treated with ‘reserpine’ (a naturally occurring substance that depletes neurotransmitters) lost their ability to perform spontaneous movements. But the breakthrough occurred when Carlsson treated these animals with ‘levadopa’ (L-dopa) – a chemical precursor of dopamine. Result: The animal regained their normal motor behaviour. Carlsson experiments showed that the persons suffering from parkinsons disease or the ‘shaking palsy’ have a very low concentration of dopamine in the basal ganglia of their brains as neurons producing dopamine are degenerated.

This causes difficulty in body movements and severe muscle rigidity marked by tremors. Carlsons’s research thus, conclusively established the role of dopamine in the brain. A direct impact of this discovery has been the development of an efficient remedy for parkinsons disease. As the drug, L-dopa, gets transformed to dopamine in the brain, this chemical brings back the required levels of dopamine in the basal ganglion which, restores to quite an extent, normal muscle movements in Parkinson patients.

On the contrary, increased level of dopamine is the hallmark of the psychiatric disorder named schizophrenia. Based on Carlsson’s research, anti-psychiatric drugs have been developed which act preferentially on the synaptic functions, blocking dopamine receptors on dendrites of neurons receiving the electrical impulses. Thus, the passage of ‘unwanted electrical impulses is hampered. A new generation of anti-depressive drugs, which similarly block the receptor of another neurotransmitter namely, serotonin has been developed, thanks to Carlsson who discovered the importance of chemical signaling between nerve cells – the essence of all brain functions.

Even though the existence of neurotransmitters in the brain was known, the precise mechanism of action at molecular level became clear only in 1960s through Paul Greengard who discovered the key chemical reaction that marks all communications between neurons. Called ‘protein phosphorylation’, this chemical reaction involves the addition of phosphate groups to a protein which rather dramatically changes the form and function of the altered protein. Greengard showed that when the dopamine produced by a neuron, blinds to a receptor or an adjacent neuron, a cascade of reactions occur instantly. To start with, levels of messenger molecule, cyclic adenosine monophosphate (cAMP) rise which, in turn activates the protein kinases.

Activated protein kinases further add phosphate molecules to other proteins present in neurons. An important group of such proteins are the ones which constitutes the cell’s gateways. Called the ‘ion channels’, such proteins are obviously located in the cell membrane allowing the entry and exit of only select molecules in or out of the cell. As phosphate groups are added to an ion channel protein, it gets activated, thus allowing the entry and exit of certain ions. This causes the release of neurotransmitters.

Thus, Greengard showed that several neurotransmitters trigger a cascade of reactions in a neuron which involves the addition or removal of phosphate groups from proteins. A regulatory protein called DARPP-32 was discovered by Greengard which when activated, affects several ion channels of neurons, thus controlling the transmission of electrical signals through a synapse. The discovery of protein phosphorylation that influences signal transmission in neurons has ultimately helped in understanding the mechanism of action of many drugs. Phosphorylation of proteins is indeed a very significant event occurring in neurons. The work of Eric Kandel revealed its importance in the formation of memories.

Basically, Kandel worked on Aplysia, the sea slug a experimental model and showed how changes in the shape an function of a synapse in its neuronal network play a key role in the learning process and storing memories. A sea slug has neurons, many of which are quite large. A simple reflex of this animal that protects the gills was used by Kandel to study its basic learning mechanism. Certain external stimuli are known to enhance this protective gill withdrawal reflex of sea slug. As the strengthening of the reflex remains for several days, it shows that the sea slug ‘remembers’ the stimuli. Kandel showed that learning in sea slug was due to an increase in the size of synapse that connects sensory neutrons to those motor neurons which activate muscles responsible for the protective reflex.

Such classic experiments in sea slug have further revealed that protein phosphorylation of ion channels present in synaptic junctions play an important role in developing short term memory. As these ion channels are phosphorylated, they allow the entry of more calcium ions into the neurons which enhances the release of neuro-transmitters at synapse. This molecular event actually took place in sea slug which developed a short-term memory for the protective reflex in response to a weak, external stimulus.

Kandel showed that a more powerful, long lasting stimulus is required for the formation of long-term memory in the sea slug-Deciphering the changes occurring at molecular level for developing long-term memory, Kandel showed that a strong external stimulus increases the levels of cAMP in neurons. This activates protein kinases which, in turn, trigger the activity of certain genes in the neurons. The two proteins encoded by these genes affect the shape of synapse. An increase in the size of a synaptic junction creates a long-lasting transmission of chemical signals between the connected neurons.

Kandel also showed that if the synthesis of new protein is prevented, the long-term memory gets blocked but not the short-term memory. Repeating these experiments in mice, Kandel proved that the basic learning processes as studied in the sea slug were same in all mammals. As cellular and molecular mechanisms which make us learn and remember things are understood, there is a sure possibility of developing new drugs for enhancing memory power in patients who suffer from various types of dementia and memory loss, typical of Alzheimer’s disease.

This award winning work has thus, helped us to understand how the human brain functions and performs the bewildering range of tasks assigned to it. It has provided the key to unraveling the changes in brain chemistry which gives rise to many neurological and psychiatric diseases.

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