Science, Vol 290, Issue 5494, 1113-1120 , 10
November 2000
[DOI: 10.1126/science.290.5494.1113]
Neuroscience: Breaking Down Scientific Barriers
to the Study of Brain and MindEric R. Kandel and Larry
R. Squire
During the 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 neuroscience that now occupies a central position within each
discipline. This realignment occurred because the biological study
of the brain became incorporated into a common framework with cell
and molecular biology on the one side and with psychology on the
other. Within this new framework, the 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 perspective of biology at the beginning of the 20th century, the
task of neuroscience--to understand how the brain develops and then
functions to perceive, think, move, and remember--seemed impossibly
difficult. In addition, an intellectual barrier separated
neuroscience from biology, because the language of neuroscience was
based more on neuroanatomy and electrophysiology than on the
universal biological language of biochemistry. During the last 2
decades this barrier has been largely removed. A molecular
neuroscience became established by focusing on simple systems where
anatomy and physiology were tractable. As a result, neuroscience
helped delineate a general plan for neural cell function in which
the cells of the nervous system are understood to be governed by
variations on universal biological themes.
From the perspective of psychology, a neural approach to mental
processes seemed too reductionistic to do justice to the complexity
of cognition. Substantial progress was required to demonstrate that
some of these reductionist goals were achievable within a
psychologically meaningful framework. The work of Vernon
Mountcastle, David Hubel, Torsten Wiesel, and Brenda Milner in the
1950s and 1960s, and the advent of brain imaging in the 1980s,
showed what could be achieved for sensory processing, perception,
and memory. As a result of these 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
particularly important for the maturation of neuroscience and for
the restructuring of its relationship to biology and psychology.
The Emergence of a Cellular and Molecular
Neuroscience 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 advanced the principle of connection specificity, the
central tenet of which is that neurons form 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 terminals (the output component). Although
exceptions to this principle have emerged, it has proved extremely
influential, because it tied structure to function and provided
guidelines for constructing circuits from the images provided in
histological sections of the brain.
Cajal and his contemporary Charles Sherrington (2)
further proposed that neurons contact one another only at
specialized points called synapses, the sites where one neuron's
processes contact and communicate with another neuron. We now know
that at most synapses, there is a gap of 20 nm--the synaptic
cleft--between the pre- and postsynaptic cell. In the 1930s, Otto
Loewi, Henry Dale, and Wilhelm Feldberg established (at peripheral
neuromuscular and autonomic synapses) that the signal that bridges
the synaptic cleft is usually a small chemical, or neurotransmitter,
which is released from the presynaptic terminal, diffuses across the
gap, and binds to receptors on the postsynaptic target cell.
Depending on the specific receptor, the postsynaptic cell can either
be excited or inhibited. It took some time to establish that
chemical transmission also occurs in the central nervous system, but
by the 1950s the idea had become widely accepted.
Even early in the 20th century, it was already understood that
nerve cells have an electrical potential, the resting membrane
potential, across their membrane, and that signaling along the axon
is conveyed by a propagated electrical signal, the action potential,
which was thought to nullify the resting potential. In 1937 Alan
Hodgkin discovered that the action potential gives rise to local
current flow on its advancing edge and that this current depolarizes
the adjacent region of the axonal membrane sufficiently to trigger a
traveling wave of depolarization. In 1939 Hodgkin and Andrew Huxley
made the surprising discovery that the action potential more than
nullifies the resting potential--it reverses it. Then, in the late
1940s, Hodgkin, Huxley, and Bernard Katz explained the resting
potential and the action potential in terms of the movement of
specific ions--potassium (K+), sodium (Na+),
and chloride (Cl-)--through pores (ion channels) in the
axonal membrane. This ionic hypothesis unified a large body of
descriptive data and offered the first realistic promise that the
nervous system could be understood in terms of physicochemical
principles common to all of cell biology (3).
The next breakthrough came when Katz, Paul Fatt, and John Eccles
showed that ion channels are also fundamental to signal transmission
across the synapse. However, rather than being gated by voltage like
the Na+ and K+ channels critical for action
potentials, excitatory synaptic ion channels are gated chemically by
ligands such as the transmitter acetylcholine. During the 1960s and
1970s, neuroscientists identified many amino acids, peptides, and
other small molecules as chemical transmitters, including
acetylcholine, glutamate, GABA, glycine, serotonin, dopamine, and
norepinephrine. On the order of 100 chemical transmitters have been
discovered to date. In the 1970s, some synapses were found to
release a peptide cotransmitter that can modify the action of the
classic, small-molecule transmitters. The discovery of chemical
neurotransmission was followed by the remarkable discovery that
transmission between neurons is sometimes electrical (4).
Electrical synapses have smaller synaptic clefts, which are bridged
by gap junctions and allow current to flow between neurons.
In the late 1960s information began to become available about the
biophysical and biochemical structure of ionic pores and the
biophysical basis for their selectivity and gating--how they open
and close. For example, transmitter binding sites and their ion
channels were found to be embodied within different domains of
multimeric proteins. Ion channel selectivity was found to depend on
physical-chemical interaction between the channel and the ion, and
channel gating was found to result from conformational changes
within the channel (5).
