Brain Facts - Neurons

A specialized cell designed to transmit information

to other nerve cells, muscle, or gland cells, the neuron is the

basic working unit of the brain. The brain is what it is because of

the structural and functional properties of interconnected neurons.

The brain contains between 1 billion and 100 billion neurons,

depending on the species.

The neuron consists of a cell body, dendrites, and an axon. The

cell body contains the nucleus and cytoplasm. The electrically

excitable axon extends from the cell body and often gives rise to

many smaller branches before ending at nerve terminals. Dendrites

extend from the neuron cell body and receive messages from other

neurons. Synapses are the contact points where one neuron communicates

with another. The dendrites and cell body are covered with

synapses formed by the ends of axons from other neurons.

Neurons signal by transmitting electrical impulses along their

axons, which can range in length from a tiny fraction of an inch to

three feet or more. Many axons are covered with a layered myelin

sheath, which speeds the transmission of electrical signals along the

axon. This sheath is made of specialized cells called oligodendrocytes

in the brain and Schwann cells in the peripheral nervous system.

Nerve impulses involve the opening and closing of ion channels,

which are selectively permeable, water-filled molecular tunnels

that pass through the cell membrane and allow ions — electrically

charged atoms — or small molecules to enter or leave the cell. The

flow of these ions creates an electrical current that produces tiny

voltage changes across the neuron’s cell membrane.

The ability of a neuron to generate an electrical impulse

depends on a difference in charge between the inside and outside

of the cell. When a nerve impulse begins, a dramatic reversal in

the electrical potential occurs at one point on the cell’s membrane,

when the neuron switches from an internal negative charge to a

positive charge state. The change, called an action potential, then

passes along the membrane of the axon at speeds up to several

hundred miles per hour. In this way, a neuron may be able to fire

impulses multiple times every second.

Upon reaching the end of an axon, these voltage changes trigger

the release of neurotransmitters, the brain’s chemical messengers.

Neurotransmitters are released at nerve terminals, diffuse across the

intrasynaptic space, and bind to receptors on the surface of the target

cell (often another neuron but also possibly a muscle or gland cell).

These receptors act as on-and-off switches for the next cell.

Each receptor has a distinctly shaped region that selectively recognizes

a particular chemical messenger. A neurotransmitter fits into

this region in much the same way that a key fits into a lock. And

when the transmitter is in place, this interaction alters the target

cell’s membrane potential and triggers a response, such as the generation

of an action potential, contraction of a muscle, stimulation

of enzyme activity, or inhibition of neurotransmitter release from

the target cell.

Increased understanding of neurotransmitters in the brain and

of the action of drugs on these chemicals — gained largely through

animal research — guides one of the largest fields in neuroscience.

Armed with this information, scientists hope to understand the circuits

responsible for disorders such as Alzheimer’s disease and Parkinson’s

disease. Sorting out the various chemical circuits is vital to understanding

how the brain stores memories, why sex is such a powerful motivation,

and what makes up the biological basis of mental illness.

Neurotransmitters and neuromodulators

Acetylcholine 

The first neurotransmitter, identified about 75

years ago, was acetylcholine (ACh). This chemical is released by

neurons connected to voluntary muscles (causing them to contract)

and by neurons that control the heartbeat. ACh also serves as a

transmitter in many regions of the brain.

ACh is formed at the axon terminals. When an action potential

arrives at the nerve terminal, the electrically charged calcium

ion rushes in, and ACh is released into the synapse, where it attaches

to ACh receptors on the target cells. On voluntary muscles,

this opens sodium channels and causes the muscle to contract.

ACh is then broken down by the enzyme acetylcholinesterase and

resynthesized in the nerve terminal. Antibodies that block one type

of receptor for ACh cause myasthenia gravis, a disease characterized

by fatigue and muscle weakness.

Much less is known about ACh in the brain. Recent discoveries

suggest, however, that it may be critical for normal attention,

memory, and sleep. Because ACh-releasing neurons die in Alzheimer’s

patients, finding ways to restore this neurotransmitter is one

goal of current research. Drugs that inhibit acetylcholinesterase are

presently the main drugs used to treat Alzheimer’s disease.

