Brain Facts A P R I M E R O N T H E B R A I N A N D N E R VO U S SYST E M T H E S O C I E T Y F O R N E U R O S C I E N C E Brain Facts A PRIMER ON THE BRAIN AND NERVOUS SYSTEM THE SOCIETY FOR NEUROSCIENCE THE SOCIETY FOR NEUROSCIENCE The Society for Neuroscience is the world’s largest organization of sci- entists and physicians dedicated to understanding the brain,spinal cord and peripheral nervous system. Neuroscientists investigate the molecular and cellular levels of the nervous system; the neuronal systems responsible for sensory and motor function;and the basis of higher order processes,such as cog- nition and emotion.This research provides the basis for understand- ing the medical fields that are concerned with treating nervous system disorders.These medical specialties include neurology,neurosurgery, psychiatry and ophthalmology. Founded in 1970,the Society has grown from 500 charter members to more than 29,000 members.Regular members are residents of Canada, Mexico and the United States—where more than 100 chapters organize local activities.The Society’s membership also includes many scientists from throughout the world,particularly Europe and Asia. The purposes of the Society are to: ∫Advance the understanding of the nervous system by bringing together scientists from various backgrounds and by encouraging research in all aspects of neuroscience. ∫Promote education in the neurosciences. ∫Inform the public about the results and implications of new research. The exchange of scientific information occurs at an annual fall meeting that presents more than 14,000 reports of new scientific findings and includes more than 25,000 participants.This meeting,the largest of its kind in the world,is the arena for the presentation of new results in neuroscience. The Society’s bimonthly journal,The Journal ofNeuroscience,con- tains articles spanning the entire range of neuroscience research and has subscribers worldwide.A series of courses,workshops and sym- posia held at the annual meeting promote the education of Society members.The Neuroscience Newsletter informs members about Society activities. A major mission of the Society is to inform the public about the progress and benefits of neuroscience research.The Society provides information about neuroscience to school teachers and encourages its members to speak to young people about the human brain and nervous system. Brain Facts INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 THE NEURON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Neurotransmitters ∫Second Messengers BRAIN DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Birth of Neurons and Brain Wiring ∫Paring Back ∫Critical Periods SENSATION AND PERCEPTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Vision ∫Hearing ∫Taste and Smell ∫Touch and Pain LEARNING AND MEMORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 MOVEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20 SLEEP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 The Stu∑ of Sleep ∫Sleep Disorders ∫How is Sleep Regulated? STRESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 The Immediate Response ∫Chronic Stress AGING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Aging Neurons ∫Intellectual Capacity ADVANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Parkinson’s Disease ∫Pain ∫Epilepsy ∫Major Depression Manic-Depressive Illness CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Addiction ∫Alzheimer’s Disease ∫Learning Disorders Stroke ∫Neurological Trauma ∫Anxiety Disorders Schizophrenia ∫Neurological AIDS ∫Multiple Sclerosis Down Syndrome ∫Huntington’s Disease ∫Tourette Syndrome Brain Tumors ∫Amyotrophic Lateral Sclerosis NEW DIAGNOSTIC METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Imaging Techniques ∫Gene Diagnosis POTENTIAL THERAPIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 New Drugs ∫Trophic Factors ∫Cell and Gene Therapy GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Introduction I t sets humans apart from all other species by allowing us disease mechanisms and is beginning to suggest new treatments. to achieve the wonders of walking on the moon and com- With the mapping of the human genome,neuroscientists posing masterpieces of literature,art and music.Through- will be able to make more rapid progress in identifying genes that out recorded time,the human brain—a spongy,three- either contribute to human neurological disease or that directly pound mass of fatty tissue—has been compared to a cause disease.Mapping animal genomes will aid the search for telephone switchboard and a supercomputer. genes that regulate and control many complex behaviors. But the brain is