The study of ion channels changed radically with the development
of the patch-clamp method in 1976 by Erwin Neher and Bert Sakmann
(6),
which enabled measurement of the current flowing through a single
ion channel. This powerful advance set the stage for the analysis of
channels at the molecular level and for the analysis of functional
and conformational change in a single membrane protein. When applied
to non-neuronal cells, the method also revealed that all cells--even
bacteria--express remarkably similar ion channels. Thus, neuronal
signaling proved to be a special case of a signaling capability
inherent in most cells.
The development of patch clamping coincided with the advent of
molecular cloning, and these two methods brought neuroscientists new
ideas based on the first reports of the amino acid sequences of
ligand- and voltage-gated channels. One of the key insights to
emerge from molecular cloning was that amino acid sequences contain
clues about how receptor proteins and voltage-gated ion channel
proteins are arranged across the cell membrane. The sequence data
also often pointed to unexpected structural relationships
(homologies) among proteins. These insights, in turn, revealed
similarities between molecules found in quite different neuronal and
non-neuronal contexts, suggesting that they may serve similar
biological functions.
By the early 1980s, it became clear that synaptic actions were
not always mediated directly by ion channels. Besides ionotropic
receptors, in which ligand binding directly gates an ion channel, a
second class of receptors, the metabotropic receptors, was
discovered. Here the binding of the ligand initiates intracellular
metabolic events and leads only indirectly, by way of "second
messengers," to the gating of ion channels (7).
The cloning of metabotropic receptors revealed that many of them
have seven membrane-spanning regions and are homologous to bacterial
rhodopsin as well as to the photoreceptor pigment of organisms
ranging from fruit flies to humans. Further, the recent cloning of
receptors for the sense of smell (8)
revealed that at least 1000 metabotropic receptors are expressed in
the mammalian olfactory epithelium and that similar receptors are
present in flies and worms. Thus, it was instantly understood that
the class of receptors used for phototransduction, the initial step
in visual perception, is also used for smell and aspects of taste,
and that these receptors share key features with many other brain
receptors that work through second-messenger signaling. These
discoveries demonstrated the evolutionary conservation of receptors
and emphasized the wisdom of studying a wide variety of experimental
systems--vertebrates, invertebrates, even single-celled
organisms--to identify broad biological principles.
The seven transmembrane-spanning receptors activate ion channels
indirectly through coupling proteins (G proteins). Some G proteins
have been found to activate ion channels directly. However, the
majority of G proteins activate membrane enzymes that alter the
level of second messengers, such as cAMP, cGMP, or inositol
triphosphate, which initiate complex intracellular events leading to
the activation of protein kinases and phosphatases and then to the
modulation of channel permeability, receptor sensitivity, and
transmitter release. Neuroscientists now appreciate that many of
these synaptic actions are mediated intracellularly by protein
phosphorylation or dephosphorylation (9).
Nerve cells use such covalent modifications to control protein
activity reversibly and thereby to regulate function.
Phosphorylation is also critical in other cells for the action of
hormones and growth factors, and for many other processes.
Directly controlled synaptic actions are fast, lasting
milliseconds, but second-messenger actions last seconds to minutes.
An even slower synaptic action, lasting days or more, has been found
to be important for long-term memory. In this case, protein kinases
activated by second messengers translocate to the nucleus, where
they phosphorylate transcription factors that alter gene expression,
initiate growth of neuronal processes, and increase synaptic
strength.
Ionotropic and metabotropic receptors have helped to explain the
postsynaptic side of synaptic transmission. In the 1950s and 1960s,
Katz and his colleagues turned to the presynaptic terminals and
discovered that chemical transmitters, such as acetylcholine, are
released not as single molecules but as packets of about 5000
molecules called quanta (10).
Each quantum is packaged in a synaptic vesicle and released by
exocytosis at sites called active zones. The key signal that
triggers this sequence is the influx of Ca2+ with the
action potential.
In recent years, many proteins involved in transmitter release
have been identified (11).
Their functions range from targeting vesicles to active zones,
tethering vesicles to the cell membrane, and fusing vesicles with
the cell membrane so that their contents can be released by
exocytosis. These molecular studies reflect another example of
evolutionary conservation: The molecules used for vesicle fusion and
exocytosis at nerve terminals are variants of those used for vesicle
fusion and exocytosis in all cells.
A Mechanistic View of Brain
Development The discoveries of molecular
neuroscience have dramatically improved the understanding of how the
brain develops its complexity. The modern molecular era of
developmental neuroscience began when Rita Levi-Montalcini and
Stanley Cohen isolated nerve growth factor (NGF), the first peptide
growth factor to be identified in the nervous system (12).
They showed that injection of antibodies to NGF into newborn mice
caused the death of neurons in sympathetic ganglia and also reduced
the number of sensory ganglion cells. Thus, the survival of both
sympathetic and sensory neurons depends on NGF. Indeed, many neurons
depend for their survival on NGF or related molecules, which
typically provide feedback signals to the neurons from their
targets. Such signals are important for programmed cell
death--apoptosis--a developmental strategy which has now proved to
be of general importance, whereby many more cells are generated than
eventually survive to become functional units with precise
connectivity. In a major advance, genetic study of worms has
revealed the ced genes and with them a universal cascade
critical for apoptosis in which proteases--the caspases--are the
final agents for cell death (13).
