JANUARY PATHWAYS OF DISCOVERY "Science Wars" Neuroscience: FEBRUARY Planetary Breaking Down Scientific Barriers Sciences to the Study of Brain and Mind MARCH Eric R. Kandel and Larry R. Squire Cenomics During tlic latter part of the 20th century,, the study of the brain moved from a peripheral position within both the biological and psychological sciences to become an interdisciplinary field called neu- APRIL roscience that now occupies a central position within each discipline. This realignment occurred be- cause the biological study of the brain became incorporated inlo a common framework with ceil and Infectious molecular biology on the one side and with psychology on the other. Within this new framework, the Diseases scope of neuroscience ranges from genes to cognition, from molecules to mind. What led to the gradual incorporation of neuroscience into the central core of biology and to its alignment with psychology? From the MAY perspective of biology at the beginning of the 20th century, the Materials task of neuroscience—to understand how the brain develops Science and then functions to perceive, think, move, and remember— seemed impossibly difficult. In addition, an intellecmal barri- er separated neuroscience from biology, because the lan- JUNE guage of neuroseience was based more on neuroanatomy Ctoning and and electrophysiology than on the universal biological language of biochemistry. During the last 2 decades this Stem Cells barrier has been largely removed. A molecular neuro- seience became established by focusing on simple sys- tems where anatomy and physiology were tractable. As a juty. result, neuroseience helped delineate a general plan for Communications I neural cell function in whieh the cells of the ner\'ous sys- and Science tem are understood to be governed by variations on uni- versal biological themes. From the perspective of psychology, a neural approach to AUGUST mental processes seemed too reductionistic to do justice to Quantum the complexity of cognition. Substantial progress was re- Artful brain. Cross anatomy made Physics beautiful in a Christopher Wren illus- quired to demonstrate that some of these reductionist goals tration from a 1664 anatomy text. were achievable within a psychologically meaningful frame- work. The work olVemon Mountcastle, David Hubci. Torsten Wiesel, and Brenda Milner in the 1950s and 1960s, and the advent of brain Imaging in the 1980s, SEPTEMBER showed what could be achieved for sensory processing, perception, and memory. As a result of these The Cell Cycle advances, the view gradually developed that only by exploring the brain could psychologists fully satisfy their interest in the cognitive processes that intervene between stimulus and response. Here, we consider several developments that have been partieularly important for the maturation of neuroseience and for the restmcturing of its relationship to biology and psychology. OCTOBER Atmospheric The Emergence of a Cellular and Molecular Neuroseience Sciences The modern cellular science of the nervous system was founded on two important advances: the neuron doctrine and the ionic hypothesis. The neuron doctrine was established by the brilliant Spanish anatomist Santiago Ramón y Cajal (1). who showed that the brain is composed of discrete cells, called neurons, and that these likely serve as elementary signaling units. Cajal also ad- NOVEMBER vanced the principle of connection specificity, the central tenet of which is that neurons form Neuroseience highly specific connections with one another and that these connections are invariant and defining for each species. Finally, Cajal developed the principle of dynamic polarization, according to which information flows in only one direction within a neuron., usually from the dendrites (the neuron's input component) down the axon shaft to the axon tenninals {the output component). Al- DECEMBER though exceptions to this principle have emerged, it has proved extremely influential, beeause it Astrophysics and tied structure to function and provided guidelines for eonstrueting circuits from the images pro- Cosmology vided in histological sections of the brain. www.sciencemag.org SCIENCE VOL 290 10 NOVEMBER 2000 1113 PATHWAYS OF DISCOVERY Cajal and his contemporary Charles Sherrington (2) fur- pores and the biophysical basis for their selectivity and gat- A Timeline of ther proposed that neurons contact one another only at spe- ing^how they open and close. For example, transmitter Neuroscience cialized points called synapses, the sites where one neuron's binding sites and their ion channels were found to be em- processes contact and communicate with another neuron. We bodied within different domains of multimeric proteins. Ion now know that at most synapses, there is