much more complicated than any of these ∫Brain Plasticity.Scientists began to uncover the molecular devices,a fact scientists confirm almost daily with each new bases of neural plasticity,revealing how learning and memory discovery.The extent of the brain’s capabilities is unknown,but occur and how declines might be reversed.It also is leading to it is the most complex living structure known in the universe. new approaches to the treatment of chronic pain. This single organ controls all body activities,ranging from ∫New Drugs.Researchers gained new insights into the mech- heart rate and sexual function to emotion,learning and mem- anisms of molecular neuropharmacology,which provides a new ory.The brain is even thought to influence the response to dis- understanding of the mechanisms of addiction.These advances ease of the immune system and to determine,in part,how well also have led to new treatments for depression and obsessive- people respond to medical treatments.Ultimately,it shapes our compulsive disorder. thoughts,hopes,dreams and imagination.In short,the brain is ∫Imaging.Revolutionary imaging techniques,including mag- what makes us human. netic resonance imaging and positron emission tomography, Neuroscientists have the daunting task of deciphering the now reveal brain systems underlying attention,memory and mystery of this most complex of all machines:how as many as emotions and indicate dynamic changes that occur in schizo- a trillion nerve cells are produced,grow and organize them- phrenia. selves into e∑ective,functionally active systems that ordinarily ∫Cell Death.The discovery of how and why neurons die,as remain in working order throughout a person’s lifetime. well as the discovery of stem cells,which divide and form new The motivation of researchers is twofold: to understand neurons,has many clinical applications.This has dramatically human behavior better—from how we learn to why people improved the outlook for reversing the e∑ects of injury both in have trouble getting along together—and to discover ways to the brain and spinal cord.The first e∑ective treatments for prevent or cure many devastating brain disorders. stroke and spinal cord injury based on these advances have been The more than 1,000 disorders of the brain and nervous brought to clinical practice. system result in more hospitalizations than any other disease ∫Brain Development.New principles and molecules respon- group,including heart disease and cancer.Neurological illnesses sible for guiding nervous system development now give scien- a∑ect more than 50 million Americans annually at costs exceed- tists a better understanding of certain disorders of childhood. ing $400 billion.In addition,mental disorders,excluding drug Together with the discovery of stem cells,these advances are and alcohol problems,strike 44 million adults a year at a cost pointing to novel strategies for helping the brain or spinal cord of some $148 billion. regain functions lost to diseases. However,during the congressionally designated Decade of Federal neuroscience research funding of more than $4 bil- the Brain,which ended in 2000,neuroscience made significant lion annually and private support should vastly expand our discoveries in these areas: knowledge of the brain in the years ahead. ∫Genetics.Key disease genes were identified that underlie sev- This book only provides a glimpse of what is known about eral neurodegenerative disorders—including Alzheimer’s dis- the nervous system,the disorders of the brain and some of the ease,Huntington’s disease,Parkinson’s disease and amyotrophic exciting avenues of research that promise new therapies for lateral sclerosis.This has provided new insights into underlying many neurological diseases. 2 THE BRAIN. Cerebral cortex (above). This part of the brain is divided into four sections: the Motor cortex Sensory cortex occipital lobe, the temporal lobe, the parietal lobe and the Frontal lobe frontal lobe. Functions, such as Parietal lobe vision, hearing and speech, are distributed in selected regions. Some regions are associated Occipital lobe with more than one function. Major internal structures Temporal lobe (below). The (1) forebrain is credited with the highest intel- lectual functions—thinking, planning and problem-solving. The hippocampus is involved in memory. The thalamus serves as a relay station for almost all of Cerebrum the information coming into the Thalamus brain. Neurons in the hypothala- mus serve as relay stations for Hypothalamus internal regulatory systems by monitoring information coming 1Forebrain in from the autonomic nervous system and commanding the body through those nerves and Amygdala the pituitary