Cajal pointed out the extraordinary precision of neuronal
connections. The first compelling insights into how neurons develop
their precise connectivity came from Roger Sperry's studies of the
visual system of frogs and salamanders beginning in the 1940s, which
suggested that axon outgrowth is guided by molecular cues. Sperry's
key finding was that when the nerves from the eye are cut, axons
find their way back to their original targets. These seminal studies
led Sperry in 1963 to formulate the chemoaffinity hypothesis (14),
the idea that neurons form connections with their targets based on
distinctive and matching molecular identities that they acquire
early in development.
Stimulated by these early contributions, molecular biology has
radically transformed the study of nervous system development from a
descriptive to a mechanistic field. Three genetic systems, the worm
Caenorhabditis elegans, the fruit fly Drosophila
melanogaster, and the mouse, have been invaluable; some of the
molecules for key developmental steps in the mouse were first
characterized by genetic screens in worms and flies. In some cases,
identical molecules were found to play an equivalent role throughout
phylogeny. The result of this work is that neuroscientists have
achieved in broad outline an understanding of the molecular basis of
nervous system development (15).
A range of key molecules has been identified, including specific
inducers, morphogens, and guidance molecules important for
differentiation, process outgrowth, pathfinding, and synapse
formation. For example, in the spinal cord, neurons achieve their
identities and characteristic positions largely through two classes
of inductive signaling molecules of the Hedgehog and bone
morphogenic protein families. These two groups of molecules control
neuronal differentiation in the ventral and dorsal halves of the
spinal cord, respectively, and maintain this division of labor
through most of the rostrocaudal length of the nervous system.
The process of neuronal pathfinding is mediated by both
short-range and long-range cues. An axon's growth cone can encounter
cell surface cues that either attract or repel it. For example,
ephrins are membrane-bound, are distributed in graded fashion in
many regions of the nervous system, and can repel growing axons.
Other cues, such as the netrins and the semaphorins, are secreted in
diffusible form and act as long-range chemoattractants or
chemorepellents. Growth cones can also react to the same cues
differently at different developmental phases, for example, when
crossing the midline or when switching from pathfinding to synapse
formation. Finally, a large number of molecules are involved in
synapse formation itself. Some, such as neuregulin, erbB kinases,
agrin, and MuSK, organize the assembly of the postsynaptic
machinery, whereas others, such as the laminins, help to organize
the presynaptic differentiation of the active zone.
These molecular signals direct differentiation, migration,
process outgrowth, and synapse formation in the absence of neural
activity. Neural activity is needed, however, to refine the
connections further so as to forge the adult pattern of connectivity
(16).
The neural activity may be generated spontaneously, especially early
in development, but later depends importantly on sensory input. In
this way, intrinsic activity or sensory and motor experience can
help specify a precise set of functional connections.
The Impact of Neuroscience on Neurology and
Psychiatry Molecular neuroscience has also reaped
substantial benefits for clinical medicine. To begin with, recent
advances in the study of neural development have identified stem
cells, both embryonic and adult, which offer promise in cell
replacement therapy in Parkinson's disease, demyelinating diseases,
and other conditions. Similarly, new insights into axon guidance
molecules offer hope for nerve regeneration after spinal cord
injury. Finally, because most neurological diseases are associated
with cell death, the discovery in worms of a universal genetic
program for cell death opens up approaches for cell rescue based on,
for example, inhibition of the caspase proteases.
Next, consider the impact of molecular genetics. Huntington's
disease is an autosomal dominant disease marked by progressive motor
and cognitive impairment that ordinarily manifests itself in middle
age. The major pathology is cell death in the basal ganglia. In
1993, the Huntington's Disease Collaborative Research Group isolated
the gene responsible for the disease (17).
It is marked by an extended series of trinucleotide CAG (cytosine,
adenine, guanine) repeats, thereby placing Huntington's disease in a
new class of neurological disorders--the trinucleotide repeat
diseases--that now constitute the largest group of dominantly
transmitted neurological diseases.
The molecular genetic analysis of more complex degenerative
disorders has proceeded more slowly. Still, three genes associated
with familial Alzheimer's disease--those that code for the amyloid
precursor protein, presenilin 1, and presenilin 2--have been
identified. Molecular genetic studies have also identified the first
genes that modulate the severity and risk of a degenerative disease
(18).
One allele (APO E4) is a significant risk factor for late-onset
Alzheimer's disease. Conversely, the APO E2 allele may actually be
protective. A second risk factor is a2-macroglobulin. All the
Alzheimer's-related genes so far identified participate in either
generating or scavenging a protein (the amyloid peptide), which is
toxic at elevated levels. Studies directed at this peptide may lead
to ways to prevent the disease or halt its progression. Similarly,
the discovery of b-secretase and perhaps
g-secretase, the enzymes involved in the
processing of b amyloid, represent dramatic
advances that may also lead to new treatments.
