We have 2 brains: Fascinating but long: please delete when/if responding

[Guest guest]

http://www.nytimes.com/1996/01/23/science/complex-and-hidden-brain-in-gut-makes-\

stomachaches-and-butterflies.html?pagewanted=all & src=pm

Complex and Hidden Brain in Gut Makes Stomachaches and Butterflies

By SANDRA BLAKESLEE

Published: January 23, 1996Sign In to E-Mail NY Times

EVER wonder why people get " butterflies " in the stomach before going on stage?

Or why an impending job interview can cause an attack of intestinal cramps? And

why antidepressants targeted for the brain cause nausea or abdominal upset in

millions of people who take such drugs?

The reason for these common experiences, scientists say, is that the body has

two brains -- the familiar one encased in the skull and a lesser known but

vitally important one found in the human gut. Like Siamese twins, the two brains

are interconnected; when one gets upset, the other does, too.

The gut's brain, known as the enteric nervous system, is located in sheaths of

tissue lining the esophagus, stomach, small intestine and colon. Considered a

single entity, it is a network of neurons, neurotransmitters and proteins that

zap messages between neurons, support cells like those found in the brain proper

and a complex circuitry that enables it to act independently, learn, remember

and, as the saying goes, produce gut feelings.

The brain in the gut plays a major role in human happiness and misery. But few

people know it exists, said Dr. Gershon, a professor of anatomy and cell

biology at Columbia-Presbyterian Medical Center in New York. For years, people

who had ulcers, problems swallowing or chronic abdominal pain were told that

their problems were imaginary, emotional, simply all in their heads, Dr. Gershon

said. They were shuttled to psychiatrists for treatment.

Doctors were right in ascribing these problems to the brain, Dr. Gershon said,

but they blamed the wrong one. Many gastrointestinal disorders like colitis and

irritable bowel syndrome originate from problems within the gut's brain, he

said. And the current wisdom is that most ulcers are caused by a bacterium, not

by hidden anger at one's mother.

Symptoms stemming from the two brains get confused, Dr. Gershon said. " Just as

the brain can upset the gut, the gut can also upset the brain " he said. " If you

were chained to the toilet with cramps, you'd be upset, too. "

Details of how the enteric nervous system mirrors the central nervous system

have been emerging in recent years, said Dr. Gershon, who is considered one of

the founders of a new field of medicine called neurogastroenterology.

Nearly every substance that helps run and control the brain has turned up in the

gut, Dr. Gershon said. Major neurotransmitters like serotonin, dopamine,

glutamate, norepinephrine and nitric oxide are there. Two dozen small brain

proteins, called neuropeptides, are in the gut, as are major cells of the immune

system. Enkephalins, one class of the body's natural opiates, are in the gut.

And in a finding that stumps researchers, the gut is a rich source of

benzodiazepines -- the family of psychoactive chemicals that includes such ever

popular drugs as Valium and Xanax.

In evolutionary terms, it makes sense that the body has two brains, said Dr.

Wingate, a professor of gastrointestinal science at the University of

London and a consultant at Royal London Hospital. The first nervous systems were

in tubular animals that stuck to rocks and waited for food to pass by, Dr.

Wingate said. The limbic system is often referred to as the " reptile brain. "

As life evolved, animals needed a more complex brain for finding food and sex

and so developed a central nervous system. But the gut's nervous system was too

important to put inside the newborn head with long connections going down to the

body, Dr. Wingate said. Offspring need to eat and digest food at birth.

Therefore, nature seems to have preserved the enteric nervous system as an

independent circuit inside higher animals. It is only loosely connected to the

central nervous system and can mostly function alone, without instructions from

topside.

This is indeed the picture seen by developmental biologists. A clump of tissue

called the neural crest forms early in embryogenesis, Dr. Gershon said. One

section turns into the central nervous system. Another piece migrates to become

the enteric nervous system. Only later are the two nervous systems connected via

a cable called the vagus nerve.