Amino acids

Amino acids, widely distributed throughout the

body and the brain, serve as the building blocks of proteins. Certain

amino acids can also serve as neurotransmitters in the brain.

The neurotransmitters glycine and gamma-aminobutyric acid

(GABA) inhibit the firing of neurons. The activity of GABA is

increased by benzodiazepines (e.g., Valium) and by anticonvulsant

drugs. In Huntington’s disease, a hereditary disorder that begins during

midlife, the GABA-producing neurons in brain centers that coordinate

movement degenerate, thereby causing uncontrollable movements.

Glutamate and aspartate act as excitatory signals, activating,

among others, N-methyl-d-aspartate (NMDA) receptors, which have

been implicated in activities ranging from learning and memory to

development and specification of nerve contacts in a developing

animal. The stimulation of NMDA receptors may promote beneficial

changes in the brain, whereas overstimulation can cause nerve

cell damage or cell death in trauma and stroke.

Key questions remain about the NMDA receptor’s precise structure,

regulation, location, and function. Developing drugs to block or

stimulate activity at NMDA receptors holds promise for improving

brain function and treating neurological and psychiatric disorders.

Catecholamines 

Dopamine and norepinephrine are widely

present in the brain and peripheral nervous system. Dopamine is

present in three principal circuits in the brain; these circuits control

movement, cause psychiatric symptoms such as psychosis, and

regulate hormonal responses.

The dopamine circuit that regulates movement has been

directly linked to disease. Due to dopamine deficits in the brain,

people with Parkinson’s disease show symptoms

including muscle tremors, rigidity, and

difficulty in moving. Thus, medical scientists

have found that the administration of

levodopa, a substance from which dopamine

is synthesized, is an effective treatment for

Parkinson’s, allowing patients to walk and

perform skilled movements more successfully.

Another dopamine circuit is thought

to be important for cognition and emotion;

abnormalities in this system have been

implicated in schizophrenia. Because drugs

that block certain dopamine receptors in the

brain are helpful in diminishing psychotic

symptoms, learning more about dopamine is

important to understanding mental illness.

In a third circuit, dopamine regulates

the endocrine system. Dopamine directs

the hypothalamus to manufacture hormones

and hold them in the pituitary gland for

release into the bloodstream or to trigger

the release of hormones held within cells in

the pituitary.

NEURON. A neuron fires by transmitting

electrical signals along its axon. When signals

reach the end of the axon, they trigger the release

of neurotransmitters that are stored in pouches

called vesicles. Neurotransmitters bind to receptor

molecules on the surfaces of adjacent neurons. The

point of virtual contact is known as the synapse.

Nerve fibers containing norepinephrine are present throughout

the brain. Deficiencies in this transmitter occur in patients with

Alzheimer’s disease, Parkinson’s disease, and Korsakoff’s syndrome,

a cognitive disorder associated with chronic alcoholism. Thus,

researchers believe norepinephrine may play a role in both learning

and memory. Norepinephrine is also secreted by the sympathetic

nervous system in the periphery to regulate heart rate and blood

pressure. Acute stress increases the release of norepinephrine from

sympathetic nerves and the adrenal medulla.

Serotonin

This neurotransmitter is present in the brain

and other tissues, particularly blood platelets and the lining of the

digestive tract. In the brain, serotonin has been implicated in sleep,

mood, depression, and anxiety. Because serotonin controls the different

switches affecting various emotional states, scientists believe

these switches can be manipulated by analogs, chemicals with

molecular structures similar to that of serotonin. Drugs that alter

serotonin’s action, such as fluoxetine, relieve symptoms of depression

and obsessive-compulsive disorder.

Peptides 

These are chains of amino acids linked together.

Peptides differ from proteins, which are much larger and have more

complex combinations of amino acids.