With psychiatric disorders, progress has been slower for two
reasons. First, diseases such as schizophrenia, depression,
obsessive compulsive disorders, anxiety states, and drug abuse tend
to be complex, polygenic disorders that are significantly modulated
by environmental factors. Second, in contrast to neurological
disorders, little is known about the anatomical substrates of most
psychiatric diseases. Given the difficulty of penetrating the deep
biology of mental illness, it is nevertheless remarkable how much
progress has been made during the past 3 decades (19).
Arvid Carlsson and Julius Axelrod carried out pioneering studies of
biogenic amines, which laid the foundation for psychopharmacology,
and Seymour Kety pioneered the genetic study of mental illness (20).
Currently, new approaches to many conditions, such as sleep
disorders, eating disorders, and drug abuse, are emerging as the
result of insights into the cellular and molecular machinery that
regulates specific behaviors (21).
Moreover, improvements in diagnosis, the better delineation of
genetic contributions to psychiatric illness (based on twin and
adoption studies as well as studies of affected families), and the
discovery of specific medications for treating schizophrenia,
depression, and anxiety states have transformed psychiatry into a
therapeutically effective medical specialty that is now closely
aligned with neuroscience.
A New Alignment of Neuroscience and
Psychological Science The brain's computational
power is conferred by interactions among billions of nerve cells,
which are assembled into networks or circuits that carry out
specific operations in support of behavior and cognition. Whereas
the molecular machinery and electrical signaling properties of
neurons are widely conserved across animal species, what
distinguishes one species from another, with respect to their
cognitive abilities, is the number of neurons and the details of
their connectivity.
Beginning in the 19th century there was great interest in how
these cognitive abilities might be localized in the brain. One view,
first championed by Franz Joseph Gall, was that the brain is
composed of specialized parts and that aspects of perception,
emotion, and language can be localized to anatomically distinct
neural systems. Another view, championed by Jean-Pierre-Marie
Flourens, was that cognitive functions are global properties arising
from the integrated activity of the entire brain. In a sense, the
history of neuroscience can be seen as a gradual ascendancy of the
localizationist view.
To a large extent, the emergence of the localizationist view was
built on a century-old legacy of psychological science. When
psychology emerged as an experimental science in the late 19th
century, its founders, Gustav Fechner and Wilhelm Wundt, focused on
psychophysics--the quantitative relationship between physical
stimuli and subjective sensation. The success of this endeavor
encouraged psychologists to study more complex behavior, which led
to a rigorous, laboratory-based tradition termed behaviorism.
Led by John Watson and later by B. F. Skinner, behaviorists
argued that psychology should be concerned only with observable
stimuli and responses, not with unobservable processes that
intervene between stimulus and response. This tradition yielded
lawful principles of behavior and learning, but it proved limiting.
In the 1960s, behaviorism gave way to a broader approach concerned
with cognitive processes and internal representations. This new
emphasis focused on precisely those aspects of mental life--from
perception to action--that had long been of interest to neurologists
and other students of the nervous system.
The first cellular studies of brain systems in the 1950s
illustrated dramatically how much neuroscience derived from
psychology and conversely how much psychology could, in turn, inform
neuroscience. In using a cellular approach, neuroscientists relied
on the rigorous experimental methods of psychophysics and
behaviorism to explore how a sensory stimulus resulted in a neuronal
response. In so doing, they found cellular support for localization
of function: Different brain regions had different cellular response
properties. Thus, it became possible in the study of behavior and
cognition to move beyond description to an exploration of the
mechanisms underlying the internal representation of the external
world.
In the late 1950s and 1960s Mountcastle, Hubel, and Wiesel began
using cellular approaches to analyze sensory processing in the
cerebral cortex of cats and monkeys (22).
Their work provided the most fundamental advance in understanding
the organization of the brain since the work of Cajal at the turn of
the century. The cellular physiological techniques revealed that the
brain both filters and transforms sensory information on its way to
and within the cortex, and that these transformations are critical
for perception. Sensory systems analyze, decompose, and then
restructure raw sensory information according to built-in
connections and rules.
Mountcastle found that single nerve cells in the primary somatic
sensory cortex respond to specific kinds of touch: Some respond to
superficial touch and others to deep pressure, but cells almost
never respond to both. The different cell types are segregated in
vertical columns, which comprise thousands of neurons and extend
about 2 mm from the cortical surface to the white matter below it.
Mountcastle proposed that each column serves as an integrating unit,
or logical module, and that these columns are the basic mode of
cortical organization.
Single-cell recording was pioneered by Edgar Adrian and applied
to the visual system of invertebrates by H. Keffer Hartline and to
the visual system of mammals by Stephen Kuffler, the mentor of Hubel
and Wiesel. In recordings from the retina, Kuffler discovered that,
rather than signaling absolute levels of light, neurons signal
contrast between spots of light and dark. In the visual cortex,
Hubel and Wiesel found that most cells no longer respond to spots of
light. For example, in area V1 at the occipital pole of the cortex,
neurons respond to specific visual features such as lines or bars in
a particular orientation. Moreover, cells with similar orientation
preferences were found to group together in vertical columns similar
to those that Mountcastle had found in somatosensory cortex. Indeed,
an independent system of vertical columns--the ocular dominance
columns--was found to segregate information arriving from the two
eyes. These results provided an entirely new view of the anatomical
organization of the cerebral cortex.