gland. On the Hippocampus upper surface of the (2) mid- 2 Midbrain brain are two pairs of small Pons hills, colliculi, collections of Cerebellum 3 Hindbrain Spinal cord cells that relay specific sensory Medulla oblongata information from sense organs to the brain. The (3) hindbrain consists of the pons and medulla oblongata, which help control respiration and heart THE TOLLOF SELECTED BRAIN AND NERVOUS SYSTEM DISORDERS* rhythms, and the cerebellum, which helps control movement Condition Total Cases Costs Per Year as well as cognitive processes HearingLoss 28 million $ 56 billion that require precise timing. All Depressive Disorders 18.8 million $ 44 billion Alzheimer’s Disease 4 million $ 100 billion Stroke 4 million $ 30 billion Schizophrenia 3 million $ 32.5 billion Parkinson’s Disease 1.5 million $ 15 billion Traumatic Head Injury 1 million $ 48.3 billion Multiple Sclerosis 350,000 $ 7 billion Spinal Cord Injury 250,000 $ 10 billion * Estimates provided by the National Institutes ofHealth and voluntary organizations. 3 The Neuron AA specialized cell designed to transmit infor- bind to receptors on the surface of the target neuron. mation to other nerve cells,muscle or gland These receptors act as on and o∑ switches for the next cell. cells,the neuron is the basic working unit of Each receptor has a distinctly shaped part that exactly matches the brain.The brain is what it is because of a particular chemical messenger.A neurotransmitter fits into the structural and functional properties of this region in much the same way as a key fits into an automo- neurons.The brain contains between one bil- bile ignition. And when it does, it alters the neuron’s outer lion and one trillion neurons. membrane and triggers a change,such as the contraction of a The neuron consists of a cell body containing the nucleus muscle or increased activity of an enzyme in the cell. and an electricity-conducting fiber,the axon,which also gives Knowledge of neurotransmitters in the brain and the action rise to many smaller axon branches before ending at nerve ter- of drugs on these chemicals—gained largely through the study minals. Synapses, from the Greek words meaning to “clasp of animals—is one of the largest fields in neuroscience.Armed together,”are the contact points where one neuron communi- with this information,scientists hope to understand the circuits cates with another.Other cell processes,dendrites,Greek for responsible for disorders such as Alzheimer’s disease and Parkin- the branches of a tree,extend from the neuron cell body and son’s disease.Sorting out the various chemical circuits is vital receive messages from other neurons.The dendrites and cell to understanding how the brain stores memories,why sex is such body are covered with synapses formed by the ends of axons of a powerful motivation and what is the biological basis of men- other neurons. tal illness. Neurons signal by transmitting electrical impulses along Neurotransmitters their axons that can range in length from a tiny fraction of an inch to three or more feet.Many axons are covered with a lay- Acetylcholine The first neurotransmitter to be identified 70 ered insulating myelin sheath,made of specialized cells,that years ago,was acetylcholine (ACh).This chemical is released speeds the transmission of electrical signals along the axon. by neurons connected to voluntary muscles (causing them to Nerve impulses involve the opening and closing of ion chan- contract) and by neurons that control the heartbeat.ACh also nels,water-filled molecular tunnels that pass through the cell serves as a transmitter in many regions of the brain. membrane and allow ions—electrically charged atoms—or ACh is formed at the axon terminals. When an action small molecules to enter or leave the cell.The flow of these ions potential arrives at the terminal,the electrically charged cal- creates an electrical current that produces tiny voltage changes cium ion rushes in,and ACh is released into the synapse and across the membrane. attaches to ACh receptors. In voluntary muscles, this opens The ability of a neuron to fire depends on a small dif- sodium channels and causes the muscle to contract. ACh is ference in electrical charge between the inside and outside of then broken down and re-synthesized in the nerve terminal. the cell. When a nerve impulse begins, a dramatic reversal Antibodies that block the receptor for ACh cause myasthenia occurs at one point on the cell’s membrane.The change,called gravis,a disease characterized by fatigue and muscle weakness. an action potential,then passes along the membrane of the axon Much less is known about ACh in the brain.Recent dis- at speeds up