In 1973, scientists discovered receptors for opiates on

neurons in several regions of the brain, suggesting that the brain

must make substances very similar to opium. Shortly thereafter,

scientists made their first discovery of an opiate produced by the

brain that resembles morphine, an opium derivative used medically

to kill pain. They named it enkephalin, literally meaning

“in the head.” Soon after, other types of opioid peptides, endorphins,

were discovered. Endorphins, whose name comes from

endogenous morphine, act like opium or morphine to kill pain

or cause sleepiness.

The precise role of the naturally occurring opioid peptides is

unclear. A simplistic hypothesis is that they are released by brain

neurons in times of stress to minimize pain and enhance adaptive

behavior. The presence of opioid peptides may explain, for example,

why injuries received during the stress of combat are often not

noticed until hours later. Neurons containing these opioid peptides,

however, are not limited to pain-sensing circuits.

Opioids and their receptors are closely associated with pathways

in the brain that are activated by painful or tissue-damaging

stimuli. These signals are transmitted to the central nervous system

— the brain and spinal cord — by special sensory nerves, small

myelinated fibers, and tiny unmyelinated C fibers. Scientists have

discovered that some C fibers contain a peptide called substance P

that causes the sensation of burning pain. The active component of

chili peppers, capsaicin, causes the release of substance P.

Trophic factors

 Researchers have discovered several small

proteins in the brain that are necessary for the development, function,

and survival of specific groups of neurons. These small proteins

are made in brain cells, are released locally in the brain, and bind to

receptors expressed by specific neurons. Researchers also have identified

genes that code for receptors and are involved in the signaling

mechanisms of trophic factors. These findings are expected to result

in a greater understanding of how trophic factors work in the brain.

This information should also prove useful for the design of new therapies

for brain disorders of development and for degenerative diseases,

including Alzheimer’s disease and Parkinson’s disease.

Hormones 

In addition to the nervous system, the endocrine

system is a major communication system of the body. While the

nervous system uses neurotransmitters as its chemical signals, the

endocrine system uses hormones for its chemical signals. The pancreas,

kidneys, heart, adrenal glands, gonads, thyroid, parathyroid,

thymus, and pituitary gland are sources of hormones. The endocrine

system works in large part through the pituitary gland, which

secretes hormones into the blood. Because fragments of endorphins

are released from the pituitary gland into the bloodstream, they

might also function as endocrine hormones. This system is very important

for the activation and control of basic behavioral activities

such as sex, emotion, responses to stress, and the regulation of body

functions, including growth, reproduction, energy use, and metabolism.

Actions of hormones show the brain to be very malleable and

capable of responding to environmental signals.

The brain contains receptors for thyroid hormones and the six

classes of steroid hormones — androgens, estrogens, progestins, glucocorticoids,

mineralocorticoids, and vitamin D. The receptors are found

in selected populations of neurons in the brain and relevant organs

in the body. Thyroid and steroid hormones bind to receptor proteins

that in turn bind to DNA and regulate the action of genes. This can

result in long-lasting changes in cellular structure and function.

The brain has receptors for many hormones; for example, the

metabolic hormones insulin, insulinlike growth factor, ghrelin, and

leptin. These hormones are taken up from the blood and act to affect

neuronal activity and certain aspects of neuronal structure.

In response to stress and changes in our biological clocks, such

as day and night cycles and jet lag, hormones enter the blood and

travel to the brain and other organs. In the brain, hormones alter the

production of gene products that participate in synaptic neurotransmission

as well as the structure of brain cells. As a result, the circuitry

of the brain and its capacity for neurotransmission are changed over a

course of hours to days. In this way, the brain adjusts its performance

and control of behavior in response to a changing environment. Hormones

are important agents of protection and adaptation, but stress

and stress hormones, such as the glucocorticoid cortisol, can also alter

brain function, including learning. Severe and prolonged stress can

cause permanent brain damage.

Reproduction in females is a good example of a regular, cyclic

process driven by circulating hormones: The neurons in the hypothalamus

produce gonadotropin-releasing hormone (GnRH), a peptide

that acts on cells in the pituitary. In both males and females, this

causes two hormones — the follicle-stimulating hormone (FSH) and

the luteinizing hormone (LH) — to be released into the bloodstream.

