GENE IS THE KEY: Nobel Laureate Eric Kandel identified the gene called stathmin, as the one that controls both innate and learned fear in mice — AP

FEAR IS an essential emotion that enables animals to protect themselves from potential danger.

It is of two kinds: innate fear and learned fear. Innate or instinctive fear comes to animals naturally, in response to predators. The other kind, learned fear, arises as a conditioned reflex. It involves the pairing of two stimuli.

One of them is neutral, such as a ringing bell or flashing red light. The associated one is potentially dangerous, such as an electric shock or fire. If an animal is given the shock immediately after the bell or light, it learns to associate the latter with the former and shows fearful behaviour when it hears the sound or sees the flashing light.

Of the two, learned fear can often manifest itself as anxiety disorder or mental illness. It thus becomes of medical interest to understand the biological basis of fear — both instinctive and learned fear so that we can better understand some forms of these pathologies.

Having too much fear can be harmful since it can freeze one into inaction and can even be life-threatening.

Neural pathways

Neurologists have thus focused their attention on trying to learn the genetic and biochemical mechanisms underlying the neural pathways in the brain that are involved in fear. The Nobel Prize for Medicine/Physiology was awarded in 2000 to Drs. Arvid Carlsson of Goteborg University, Sweden, Paul Greengard of Rockefeller University and Eric Kandel of Columbia University of New York for their elucidating some aspects of brain function. Carlsson was the one to show that dopamine is a transmitter of information across nerve cells in the brain. Greengard elucidated some of the biochemical processes involved in such information transfer. Kandel worked with the sea slug as a simple animal model (it has only 20,000 cells in its brain, versus billions in ours), and identified the synaptic circuitry connecting the sensory nerve cells (which sense the signal) to the muscle cells that produce the reflex action.

Where the action is

Professor Kandel has continued his work on the brain functions in higher animals and in particular the mouse. The sensation of fear in mammals (including humans) is felt and processed in the small almond-shaped pair of tissues, in the rear middle part of the brain, called amygdala (named after the Greek word for the almond).

Studies by Dr. Gleb Shumyatsky and colleagues in his laboratory, published in the year 2002, indicated that a gene designated as GRP (encoding the molecule called gastrin releasing peptide) appears to inhibit the action of the `circuitry' in the amygdala that is associated with learned or conditioned fear reflex.

Using the technology of gene knockout, the group bred in the laboratory two groups of mice — one normal and the other wherein the GRP gene was knocked out.

Both groups were taught fear by linking a particular sound with an electric shock. If they hear the sound, they anticipate and react to the forthcoming shock. The contrast in behaviour between the two groups was distinct. Mice lacking the GRP gene were far more afraid than the normal mice. They showed a greatly enhanced fear response, `freezing' for a longer time than the normal ones.

This was the only difference between the two. Bring a cat near and the two groups ran for safety just as fast. In their innate or instinctive fear response, there was no difference. Also, in their sensitivity to pain itself they were no different.

The researchers could thus identify a signalling network important for inhibiting memory specifically related to learned fear. Their results thus suggest that the GRP gene acts to dampen fear.

Would it therefore be possible to treat anxiety disorders in humans by developing drugs that activate or `overexpress' the GRP — a tantalizing question.

Stathmin relates to both forms of fear: This work has been concerning the implication of GRP with learned fear.

Now comes another paper in the November 18, 2005 issue of Cell by Gleb Shumyatsky (who has since moved to the Rutgers University in New Jersey), Eric Kandel and others, identifying the gene called stathmin, which is enriched in the amygdala, as the one that controls both innate and learned fear in mice.

Here again, they used gene knockout technology and created a group of mice that lacked the stathmin gene. They next compared the fear reaction of these knockout mice with that of normal mice (that have the stathmin gene intact).

The difference was dramatic. Mice lacking the stathmin gene were fearless daredevils. Knocking out the stathmin gene knocked out any kind of fear in them — both innate and acquired fear.

Stathmin-knockouts

They ventured out into open spaces fearlessly and also forgot, more often than not, to freeze when sighting cats. However, stathmin-knockouts were seen to be normal in their spatial memory, pain response and other types of brain activity, and comparable to normal mice.

Their behaviour was similar, in effect, to the fearlessness seen in individuals with damaged amygdala.

The stathmin gene encodes the production of the protein stathmin, which controls the formation of architectural assembly molecules called microtubules in cells.

While the stathmin gene is present in most cells in the body, its expression is particularly rich in (and also largely restricted to) the brain. This feature, namely that stathmin is active only in the brain's amygdala, offers the possibility of developing drugs that can tone down its effect (to lessen fear and anxiety) or enhance it (to control excessive aggressive behaviour or daredevilry).

It is to be noted that the stathmin gene is also present in humans and presumably performs the same role in us, as in mice. Sports authorities and Olympics officials beware — there might now be a new class of performance-enhancing substances!

D. Balasubramanian

dbala@lvpei.org

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