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USC Health & Medicine, Winter 1995:  "The Mind's Eye" 

by Richard Cox

The debate regarding the relationship between the mind and the brain has raged literally for centuries, capturing the imaginations of philosophers and scientists alike.  Three centuries ago French philosopher Rene Descartes held forth on the subject of dualism, depicting the mind as separate from the brain.  He perceived the mind as some sort of out-of-body experience expressed through the pineal gland, a small, pea-sized organ buried deep within the brain.

While he was wrong about casting the pineal in this exalted role, Descarte certainly gave scientists a lot to talk about.  Given the era, he was at a distinct scientific disadvantage.  Today, neuroscientists realize that the pineal gland is actually only one element of an interdependent system governing how we think, feel and act.  Applying the powerful tools of cellular and molecular biology, researchers at USC and other institutions are beginning to decipher this complex physiologic process, a process that begins with our eyes.

“Vision and the processing of visual information is initiated in the retina, but the retina also has been useful as a model for understanding information processing in the brain.  The visual system offers a perfect place for researchers to begin to study the brain, since so much of the human experience is based upon what we see,” says Cheryl Craft, Ph.D., Mark D. Allen Professor and chair of USC’s Department of Cell and Neurobiology.  Craft joined USC in the summer of 1994 and continues to investigate how the hormonal and behavioral activities of a person are modulated by the visual input from the eye influencing the biological clock of the hypothalamus, the part of the brain which regulates spontaneous activities such as body temperature and metabolic process.

“We may learn more about the brain by coming to understand the eye,” she says.  “the eye is so accessible.  The brain, of course, isn’t.

“By monitoring the metabolic processes and shifts in cerebral blood flow into different parts of the prestriate cortex—that part of the brain connected to the retina by the optic nerve—we can tell where those elements of the visual world, like color, form, and motion, are processed,” she says.  “But how the brain attaches meaning to this information remains the unsolved mystery.”

The pineal gland has intrigued Craft since her graduate student days when she first understood the evolutionary change to which the pineal has been subjected.  While its role in humans has yet to be fully understood, much has been gleaned about its impact on other vertebrates.

Under the skin in the skull of a lizard lies a light-responsive “third eye” which is the evolutionary equivalent of the bone-encased, hormone-secreting pineal gland in the human brain.  The human pineal is denied access to light directly, but like the lizard’s “third eye,” it shows enhanced release of its hormone, melatonin, during the night.  Craft notes, “The challenge is to understand the mechanisms which regulate the synthesis and release of melatonin.  The pineal gland is the ‘mind’s eye.’  Dissected, the reptile’s pineal looks much like an eye, with the same shape and tissue.

“The pineal is one of several interactive centers in the brain that can alter an individual’s behavior.  However, it uniquely remains the major source of circulating melatonin, an essential hormonal component in the neuronal circuitry of behavior which occurs during the nighttime.”  Melatonin synchronizes the pineal gland so we know when to go to sleep at night and when to get up in the morning.  It tells the body how the outside world is perceived.

“Melatonin has received a lot of attention lately in the popular press,” continues Craft.  “It has been professed to have many functions, from inducing sleep to increasing precocious sexual behavior.  The widespread belief that melatonin intake is a sure cure for jet lag has made it a steady seller in health food stores.”

The presence of light reduces the pineal gland’s secretion of melatonin, and darkness stimulates production.  Since daylight and darkness affect the gland’s production of the hormone, the pineal functions as a kind of internal timepiece.

“The pineal is no master gland where human experience is somehow embedded, controlling interaction between mind and body, as Descartes thought,” she says.  While researchers are reluctant to label the pineal gland as the ultimate source of our daily metabolic cycle—the so-called “circadian clock”—they have been able to gauge melatonin’s impact on the natural rhythm of our bodies.  Increase production of melatonin lengthens the amount of sleep we need, influences the foods we choose to eat, and the amount of weight we gain.  Affected by seasonal changes detected by the eyes, our bodies shift forward or slow down when stimulated or deprived of light.

“The retina is the ‘window to the brain’ through which the eyes reveal the external environment to the interpretative action of the brain,” Craft comments.  “For example, we recognize that the length of day becomes shorter in the winter.  Sensing the reduced hours of sunlight, deciduous trees drop their leaves.  Humans don’ have leaves to drop, but our brain is acutely aware of the diminished period of sunlight.  In some individual the winter may be accompanied by feeling of sadness or depression.”

This depressing effect of light deprivation is characterized in a form of an illness called seasonal affective disorder (SAD).  The "blues" can be so disabling in some people that they are unable to function during the darker periods of the year.  Yet, with the advent of spring, many SAD sufferers have a spontaneous remission of their depression.  Treatment often consists of prolonging the positive affects of daylight through the use of intense artificial light.  Recent research suggests that this light therapy is effective in alleviating depression even when patients are blind, revealing the complex role vision plays in our neurobiology.

From an evolutionary standpoint, the pineal may have been intended to work in concert with our eyes.  Using molecular biology techniques, Craft has shown that the pineal and retina express a number of genes in common.  "The photoreceptors cells of the mammalian retina, as well as the pineal are able to produce melatonin," explains Craft.  "Our current findings suggest that retinal melatonin is sequestered, at least partially, from the blood circulation, leaving the pineal melatonin to be the dominant source for the body."

The clock mechanism that drives hormonal and metabolic changes in darkness or light lies deep within the brain in a collection of about 10,000 neurons known as the suprachiasmatic nucleus.  Craft says, "The informational message center of this nucleus communicates with the pineal and other regions of the hypothalamus that influence the hormonal regulation of body activities.  Somehow, between the cycles of day and night and production of melatonin from the pineal, the nucleus may help to determine, among other things, when you feel sad, sleepy, optimistic, or energized."

While these findings represent an important contribution toward understanding certain types of human behavior, Craft believes the most important discoveries have yet to be made.  She points out, "There is much to learn about the function of melatonin and its role in health maintenance or disease."

Answers will have to wait as researchers continue to grapple with some of the most fundamental matters involving the human biological clock.  For Craft, that means cloning the enzymes that regulate the synthesis of melatonin in the pineal and retina and improving our understanding of the melatonin receptor.

Craft admits, "There are unrealized potentials in neuroscience that relate to affective disorders and cognition.  It seems reasonable that the circadian clock, acting through the pineal, will turn out to be a powerful instrument to which the stability of our mental health is firmly synchronized."

She notes that a major step toward resolving a functional role for melatonin will occur when scientists are able to breed laboratory mice that lack the melatonin receptor gene.  "Without this receptor gene, we will be able to see how the mice are affected by the loss of a melatonin target," explains Craft.

"Who knows?  Maybe we'll be the ones who resolve the big questions about mind, matter, and a clockwork universe.  Only time will tell," she says, no pun intended.

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