When I was a medical student in the late 1950s, I was taught that a simple rule governed the workings of the entire body. That rule, called homeostasis, stated that the constituents of blood, along with physical characteristics such as blood pressure and temperature, were maintained within a narrow range by feedback loops. These closed-loop systems would simply not allow blood pressure, for example, to rise or fall beyond a certain set point.
However, the systems could sometimes be interrupted by stress or disease, and the set points could vary somewhat with the time of day. For instance, body temperature is normally about a degree lower at 6 A.M. than at 6 P.M. Still, it was an article of faith that no important compound or process in the body could go unregulated. That rule included the processes by which the body converts nutrients from the diet into the chemicals it uses to transmit messages.
These chemical messengers act in two ways. Some transmit a specific message from one nerve cell across a narrow gap known as a synapse to another nerve cell; these are known as neurotransmitters. Other chemicals, called hormones, flood the bloodstream, carrying messages to all parts of the body. Together, these chemicals provide a remarkably effective communication system that permits the brain to control behavior as well as most bodily functions and growth.
Under the rule of homeostasis, the rate at which the body produces these chemicals from nutrients would not be affected by the timing of a person’s meals. For example, many of the body’s hormones, such as the testosterone or estrogen that regulate sexual development, are made from cholesterol. Yet scientists had (and still have) no reason to think that eating a cholesterol-rich meal would increase the production of either.
However, my associates and I have found that homeostasis does not govern the production of some of the most important neurotransmitters. The frequencies with which nerve cells make and release acetylcholine, serotonin, norepinephrine, and some other neurotransmitters are not controlled by closed feedback loops. Their production depends very much on the amount of certain nutrients that happen to be available at a particular time. And the availability of those nutrients, in turn, can depend on what one has eaten at a recent meal or snack.
A carbohydrate-rich breakfast (containing, say, orange juice, toast, and jelly) increases the level of serotonin in the brain, while a protein-rich meal does the opposite. This “open loop’ is not something that nature overlooked in the course of natural selection. Rather, it serves the crucial function of providing the brain with information on what the body has just digested.
The ability of some neurons to make more of their neurotransmitter when given the appropriate nutrient is also providing physicians with a new strategy for treating other disturbances in brain function. Mixtures of purified nutrients can be given to patients to increase the production of neurotransmitters that are thought deficient in certain diseases.
This method has proven quite successful in treating Parkinson’s disease, a motor-control disorder that results from a deficiency of the neurotransmitter dopamine. The strategy is now being tested on other brain disorders, including depression and Alzheimer’s disease, a tragic disorder that robs people of their memory, intellect, and eventually the ability to care for themselves.
The Amino Acid Clue
Subsequent research revealed that the changes in amino-acid levels are caused not by some intrinsic “clock’ mechanism but by what the subjects happen to have eaten. If, for instance, food is rich in protein, then levels of amino acids in blood plasma increase markedly, in proportion to the amounts of each amino acid in the proteins being consumed.
Conversely, if the food contains only a little protein but a lot of carbohydrate, then blood levels of most of the amino acids fall. This occurs because eating carbohydrates immediately prompts the pancreas to release insulin. The insulin acts on many cell membranes to ease the entry of sugars, fats, and amino acids into the tissues, hastening their departure from the bloodstream. (In diabetics, the blood levels of sugar and amino acids can rise precipitously after eating, because there is insufficient insulin to shepherd these nutrients into the body’s tissue reservoirs.)
But, we wondered, did these food-induced variations in amino-acid levels in the blood have any effect of their own? More specifically, would eating a meal that raised blood levels of an amino acid lead to a parallel increase in its conversion to neurotransmitter?
Even asking such a question seemed a little inappropriate, as it smacked of teleology–the idea that everything in the body exists for a purpose. At the time, many scientists regarded that concept with suspicion. Furthermore, the question implied that the brain’s ability to make some of its important constituents might be beyond its control, subject to such vagaries as whether one ate pizza for lunch on Tuesdays.
To probe this hypothesis, we decided to study the synthesis and release of serotonin, a neurotransmitter of particular interest because its levels in the brain were known to be affected by psychoactive drugs. It was also known to be involved in sleep. Serotonin is formed from tryptophan and released throughout the brain from terminals of neurons in the brain stem, which controls basic functions such as breathing and blood pressure.
John Fernstrom, then a graduate student, and I wondered whether giving rats low doses of tryptophan could cause enough of an increase in brain tryptophan levels to accelerate the production of serotonin. We measured brain levels of both serotonin and a particular waste product–5-hydroxyindole acetic acid (5-HIAA)–that is formed whenever serotonin is released from nerve endings. That gave us an index of how much serotonin was being released when the neurons fired.