Wiesel and Hubel also investigated the effects of early sensory
deprivation on newborn animals. They found that visual deprivation
in one eye profoundly alters the organization of ocular dominance
columns (23).
Columns receiving input from the closed eye shrink, and those
receiving input from the open eye expand. These studies led to the
discovery that eye closure alters the pattern of synchronous
activity in the two eyes and that this neural activity is essential
for fine-tuning synaptic connections during visual system
development (16).
In the extrastriate cortex beyond area V1, continuing
electrophysiological and anatomical studies have identified more
than 30 distinct areas important for vision (24).
Further, visual information was found to be analyzed by two parallel
processing streams (25).
The dorsal stream, concerned with where objects are located in space
and how to reach objects, extends from area V1 to the parietal
cortex. The ventral stream extends from area V1 to the inferior
temporal cortex and is concerned with analyzing the visual form and
quality of objects. Thus, even the apparently simple task of
perceiving an object in space engages a disparate collection of
specialized neural areas that represent different aspects of the
visual information--what the object is, where it is located, and how
to reach for it.
A Neuroscience of
Cognition The initial studies of the visual
system were performed in anaesthetized cats, an experimental
preparation far removed from the behaving and thinking human beings
that are the focus of interest for cognitive psychologists. A
pivotal advance occurred in the late 1960s when single-neuron
recordings were obtained from awake, behaving monkeys that had been
trained to perform sensory or motor tasks (26).
With these methods, the response of neurons in the posterior
parietal cortex to a visual stimulus was found to be enhanced when
the animal moved its eyes to attend to the stimulus. This moved the
neurophysiological study of single neurons beyond sensory processing
and showed that reductionist approaches could be applied to higher
order psychological processes such as selective attention.
It is possible to correlate neuronal firing with perception
rather directly. Thus, building on earlier work by Mountcastle, a
monkey's ability to discriminate motion was found to closely match
the performance of individual neurons in area MT, a cortical area
concerned with visual motion processing. Further, electrical
microstimulation of small clusters of neurons in MT shifts the
monkey's motion judgments toward the direction of motion that the
stimulated neurons prefer (27).
Thus, activity in area MT appears sufficient for the perception of
motion and for initiating perceptual decisions.
These findings, based on recordings from small neuronal
populations, have illuminated important issues in perception and
action. They illustrate how retinal signals are remapped from
retinotopic space into other coordinate frames that can guide
behavior; how attention can modulate neuronal activity; and how
meaning and context influence neuronal activity, so that the same
retinal stimulus can lead to different neuronal responses depending
on how the stimulus is perceived (28).
This same kind of work (relating cellular activity directly to
perception and action) is currently being applied to the so-called
binding problem--how the multiple features of a stimulus object,
which are represented by specialized and distributed neuronal
groups, are synthesized into a signal that represents a single
percept or action and to the fundamental question of what aspects of
neuronal activity (e.g., firing rate or spike timing) constitute the
neural codes of information processing (29).
Striking parallels to the organization and function of sensory
cortices have been found in the cortical motor areas supporting
voluntary movement. Thus, there are several cortical areas directed
to the planning and execution of voluntary movement. Primary motor
cortex has columnar organization, with neurons in each column
governing movements of one or a few joints. Motor areas receive
input from other cortical regions, and information moves through
stages to the spinal cord, where the detailed circuitry that
generates motor patterns is located (30).
Although studies of single cells have been enormously
informative, the functioning brain consists of multiple brain
systems and many neurons operating in concert. To monitor activity
in large populations of neurons, multielectrode arrays as well as
cellular and whole-brain imaging techniques are now being used.
These approaches are being supplemented by studying the effect of
selective brain lesions on behavior and by molecular methods, such
as the delivery of markers or other molecules to specific neurons by
viral transfection, which promise fine-resolution tracing of
anatomical connections, activity-dependent labeling of neurons, and
ways to transiently inactivate specific components of neural
circuits.
Invasive molecular manipulations of this kind cannot be applied
to humans. However, functional neuroimaging by positron emission
tomography (PET) or functional magnetic resonance imaging (fMRI)
provides a way to monitor large neuronal populations in awake humans
while they engage in cognitive tasks (31).
PET involves measuring regional blood flow using H2
15O and allows for repeated measurements on the
same individual. fMRI is based on the fact that neural activity
changes local oxygen levels in tissue and that oxygenated and
deoxygenated hemoglobin have different magnetic properties. It is
now possible to image the second-by-second time course of the
brain's response to single stimuli or single events with a spatial
resolution in the millimeter range. Recent success in obtaining fMRI
images from awake monkeys, combined with single-cell recording,
should extend the utility of functional neuroimaging by permitting
parallel studies in humans and nonhuman primates.