to several hundred miles an hour.In this way,a coveries suggest, however, that it may be critical for normal neuron may be able to fire impulses scores or even hundreds attention,memory and sleep.Since ACh-releasing neurons die of times every second. in Alzheimer’s patients, finding ways to restore this neuro- On reaching the ends of an axon, these voltage changes transmitter is one goal of current research. trigger the release of neurotransmitters,chemical messengers. Amino Acids Certain amino acids, widely distributed Neurotransmitters are released at nerve ending terminals and throughout the body and the brain,serve as the building blocks 4 of proteins. However, it is now apparent that certain amino Glutamate or aspartate activate N-methyl-D-aspartate acids can also serve as neurotransmitters in the brain. (NMDA) receptors,which have been implicated in activities The neurotransmitters glutamate andaspartateact as exci- ranging from learning and memory to development and speci- tatory signals.Glycineand gamma-aminobutyricacid(GABA) fication of nerve contacts in a developing animal.The stimula- inhibit the firing of neurons.The activity of GABA is increased tion of NMDA receptors may promote beneficial changes in by benzodiazepine (Valium) and by anticonvulsant drugs. In the brain,whereas overstimulation can cause nerve cell damage Huntington’s disease,a hereditary disorder that begins during or cell death in trauma and stroke. mid-life,the GABA-producing neurons in the brain centers Key questions remain about this receptor’s precise structure, coordinating movement degenerate,thereby causing incontrol- regulation, location and function. For example, developing lable movements. drugs to block or stimulate activity at NMDA receptors holds NEURON.A neuron fires by transmitting electrical signals along its axon. When signals reach the end of the axon, they trigger the release of neuro- transmitters that are stored in Dendrites pouches called vesicles. Neuro- transmitters bind to receptor molecules that are present on Nucleus the surfaces of adjacent neu- rons. The point of virtual contact is known as the synapse. Cell body Axon Myelin sheath Nerve impulse Axon Vesicle Direction Synapse of impulse Axon terminals Dendrite of receiving Neurotransmitters neuron Receptor molecules 5 promise for improving brain function and treating neurologi- more complex combinations of amino acids.) cal disorders.But this work is still in the early stage. In 1973,scientists discovered receptors for opiates on neu- Catecholamines Dopamine and norepinephrine are widely rons in several regions in the brain that suggested the brain present in the brain and peripheral nervous system.Dopamine, must make substances very similar to opium.Shortly thereafter, which is present in three circuits in the brain,controls move- scientists made their first discovery of an opiate produced by ment,causes psychiatric symptoms such as psychosis and reg- the brain that resembles morphine,an opium derivative used ulates hormonal responses. medically to kill pain.They named it enkephalin,literally mean- The dopamine circuit that regulates movement has been ing “in the head.”Subsequently,other opiates known as endor- directly related to disease.The brains of people with Parkinson’s phins—from endogenous morphine—were discovered. disease—with symptoms of muscle tremors, rigidity and The precise role of the opioids in the body is unclear.A di≈culty in moving—have practically no dopamine. Thus, plausible guess is that enkephalins are released by brain neurons medical scientists found that the administration of levodopa,a in times of stress to minimize pain and enhance adaptive behav- substance from which dopamine is synthesized,is an e∑ective ior.The presence of enkephalinsmay explain,for example,why treatment for Parkinson’s,allowing patients to walk and per- injuries received during the stress of combat often are not form skilled movements successfully. noticed until hours later. Another dopamine circuit is thought to be important for Opioids and their receptors are closely associated with path- cognition and emotion;abnormalities in this system have been ways in the brain that are activated by painful or tissue-damag- implicated in schizophrenia.Because drugs that block dopamine ing stimuli.These signals are transmitted to the central nervous receptors in the brain are helpful in diminishing psychotic system—the brain and spinal cord—by special sensory nerves, symptoms, learning more about dopamine is important to small myelinated fibers and tiny unmyelinated or Cfibers. understanding mental illness. Scientists have discovered that some C fibers contain a pep- In