Until relatively recently, people thought that the gut's muscles and sensory

nerves were wired directly to the brain and that the brain controlled the gut

through two pathways that increased or decreased rates of activity, Dr. Wingate

said. The gut was simply a tube with simple reflexes. Trouble is, no one

bothered to count the nerve fibers in the gut. When they did, he said, they were

surprised to find that the gut contains 100 million neurons -- more than the

spinal cord has. Yet the vagus nerve only sends a couple of thousand nerve

fibers to the gut.

The brain sends signals to the gut by talking to a small number of " command

neurons, " which in turn send signals to gut interneurons that carry messages up

and down the pike, Dr. Gershon said. Both command neurons and interneurons are

spread throughout two layers of gut tissue called the myenteric plexus and the

submuscosal plexus. ( " Solar plexus " is actually a boxing term that refers simply

to nerves in the abdomen.) Command neurons control the pattern of activity in

the gut, Dr. Gershon said. The vagus nerve only alters the volume by changing

its rates of firing.

The plexuses also contain glial cells that nourish neurons, mast cells involved

in immune responses, and a " blood brain barrier " that keeps harmful substances

away from important neurons, Dr. Gershon said. They have sensors for sugar,

protein, acidity and other chemical factors that might monitor the progress of

digestion, determining how the gut mixes and propels its contents. " It's not a

simple pathway, " he said. " It uses complex integrated circuits not unlike those

found in the brain. "

The gut's brain and the head's brain act the same way when they are deprived of

input from the outside world, Dr. Wingate said. During sleep, the head's brain

produces 90-minute cycles of slow wave sleep punctuated by periods of rapid eye

movement sleep in which dreams occur. During the night, when it has no food, the

gut's brain produces 90-minute cycles of slow wave muscle contractions

punctuated by short bursts of rapid muscle movements, Dr. Wingate said.

The two brains may influence each other while in this state, Dr. Wingate said.

Patients with bowel problems have been shown to have abnormal rem sleep. This

finding is not inconsistent with the folk wisdom that indigestion can produce

nightmare.

As light is shed on the circuitry between the two brains, researchers are

beginning to understand why people act and feel the way they do. When the

central brain encounters a frightening situation, it releases stress hormones

that prepare the body to fight or flee, Dr. Gershon said. The stomach contains

many sensory nerves that are stimulated by this chemical surge -- hence the

" butterflies. " On the battlefield, the higher brain tells the gut brain to shut

down, Dr. Gershon said. " A frightened, running animal does not stop to

defecate, " he said.

Fear also causes the vagus nerve to " turn up the volume " on serotonin circuits

in the gut, Dr. Gershon said. Thus overstimulated, the gut goes into higher gear

and diarrhea results. Similarly, people sometimes " choke " with emotion. When

nerves in the esophagus are highly stimulated, people have trouble swallowing.

Even the so-called " Maalox moment " of advertising fame can be explained by the

two brains interacting, said Dr. Jackie D. Wood, chairman of the department of

physiology at Ohio State University in Columbus. Stress signals from the head's

brain can alter nerve function between the stomach and esophagus, resulting in

heartburn.

In cases of extreme stress, Dr. Wood said, the higher brain seems to protect the

gut by sending signals to immunological mast cells in the plexus. The mast cells

secrete histamine, prostaglandin and other agents that help produce

inflammation, he said. " This is protective. If an animal is in danger and

subject to trauma, dirty stuff in the intestines is only a few cells away from

the rest of the body. By inflaming the gut, the brain is priming the gut for

surveillance. If the barrier breaks, the gut is ready to do repairs, " Dr. Wood

said. Unfortunately, the chemicals that get released also cause diarrhea and

cramping.

Such cross talk also explains many drug interactions, Dr. Gershon said. " When

you make a drug to have psychic effects on the brain, it's very likely to have

an effect on the gut that you didn't think about, " he said. Conversely, drugs

developed for the brain could have uses in the gut.

For example, the gut is loaded with the neurotransmitter serotonin. When

pressure receptors in the gut's lining are stimulated, serotonin is released and

starts the reflexive motion of peristalsis, Dr. Gershon said.

Now a quarter of people taking Prozac or similar antidepressants have

gastrointestinal problems like nausea, diarrhea and constipation, he said. These

drugs act on serotonin, preventing its uptake by target cells so that it remains

more abundant in the central nervous system.