One example of how parallel studies of humans and nonhuman
primates have advanced the understanding of brain systems and
cognition is in the study of memory. The neuroscience of memory came
into focus in the 1950s when the noted amnesic patient H.M. was
first described (32).
H.M. developed profound forgetfulness after sustaining a bilateral
medial temporal lobe resection to relieve severe epilepsy. Yet he
retained his intelligence, perceptual abilities, and personality.
Brenda Milner's elegant studies of H.M. led to several important
principles. First, acquiring new memories is a distinct cerebral
function, separable from other perceptual and cognitive abilities.
Second, because H.M. could retain a number or a visual image for a
short time, the medial temporal lobes are not needed for immediate
memory. Third, these structures are not the ultimate repository of
memory, because H.M. retained his remote, childhood memories.
It subsequently became clear that only one kind of memory,
declarative memory, is impaired in H.M. and other amnesic patients.
Thus, memory is not a unitary faculty of the mind but is composed of
multiple systems that have different logic and neuroanatomy (33).
The major distinction is between our capacity for conscious,
declarative memory about facts and events and a collection of
unconscious, nondeclarative memory abilities, such as skill and
habit learning and simple forms of conditioning and sensitization.
In these cases, experience modifies performance without requiring
any conscious memory content or even the experience that memory is
being used.
An animal model of human amnesia in the nonhuman primate was
achieved in the early 1980s, leading ultimately to the
identification of the medial temporal lobe structures that support
declarative memory--the hippocampus and the adjacent entorhinal,
perirhinal, and parahippocampal cortices (34).
The hippocampus has been an especially active target of study, in
part because this was one of the structures damaged in patient H.M.
and also because of the early discovery of hippocampal place cells,
which signal the location of an animal in space (35).
This work led to the idea that, once learning occurs, the
hippocampus and other medial temporal lobe structures permit the
transition to long-term memory, perhaps by binding the separate
cortical regions that together store memory for a whole event. Thus,
long-term memory is thought to be stored in the same distributed set
of cortical structures that perceive, process, and analyze what is
to be remembered, and aggregate changes in large assemblies of
cortical neurons are the substrate of long-term memory. The frontal
lobes are also thought to influence what is selected for storage,
the ability to hold information in mind for the short term, and the
ability later on to retrieve it (36).
Whereas declarative memory is tied to a particular brain system,
nondeclarative memory refers to a collection of learned abilities
with different brain substrates. For example, many kinds of motor
learning depend on the cerebellum, emotional learning and the
modulation of memory strength by emotion depend on the amygdala, and
habit learning depends on the basal ganglia (37).
These forms of nondeclarative memory, which provide for myriad
unconscious ways of responding to the world, are evolutionarily
ancient and observable in simple invertebrates such as
Aplysia and Drosophila. By virtue of the
unconscious status of these forms of memory, they create some of the
mystery of human experience. For here arise the dispositions,
habits, attitudes, and preferences that are inaccessible to
conscious recollection, yet are shaped by past events, influence our
behavior and our mental life, and are a fundamental part of who we
are.
Bridging Cognitive Neuroscience and
Molecular Biology in the Study of Memory
Storage The removal of scientific barriers at the
two poles of the biological sciences--in the cell and molecular
biology of nerve cells on the one hand, and in the biology of
cognitive processes on the other--has raised the question: Can one
anticipate an even broader unification, one that ranges from
molecules to mind? A beginning of just such a synthesis may be
apparent in the study of synaptic plasticity and memory storage.
For all of its diversity, one can view neuroscience as being
concerned with two great themes--the brain's "hard wiring" and its
capacity for plasticity. The former refers to how connections
develop between cells, how cells function and communicate, and how
an organism's inborn functions are organized--its sleep-wake cycles,
hunger and thirst, and its ability to perceive the world. Thus,
through evolution the nervous system has inherited many adaptations
that are too important to be left to the vagaries of individual
experience. In contrast, the capacity for plasticity refers to the
fact that nervous systems can adapt or change as the result of the
experiences that occur during an individual lifetime. Experience can
modify the nervous system, and as a result organisms can learn and
remember.
The precision of neural connections poses deep problems for the
plasticity of behavior. How does one reconcile the precision and
specificity of the brain's wiring with the known capability of
humans and animals to acquire new knowledge? And how is knowledge,
once acquired, retained as long-term memory? A key insight about
synaptic transmission is that the precise connections between
neurons are not fixed but are modifiable by experience. Beginning in
1970, studies in invertebrates such as Aplysia showed that
simple forms of learning--habituation, sensitization, and classical
conditioning--result in functional and structural changes at
synapses between the neurons that mediate the behavior being
modified. These changes can persist for days or weeks and parallel
the time course of the memory process (38).
These cell biological studies have been complemented by genetic
studies in Drosophila. As a result, studies in
Aplysia and Drosophila have identified a number of
proteins important for memory (39).
In his now-famous book, The Organization of Behavior,
Donald Hebb proposed in 1949 that the synaptic strength between two
neurons should increase when the neurons exhibit coincident activity
(40).
In 1973, a long-lasting synaptic plasticity of this kind was
discovered in the hippocampus (a key structure for declarative
memory) (41).