a third circuit,dopamine regulates the endocrine sys- tide called substance Pthat causes the sensation of burning pain. tem.It directs the hypothalamus to manufacture hormones and The active component of chili peppers,capsaicin,causes the hold them in the pituitary gland for release into the blood- release of substance P. stream,or to trigger the release of hormones held within cells Trophic factors Researchers have discovered several small in the pituitary. proteins in the brain that are necessary for the development, Nerve fibers containing norepinephrine are present through- function and survival of specific groups of neurons.These small out the brain.Deficiencies in this transmitter occur in patients proteins are made in brain cells,released locally in the brain, with Alzheimer’s disease,Parkinson’s disease and those with and bind to receptors expressed by specific neurons.Researchers Korsako∑’s syndrome,a cognitive disorder associated with chronic also have identified genes that code for receptors and are alcoholism.Thus,researchers believe norepinephrine may play involved in the signaling mechanisms of trophic factors.These a role in both learning and memory. Norepinephrine also is findings are expected to result in a greater understanding of secreted by the sympathetic nervous system in the periphery to how trophic factors work in the brain.This information also regulate heart rate and blood pressure.Acute stress increases should prove useful for the design of new therapies for brain the release of norepinephrine. disorders of development and for degenerative diseases,includ- Serotonin This neurotransmitter is present in many tissues, ing Alzheimer’s disease and Parkinson’s disease. particularly blood platelets and the lining of the digestive tract Hormones After the nervous system,the endocrine system and the brain.Serotonin was first thought to be involved in is the second great communication system of the body.The high blood pressure because it is present in blood and induces pancreas,kidney,heart and adrenal gland are sources of hor- a very powerful contraction of smooth muscles.In the brain,it mones.The endocrine system works in large part through the has been implicated in sleep, mood, depression and anxiety. pituitary that secretes hormones into the blood.Because endor- Because serotonin controls the di∑erent switches a∑ecting var- phins are released from the pituitary gland into the blood- ious emotional states,scientists believe these switches can be stream,they might also function as endocrine hormones.Hor- manipulated by analogs,chemicals with molecular structures mones activate specific receptors in target organs that release similar to serotonin.Drugs that alter serotonin’s action,such as other hormones into the blood,which then act on other tissues, fluoxetine(Prozac),have relieved symptoms of depression and the pituitary itself and the brain.This system is very important obsessive-compulsive disorder. for the activation and control of basic behavioral activities such Peptides These chains of amino acids linked together,have as sex,emotion,response to stress and the regulation of body been studied as neurotransmitters only in recent years.Brain functions,such as growth,energy use and metabolism.Actions peptides called opioidsact like opium to kill pain or cause sleepi- of hormones show the brain to be very malleable and capable ness.(Peptides di∑er from proteins,which are much larger and of responding to environmental signals. 6 The brain contains receptors for both the thyroid hormone grip on all the pieces of this puzzle. and the six classes of steroid hormones—estrogens,androgens, Gases Very recently,scientists identified a new class of neu- progestins,glucocorticoids,mineralocorticoids andvitamin D.The rotransmitters that are gases.These molecules—nitric oxide and receptors are found in selected populations of neurons in the carbon monoxide—do not obey the “laws” governing neuro- brain and relevant organs in the body.Thyroid and steroid hor- transmitter behavior.Being gases,they cannot be stored in any mones bind to receptor proteins that in turn bind to the DNA structure,certainly not in synaptic storage structures.Instead, genetic material and regulate action of genes.This can result in they are made by enzymes as they are needed.They are released long-lasting changes in cellular structure and function. from neurons by di∑usion.And rather than acting at receptor In response to stress and changes in our biological clocks, sites,they simply di∑use into adjacent neurons and act upon such as day-and-night cycles and jet-lag,hormones enter the chemical targets,which may be enzymes. blood and