a gap of 20 nm— channel selectivity was found to depend on physical- 2nd Century the synaptic cleft—between the pre- and postsynaptic cell. In chemical interaction between the channel and the ion. and A.D. the 1930s, Otto Loewi. Henry Dale, and Wilhelm Feldberg channel gating was found to result from conformational Galen of Perga- established (at peripheral neuromuscular and autonomie changes within the channel (5). mum identifies synapses) that the signal that bridges the synaptic cleñ is usu- The study of ion channels changed radically with the de- the brain as the organ of the ally a small chemical, or neurotransmitter. which is released velopment of the pateh-clamp method in 1976 by Erwin Ne- mind. from the presynaptic temiinal, diffuses across the gap. and her and Bert Sakmann (6), which enabled measurement of binds to receptors on the postsynaptic target cell. Depending the current flowing through a single ion channel. This pow- 17th Century on the specific receptor, the postsynaptic cell can either be erful advance set the stage for the analysis of ehannels at the The brain be- comes accepted excited or iniiibited. It totik some time to establish that chem- molecular level and for the analysis of functional and con- as tKe substrate ical transmission also occurs in the central nervous system, formational change in a single of mental life but by the 1950s the idea had become widely accepted. membrane protein. When applied rather than Its ventricles, as Even early in the 20th century, it was already understood to non-neuronal cells, the method earty writers that nerve cells have an electrical potential, the resting mem- also revealed that all cells—even had proposed. brane potential, across their membrane, and that signaling bacteria—express remarkably sim- 1664 along the axon is conveyed by a prop- ilar ion channels. Thus, neuronal Thomas Willis agated electrical signal, the action po- signaling proved to be a special publishes Cerebri tential, which was thought to nullify case ofa signaling capability in- anatome, with it- herent in most cells. lustrations of the the resting potential. In 1937 Alan brain by Christo- Hodgkin discovered that the action The development of patch pher Wren. It is potential gives rise to local current clamping coincided with the ad- the most com- prehensive trea- How on its advancing edge and ihat vent of molecular cloning, and Ihesc tise on brain this current depolarizes the adjacent two methods brought neuroscientists anatomy and region of the axonal membrane suffi- new ideas based on the first reports of function ^published up to ciently to trigger a traveling wave of the amino acid sequences of ligand- and that time. depolarization. In 1939 Hodgkin and voltage-gated channels. One of the key .'Andrew Huxley made the surprising insights to emerge from molecular 1791 discovery that the action potential cloning was that amino acid sequences Luigi Calvani re- veals the electric more than nullifies the resting poten- contain clues about how receptor pro- nature of nervous tial—it reverses it. Then, in the late teins and voltage-gated ion channel pro- action by stimu- 1940s, Hodgkin, Haxley. and Bernard teins are arranged across the cell mem- lating nerves and muscles of frog Katz explained the resting potential brane. The sequenee data also often tegs. and the action potential in terms of pointed to unexpected structural rela- the movement of specific ions— tionships (homoiogies) among proteins. 1808 potassium (K"^), sodium (Na*). and These insights, in turn, revealed similar- Franz Joseph Gall Seeing neurons. Anatomist Ramón y Cajal ehloride (Cl)—through pores (ion proposes that used Colgi's stain to examine individual ities between molecules found in quite specific brain channels) in the axonal membrane. nerve cells and their processes, different neuronal and non-neuronal regions control This ionic hypothesis unified a targe contexts, suggesting that they may serve specific func- > tions. body of descriptive data and offered the first realistic promise similar biological flinctions. that the nervous system could be understood in terms of By the early 1980s, it became clear that synaptic ac- I 1852 physicoehemical principles common to all of cell biology (3). [ Hermann von tions were not always mediated directly by ion channels. f Helmholtimea- The next breakthrough came when Katz. Paul Fatt. and Besides ionotropic receptors, in which ligand binding di- • sures the speed John Eccles showed that ion channels are also ftindamental to rectly gates an ion channel, a second class of receptors, the lofa nerve im- ^ fHjbe in the frog. signal transmission across the synapse. However, rather than metabotropic receptors, was discovered, Here the binding being gated by voltage like the Na""