In response to a burst of high-frequency stimuli, the major synaptic
pathways in the hippocampus undergo a long-term change, known as
long-term potentiation or LTP. The advent in the 1990s of the
ability to genetically modify mice made it possible to relate
specific genes both to synaptic plasticity and to intact animal
behavior, including memory. These techniques now allow one to delete
specific genes in specific brain regions and also to turn genes on
and off. Such genetic and pharmacological experiments in intact
animals suggest that interference with LTP at a specific
synapse--the Schaffer collateral-CA1 synapse--commonly impairs
memory for space and objects. Conversely, enhancing LTP at the same
synapse can enhance memory in these same declarative memory tasks.
The findings emerging from these new methods (42)
complement those in Aplysia and Drosophila and
reinforce one of Cajal's most prescient ideas: Even though the
anatomical connections between neurons develop according to a
definite plan, their strength and effectiveness are not
predetermined and can be altered by experience.
Combined behavioral and molecular genetic studies in
Drosophila, Aplysia, and mouse suggest that,
despite their different logic and neuroanatomy, declarative and
nondeclarative forms of memory share some common cellular and
molecular features. In both systems, memory storage depends on a
short-term process lasting minutes and a long-term process lasting
days or longer. Short-term memory involves covalent modifications of
preexisting proteins, leading to the strengthening of preexisting
synaptic connections. Long-term memory involves altered gene
expression, protein synthesis, and the growth of new synaptic
connections. In addition, a number of key signaling molecules
involved in converting transient short-term plasticity to persistent
long-term memory appear to be shared by both declarative and
nondeclarative memory. A striking feature of neural plasticity is
that long-term memory involves structural and functional change (38,
43).
This has been shown most directly in invertebrates and is likely to
apply to vertebrates as well, including primates.
It had been widely believed that the sensory and motor cortices
mature early in life and thereafter have a fixed organization and
connectivity. However, it is now clear that these cortices can be
reshaped by experience (44).
In one experiment, monkeys learned to discriminate between two
vibrating stimuli applied to one finger. After several thousand
trials, the cortical representation of the trained finger became
more than twice as large as the corresponding areas for other
fingers. Similarly, in a neuroimaging study of right-handed string
musicians the cortical representations of the fingers of the left
hand (whose fingers are manipulated individually and are engaged in
skillful playing) were larger than in nonmusicians. Thus, improved
finger skills even involve changes in how sensory cortex represents
the fingers. Because all organisms experience a different sensory
environment, each brain is modified differently. This gradual
creation of unique brain architecture provides a biological basis
for individuality.
Coda Physicists and
chemists have often distinguished their disciplines from the field
of biology, emphasizing that biology was overly descriptive,
atheoretical, and lacked the coherence of the physical sciences.
This is no longer quite true. In the 20th century, biology matured
and became a coherent discipline as a result of the substantial
achievements of molecular biology. In the second half of the
century, neuroscience emerged as a discipline that concerns itself
with both biology and psychology and that is beginning to achieve a
similar coherence. As a result, fascinating insights into the
biology of cells, and remarkable principles of evolutionary
conservation, are emerging from the study of nerve cells. Similarly,
entirely new insights into the nature of mental processes
(perception, memory, and cognition) are emerging from the study of
neurons, circuits, and brain systems, and computational studies are
providing models that can guide experimental work. Despite this
remarkable progress, the neuroscience of higher cognitive processes
is only beginning. For neuroscience to address the most challenging
problems confronting the behavioral and biological sciences, we will
need to continue to search for new molecular and cellular approaches
and use them in conjunction with systems neuroscience and
psychological science. In this way, we will best be able to relate
molecular events and specific changes within neuronal circuits to
mental processes such as perception, memory, thought, and possibly
consciousness itself.
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Department of Veterans Affairs, NIMH, and the Metropolitan Life
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helpful comments on the manuscript.
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York, and Senior Investigator at the Howard Hughes Medical
Institute. He is a member of the National Academy of Sciences and
the Institute of Medicine and a past president of the Society for
Neuroscience. This past October, he was named a co-recipient of the
Nobel Prize in physiology or medicine.
Larry R. Squire is Research Career Scientist at the Veterans
Affairs San Diego Healthcare System and Professor of Psychiatry,
Neurosciences, and Psychology, University of California, San Diego.
He is a member of the National Academy of Sciences and the Institute
of Medicine and a past president of the Society for Neuroscience.