In males, these hormones are carried to receptors on cells in the

testes, where they release the male hormone testosterone, an

androgen, into the bloodstream. In females, FSH and LH act on the

ovaries and cause the release of the female hormones estrogen and

progesterone. Testosterone, estrogen, and progesterone are often

referred to as sex hormones.

In turn, the increased levels of testosterone in males and

estrogen in females act back on the hypothalamus and pituitary to

decrease the release of FSH and LH. The increased levels of sex

hormones also induce changes in cell structure and chemistry that

lead to an increased capacity to engage in sexual behavior. Sex hormones

also exert widespread effects on many other functions of the

brain such as attention, motor control, pain, mood, and memory.

Sexual differentiation of the brain is caused by sex hormones

acting in fetal and early postnatal life, although recent evidence

points to genes on the Y chromosome contributing to this process.

Scientists have found statistically and biologically significant differences

between the brains of men and women that are similar to sex

differences found in experimental animals. These include differences

in the size and shape of brain structures in the hypothalamus and

the arrangement of neurons in the cortex and hippocampus. Sex

differences go well beyond sexual behavior and reproduction and

affect many brain regions and functions, ranging from mechanisms

for perceiving pain and dealing with stress to strategies for solving

cognitive problems. Although differences exist, the brains of men

and women are more similar than they are different.

Anatomical differences have also been reported between the

brains of heterosexual and homosexual men. Research suggests that

hormones and genes act early in life to shape the brain in terms of

sex-related differences in structure and function, but scientists are

still putting together all the pieces of this puzzle.

Gases 

Scientists identified a new class of neurotransmitters

that are gases. These molecules — nitric oxide and carbon monoxide

— do not act like other neurotransmitters. Being gases, they are not

stored in any structure, certainly not in synaptic storage structures.

Instead, they are made by enzymes as they are needed and released

from neurons by diffusion. Rather than acting at receptor sites,

these gases simply diffuse into adjacent neurons and act upon

chemical targets, which may be enzymes.

While exact functions for carbon monoxide have not been

determined, nitric oxide has already been shown to play several

important roles. For example, nitric oxide neurotransmission governs

erection in the penis. In nerves of the intestine, it governs the

relaxation that contributes to the normal movements of digestion.

In the brain, nitric oxide is the major regulator of the intracellular

messenger molecule — cyclic GMP. In conditions of excess glutamate

release, as occurs in stroke, neuronal damage following the

stroke may be attributable in part to nitric oxide.

Second messengers

Substances that trigger biochemical communication within

cells, after the action of neurotransmitters at their receptors, are

called second messengers; these intracellular effects may be responsible

for long-term changes in the nervous system. They convey the

chemical message of a neurotransmitter (the first messenger) from

the cell membrane to the cell’s internal biochemical machinery.

Second-messenger effects may endure for a few milliseconds to as

long as many minutes.

An example of the initial step in the activation of a secondmessenger

system involves adenosine triphosphate (ATP), the

chemical source of energy in cells. ATP is present throughout the

cytoplasm of all cells. For example, when norepinephrine binds to

its receptors on the surface of the neuron, the activated receptor

binds a G protein on the inside of the membrane. The activated G

protein causes the enzyme adenylyl cyclase to convert ATP to cyclic

adenosine monophosphate (cAMP). The second messenger, cAMP,

exerts a variety of influences within the cell, ranging from changes

in the function of ion channels in the membrane to changes in the

expression of genes in the nucleus, rather than acting as a messenger

between one neuron and another.

Second messengers also are thought to play a role in the manufacture

and release of neurotransmitters and in intracellular movements

and carbohydrate metabolism in the cerebrum — the largest

part of the brain, consisting of two hemispheres — as well as the

processes of growth and development. In addition, direct effects of

second messengers on the genetic material of cells may lead to longterm

alterations in cellular functioning and ultimately in behavior.