travel to the brain and other organs.In the brain, Though only recently characterized, nitric oxide has they alter the production of gene products that participate in already been shown to play important roles.For example,nitric synaptic neurotransmission as well as the structure of brain oxide neurotransmission governs erection in neurons of the cells.As a result,the circuitry of the brain and its capacity for penis.In nerves of the intestine,it governs the relaxation that neurotransmission are changed over a course of hours to days. contributes to normal movements of digestion.In the brain, In this way,the brain adjusts its performance and control of nitric oxide is the major regulator of the intracellular messen- behavior in response to a changing environment.Hormones are ger molecule—cyclic GMP.In conditions of excess glutamate important agents of protection and adaptation,but stress and release, as occurs in stroke, neuronal damage following the stress hormones also can alter brain function,including learn- stroke may be attributable in part to nitric oxide.Exact func- ing. Severe and prolonged stress can cause permanent brain tions for carbon monoxide have not yet been shown. damage. Second messengers Reproduction is a good example of a regular,cyclic process driven by circulating hormones:The hypothalamus produces Recently recognized substances that trigger biochemical com- gonadotropin-releasing hormone(GnRH),a peptide that acts on munication within cells,second messengers may be responsi- cells in the pituitary.In both males and females,this causes two ble for long-term changes in the nervous system.They convey hormones—the follicle-stimulating hormone (FSH) and the the chemical message of a neurotransmitter (the first messen- luteinizing hormone(LH)—to be released into the bloodstream. ger) from the cell membrane to the cell’s internal biochemical In males,these hormones are carried to receptors on cells in the machinery.Second messengers take anywhere from a few milli- testes where they release the male hormone testosterone into seconds to minutes to transmit a message. the bloodstream.In females,FSH and LH act on the ovaries An example of the initial step in the activation of a second and cause the release of the female hormones estrogen and prog- messenger system involves adenosine triphosphate (ATP),the esterone.In turn,the increased levels of testosterone in males chemical source of energy in cells.ATP is present throughout and estrogen in females act back on the hypothalamus and pitu- the cell.For example,when norepinephrine binds to its recep- itary to decrease the release of FSH and LH.The increased lev- tors on the surface of the neuron,the activated receptor binds els also induce changes in cell structure and chemistry that lead G-proteins on the inside of the membrane.The activated G- to an increased capacity to engage in sexual behavior. protein causes the enzyme adenylyl cyclase to convert ATP to Scientists have found statistically and biologically signi- cyclic adenosine monophosphate(cAMP).The second messenger, ficant di∑erences between the brains of men and women that cAMP,exerts a variety of influences on the cell,ranging from are similar to sex di∑erences found in experimental animals. changes in the function of ion channels in the membrane to These include di∑erences in the size and shape of brain struc- changes in the expression of genes in the nucleus,rather than tures in the hypothalamus and the arrangement of neurons in acting as a messenger between one neuron and another.cAMP the cortex and hippocampus.Some functions can be attributed is called a second messenger because it acts after the first mes- to these sex di∑erences, but much more must be learned in senger,the transmitter chemical,has crossed the synaptic space terms of perception,memory and cognitive ability.Although and attached itself to a receptor. di∑erences exist,the brains of men and women are more sim- Second messengers also are thought to play a role in the ilar than they are di∑erent. manufacture and release of neurotransmitters, intracellular Recently,several teams of researchers have found anatom- movements, carbohydrate metabolism in the cerebrum—the ical di∑erences between the brains of heterosexual and homo- largest part of the brain consisting of two hemispheres—and sexual men. Research suggests that hormones and genes act the processes of growth and development. Direct e∑ects of early in life to shape the brain in terms of sex-related di∑erences these substances on the genetic material of cells may lead to in structure and function,but scientists still do not have a firm long-term alterations of behavior. 7