A
Timeline of Neuroscience |
A.D. |
2ND Century A.D. Galen of Pergamum
identifies the brain as the organ of the mind. |
1600s |
17TH Century The brain becomes
accepted as the substrate of mental life rather than its
ventricles, as early writers had proposed. |
1664 Thomas Willis publishes
Cerebri anatome, with illustrations of the brain by
Christopher Wren. It is the most comprehensive treatise on
brain anatomy and function published up to that time. |
1700s |
1791 Luigi Galvani reveals the
electric nature of nervous action by stimulating nerves and
muscles of frog legs. |
1800s |
1808 Franz Joseph Gall proposes
that specific brain regions control specific functions. |
1852 Hermann von Helmholtz
measures the speed of a nerve impulse in the frog. |
1879 Wilhelm Wundt establishes the
first laboratory of experimental psychology in Leipzig,
Germany. |
1891 Wilhelm von Waldeyer-Hartz
introduces the term neuron. |
1897 Charles Sherrington
introduces the term synapse. |
1898-1903 Edward Thorndike and
Ivan Pavlov describe operant and classical conditioning, two
fundamental types of learning. |
1900s |
1906 Santiago Ramón y Cajal
summarizes compelling evidence for the neuron doctrine, that
the nervous system is composed of discrete cells. |
1906 Alois Alzheimer describes the
pathology of the neurodegenerative disease that comes to bear
his name. |
1914 Henry Dale demonstrates the
physiological action of acetylcholine, which is later
identified as a neurotransmitter. |
1929 In a famous program of lesion
experiments in rats, Karl Lashley attempts to localize memory
in the brain. |
1929 Hans Berger uses human scalp
electrodes to demonstrate electroencephalography. |
1928-32 Edgar Adrian describes
method for recording from single sensory and motor axons; H.
Keffer Hartline applies this method to the recording of
single-cell activity in the eye of the horseshoe crab. |
1940s Alan Hodgkin, Andrew Huxley,
and Bernard Katz explain electrical activity of neurons by
concentration gradients of ions and movement of ions through
pores. |
1946 Kenneth Cole develops the
voltage-clamp technique to measure current flow across the
cell membrane. |
1949 Donald Hebb introduces a
synaptic learning rule, which becomes known as the Hebb
rule. |
1930s to 1950s The chemical nature
of synaptic transmission is established by Otto Loewi, Henry
Dale, Wilhelm Feldberg, Stephen Kuffler, and Bernard Katz at
peripheral synapses and is extended to the spinal cord by John
Eccles and others. |
1930s to 1950s Wilder Penfield and
Theodore Rasmussen map the motor and sensory homunculus and
illustrate localization of function in the human brain. |
1950s Karl von Frisch, Konrad
Lorenz, and Nikolaas Tinbergen establish the science of
ethology (animal behavior in natural contexts) and lay the
foundation for neuroethology. |
1955-60 Vernon Mountcastle, David
Hubel, and Torsten Wiesel pioneer single-cell recording from
mammalian sensory cortex; Nils-Ake Hillarp introduces
fluorescent microscopic methods to study cellular distribution
of biogenic amines. |
1956 Rita Levi-Montalcini and
Stanley Cohen isolate and purify nerve growth factor. |
1957 Brenda Milner describes
patient H.M. and discovers the importance of the medial
temporal lobe for memory. |
1958 Arvid Carlsson finds dopamine
to be a transmitter in the brain and proposes that it has a
role in extrapyramidal disorders such as Parkinson's
disease. |
1958 Simple invertebrate systems,
including Aplysia , Drosophila, and
C. elegans, are introduced to analyze
elementary aspects of behavior and learning at the cellular
and molecular level. |
1962-63 Brain anatomy in rodents
is found to be altered by experience; first evidence for role
of protein synthesis in memory formation. |
1963 Roger Sperry proposes a
precise system of chemical matching between pre- and
postsynaptic neuronal partners (the chemoaffinity
hypothesis). |
1966-69 Ed Evarts and Robert Wurtz
develop methods for studying movement and perception with
single-cell recordings from awake, behaving monkeys. |
1970 Synaptic changes are related
to learning and memory storage in Aplysia |
Mid-1970s Paul Greengard shows
that many neurotransmitters work by means of protein
phosphorylation. |
1973 Timothy Bliss and Terje Lomo
discover long-term potentiation, a candidate synaptic
mechanism for long-term mammalian memory. |
1976 Erwin Neher and Bert Sakmann
develop the patch-clamp technique for recording the activity
of single ion channels. |
Late 1970s Neuroimaging by
positron emission tomography is developed. |
1980s Experimental evidence
becomes available for the divisibility of memory into multiple
systems; an animal model of human amnesia is developed. |
1986 H. Robert Horvitz discovers
the ced genes, which are critical for programmed cell
death. |
1986 Patient R.B. establishes the
importance of the hippocampus for human memory. |
1990 Segi Ogawa and colleagues
develop functional magnetic resonance imaging. |
1990 Mario Capecchi and Oliver
Smythies develop gene knockout technology, which is soon
applied to neuroscience. |
1991 Linda Buck and Richard Axel
discover that the olfactory receptor family consists of over
1000 different genes. The anatomical components of the medial
temporal lobe memory system are identified. |
1993 The Huntington's Disease
Collaborative Research Group identifies the gene responsible
for Huntington's disease. |
1990s Neural development is
transformed from a descriptive to a molecular discipline by
Gerald Fischbach, Jack McMahan, Tom Jessell, and Corey
Goodman; neuroimaging is applied to problems of human
cognition, including perception, attention, and memory. |
1990s Reinhard Jahn, James
Rothman, Richard Scheller, and Thomas Sudhof delineate
molecules critical for exocytosis. |
1998 First 3D structure of an ion
channel is revealed by Rod
MacKinnon. |
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