Much to our pleasure, we observed that animals given even a very small dose of trytophan–much less than they would normally consume as part of their diet–exhibited robust increases in levels of brain serotonin and 5-HIAA. We next decided to find out whether giving tryptophan in its “natural’ form–as a constituent of food–could also cause predictable changes in brain serotonin. Thus was born research into the effects of food on chemicals in the brain.
The Blood-Brain Paradox
Our early experiments worked–but not in the way we anticipated. If we gave rats a meal rich in protein, thus providing the animals with tryptophan, brain levels of tryptophan and serotonin fell–even though blood levels of tryptophan rose. Conversely, when rats consumed a meal that lacked tryptophan entirely (containing carbohydrates and fats but not protein), brain levels of tryptophan and serotonin consistently increased.
Research done elsewhere revealed an explanation for this seeming paradox: it stems from the way amino acids are transported across the “blood-brain barrier.’ This much-vaunted membrane, which keeps many compounds that commonly circulate in the blood from entering brain tissue, exists in the cells that line each tiny capillary within the brain. To get through this barrier, an amino acid must bind to a carrier protein on the inside rim of membrane, which probably conveys it to an “assembly line’ of proteins that ultimately release it into brain tissue. However, the carrier protein that binds to tryptophan also binds to five other amino acids; hence, tryptophan must “compete’ with these other compounds to enter the brain.
We found that when rats ate protein, blood tryptophan levels rose less than the levels of other amino acids consumed, which are more abundant in protein. Thus, tryptophan’s access to the brain was diminished, and serotonin production slowed. On the other hand, when rats ate a carbohydrate-rich, protein-free meal, the resulting secretion of insulin lowered the blood levels of other amino acids without depressing those of tryptophan. (This occurred because of tryptophan’s unique property of binding to a blood protein that insulates it from insulin.) As a result, tryptophan’s competitive position improved, allowing more of the amino acid (which was in the bloodstream from previous meals) to enter the brain and be converted to serotonin.
We soon found that other neurotransmitters shared this unusual property. For instance, when we fed rats another food constituent, choline, or the larger molecule phosphatidyl lcholine (“lecithin’) which normally provides most choline in the diet, we found that both the production and release of the neurotransmitter acetylcholine increased. Similarly, giving rats tyrosine, the amino-acid precursor for a family of neurotransmitters known as the catecholamines, also accelerated the formation of these compounds.
However, this effect occurred only under certain conditions, which differed from those necessary for converting tryptophan into serotonin. For example, tyrosine and choline increased the production of their neurotransmitter products only when the neurons involved in their conversion were actively firing. Both precursors had little or no effect on the production of neurotransmitters in less active neurons. In contrast, administering tryptophan never failed to speed up serotonin production. This crucial difference stems from the way specific enzymes convert these amino acids into neurotransmitters.
More recently, we have observed that the supply of some amino acids in brain neurons declines markedly when the neurons that use them as neurotransmitter precursors fire frequently. Indeed, these neurons may completely exhaust their reservoir of these key nutrients after periods of intense activity. Other research has shown that such neurons fire frequently during periods of stress. Perhaps that is why our ability to maintain normal lives while coping with severe crises is limited.
Diet Conscious Rats
Why should evolution have provided the brain with neurons that vary the release of their transmitters according to nutrient intake? We speculated that perhaps these neurons have some special role in food choice. To test this hypothesis, Dr. Judith Wurtman, my wife and collaborator, allowed rats to choose among various foods having different proportions of carbohydrates and proteins but similar calories and–to human palates at least–similar tastes.
We hypothesized that the proportions of proteins and carbohydrates in what the animals ate for “breakfast’ would determine brain serotonin levels at “lunchtime.’ We also expected that if rats ate a breakfast causing a net increase in serotonin–one rich in carbohydrate and poor in protein–they would tend to choose a lunch with the opposite nutrient composition and neurochemical effect. Of course, laboratory rats don’t actually eat breakfast and lunch. Instead, they consume 20 to 25 small meals during 12 hours of darkness and a few nibbles during daylight. Therefore, we gave the animals a small “premeal’ of either pure carbohydrates or mixed nutrients. Then, several hours later, we allowed them to choose between two diets containing equal amounts of protein and calories but either 25 percent or 75 percent pure carbohydrate. As anticipated, the composition of the premeal had no effect on the total amount of food consumed during “lunch.’ But the carbohydrate premeal did cause the animals to choose in favor of protein.
These studies and others performed by Harvey Anderson, now at the University of Toronto, provide evidence that the brain is able to regulate the proportions of carbohydrates and proteins consumed during meals.