In a study to be published soon, Dr. Gershon and his colleagues explain Prozac's

side effects on the gut. They mounted a section of guinea pig colon on a stand

and put a small pellet in the " mouth " end. The isolated colon whips the pellet

down to the " anal " end of the column, just as it would inside an animal, Dr.

Gershon said.

When the researchers put a small amount of Prozac into the colon, the pellet

" went into high gear, " Dr. Gerhson said. The drug doubled the speed at which the

pellet passed through the colon, which would explain why some people get

diarrhea. Prozac has been used in small doses to treat chronic constipation, he

said.

But when researchers increased the amount of Prozac in the guinea pig colon, the

pellet stopped moving. The colon froze up, Dr. Gershon said, which is why some

people get constipated on the drug. And because Prozac stimulated sensory

nerves, he said, it can also cause nausea.

Some antibiotics like erythromycin act on gut receptors to produce oscillations,

Dr. Gershon said. People experience cramps and nausea. Drugs like morphine and

heroin attach to the gut's opiate receptors, producing constipation. Indeed,

both brains can be addicted to opiates.

Victims of Alzheimer's and Parkinson's diseases suffer from constipation. The

nerves in their gut are as sick as the nerve cells in their brains.

Just as the central brain affects the gut, the gut's brain can talk back to the

head, Dr. Gershon said. Most of the gut sensations that enter conscious

awareness are negative things like pain and bloatedness, Dr. Wingate said.

People do not expect to feel anything good from the gut but that does not mean

such signals are absent, he said.

Hence, the intriguing question: why does the human gut produce benzodiazepine?

The human brain contains receptors for benzodiazepine, a drug that relieves

anxiety, suggesting that the body produces its own internal source of the drug,

said Dr. Basile, a neurochemist in the Neuroscience Laboratory at the

National Institutes of Health in Bethesda, Md. Several years ago, he said, an

Italian scientist made a startling discovery. Patients with liver failure fall

into a deep coma. The coma can be reversed, in minutes, by giving the patient a

drug that blocks benzodiazepine.

When the liver fails, substances usually broken down by the liver get to the

brain, Dr. Basile said. Some are bad, like ammonia and mercaptans, which are

" smelly compounds that skunks spray on you, " he said. But a series of compounds

are also identical to benzodiazepine. " We don't know if they come from gut

itself, from bacteria in the gut or from food, " Dr. Basile said. But when the

liver fails, the gut's benzodiazepine goes straight to the brain, knocking the

patient unconscious.

The payoff for exploring gut and head brain interactions is enormous, Dr. Wood

said. For example, many people are allergic to certain foods, like shellfish.

This is because mast cells in the gut mysteriously become sensitized to antigens

in the food. The next time the antigen shows up in the gut, Dr. Wood said, the

mast cells call up a program, releasing chemical modulators that try to

eliminate the threat. The allergic person gets diarrhea and cramps, he said.

Many autoimmune diseases like Krohn's disease and ulcerative colitis may involve

the gut's brain, Dr. Wood said. The consequences can be horrible, as in Chagas

disease, which is caused by a parasite found in South America. Those infected

develop an autoimmune response to neurons in their gut, Dr. Wood said. Their

immune systems slowly destroy their own gut neurons. When enough neurons die,

the intestines literally explode.

A big question remains. Can the gut's brain learn? Does it " think " for itself?

Dr. Gershon tells a story about an old Army sergeant, a male nurse in charge of

a group of paraplegics. With their lower spinal cords destroyed, the patients

would get impacted.

" The sergeant was anal compulsive, " Dr. Gershon said. " At 10 A.M. everyday, the

patients got enemas. Then the sergeant was rotated off the ward. His replacement

decided to give enemas only after compactions occurred. But at 10 the next

morning, everyone on the ward had a bowel movement at the same time, without

enemas, " Dr. Gershon said. Had the sergeant trained those colons?

The human gut has long been seen as a repository of good and bad feelings.

Perhaps emotional states from the head's brain are mirrored in the gut's brain,

where they are felt by those who pay attention to them.