Annual Review of Neuroscience - Volume 23, 2000

The large size and extreme polarization of neurons is crucial to their ability to communicate at long distances and to form the complex cellular networks of the nervous system. The size, shape, and compartmentalization of these specialized cells must be generated and supported by the cytoskeletal systems of intracellular transport. One of the major systems is the microtubule-based transport system along which kinesin and dynein motor proteins generate force and drive the traffic of many cellular components. This review describes our current understanding of the functions of kinesins and dyneins and how these motor proteins may be harnessed to generate some of the unique properties of neuronal cells.

Cell death via apoptosis is a prominent feature in mammalian neural development. Recent studies into the basic mechanism of apoptosis have revealed biochemical pathways that control and execute apoptosis in mammalian cells. Protein factors in these pathways play important roles during development in regulating the balance between neuronal life and death. Additionally, mounting evidence indicates such pathways may also be activated during several neurodegenerative diseases, resulting in improper loss of neurons.

Many ion channels and receptors display striking phenotypes for gainof-function mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating changes including constitutive activation and slowed inactivation, elimination of a subunit that enhances inactivation, decreased drug sensitivity, changes in regulation or trafficking of the channel, or induction of apoptosis. Decreased firing frequency can occur via increased function of K⁺ or Cl⁻ channels. Channel mutants also cause gain-of-function syndromes at the cellular and circuit level; of these syndromes, the cardiac long-QT syndromes are explained in a more straightforward way than are the epilepsies. G protein– coupled receptors are also affected by activating mutations.

A neurochemically distinct population of koniocellular (K) neurons makes up a third functional channel in primate lateral geniculate nucleus. As part of a general pattern, K neurons form robust layers through the full representation of the visual hemifield. Similar in physiology and connectivity to W cells in cat lateral geniculate nucleus, K cells form three pairs of layers in macaques. The middle pair relays input from short-wavelength cones to the cytochrome-oxidase blobs of primay visual cortex (V1), the dorsal-most pair relays low-acuity visual information to layer I of V1, and the ventral-most pair appears closely tied to the function of the superior colliculus. Throughout each K layer are neurons that innervate extrastriate cortex and that are likely to sustain some visual behaviors in the absence of V1. These data show that several pathways exist from retina to V1 that are likely to process different aspects of the visual scene along lines that may remain parallel well into V1.

The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as “affect,” “hedonic tone,” or “emotional feelings,” and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior

The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.

A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.

The mammalian retina contains upward of 50 distinct functional elements, each carrying out a specific task. Such diversity is not rare in the central nervous system, but the retina is privileged because its physical location, the distinctive morphology of its neurons, the regularity of its architecture, and the accessibility of its inputs and outputs permit a unique variety of experiments. Recent strategies for confronting the retina’s complexity attempt to marry genetic approaches to new kinds of anatomical and electrophysiological techniques.

Hair cells adapt to sustained deflections of the hair bundle via Ca²⁺dependent negative feedback on the open probability of the mechanosensitive transduction channels. A model posits that adaptation relieves the input to the transduction channels—force applied by elastic tip links between stereocilia—by repositioning the insertions of the links in the stereocilium. The tip link insertion and transduction channel are dragged by myosins moving on the stereocilium’s actin core. This model accounts for many aspects of adaptation in hair cells of the frog saccule, where adaptation time constants are tens of milliseconds. Adaptation in hair cells of the turtle cochlea is much faster, possibly reflecting a more direct mechanism such as Ca²⁺ binding to the transduction channel. Adaptation mechanisms attenuate the transduction current at low frequencies and may be tuned to different corner frequencies according to the stimulus demands of the inner ear organ. Other sites of adaptation in the inner ear include accessory structures, voltage-dependent properties of hair cells, and afferent transmitter release. A remaining challenge is to understand how these processes work together to shape the output of the inner ear to natural stimuli.

A typical scene contains many different objects that, because of the limited processing capacity of the visual system, compete for neural representation. The competition among multiple objects in visual cortex can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that, both in the absence and in the presence of visual stimulation, biasing signals due to selective attention can modulate neural activity in visual cortex in several ways. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals derives from a network of areas in frontal and parietal cortex.

One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.

One fundamental function of primary motor cortex (MI) is to control voluntary movements. Recent evidence suggests that this role emerges from distributed networks rather than discrete representations and that in adult mammals these networks are capable of modification. Neuronal recordings and activation patterns revealed with neuroimaging methods have shown considerable plasticity of MI representations and cell properties following pathological or traumatic changes and in relation to everyday experience, including motor-skill learning and cognitive motor actions. The intrinsic horizontal neuronal connections in MI are a strong candidate substrate for map reorganization: They interconnect large regions of MI, they show activity-dependent plasticity, and they modify in association with skill learning. These findings suggest that MI cortex is not simply a static motor control structure. It also contains a dynamic substrate that participates in motor learning and possibly in cognitive events as well.

Mammals can discriminate among a large number (>10,000) of unique odorants. The most highly supported explanation for this ability is that olfactory neurons express a large number of seven transmembrane receptors that are not spatially organized at the level of the olfactory epithelium, but whose axonal projections form a distinct pattern within the olfactory bulb. The odor-induced signaling pathway in olfactory neurons includes a Gs-like protein (Golf) that activates a specific adenylyl cyclase (type III) isoform, resulting in elevations of cyclic AMP and subsequent activation of a cyclic nucleotide-gated channel. The channel also can be regulated by cyclic GMP. Recently, an olfactory neuron-specific guanylyl cyclase was discovered in rodents, and subsequently a large family of sensory neuronal guanylyl cyclases was identified in nematodes. These guanylyl cyclases are concentrated in the plasma membrane of the dendritic cilia and contain extracellular domains that retain many of the primary sequence characteristics of guanylyl cyclases known to be receptors for various peptides. Thus, the guanylyl cyclases appear to represent a second family of odorant/pheromone receptors.

The origin of orientation selectivity in the responses of simple cells in cat visual cortex serves as a model problem for understanding cortical circuitry and computation. The feed-forward model posits that this selectivity arises simply from the arrangement of thalamic inputs to a simple cell. Much evidence, including a number of recent intracellular studies, supports a primary role of the thalamic inputs in determining simple cell response properties, including orientation tuning. This mechanism alone, however, cannot explain the invariance of orientation tuning to changes in stimulus contrast. Simple cells receive push-pull inhibition: ON inhibition in OFF subregions and vice versa. Addition of such inhibition to the feed-forward model can account for this contrast invariance, provided the inhibition is sufficiently strong. The predictions of “normalization” and “feedback” models are reviewed and compared with the predictions of this modified feed-forward model and with experimental results. The modified feed-forward and the feedback models ascribe fundamentally different functions to cortical processing.

Associative learning enables animals to anticipate the occurrence of important outcomes. Learning occurs when the actual outcome differs from the predicted outcome, resulting in a prediction error. Neurons in several brain structures appear to code prediction errors in relation to rewards, punishments, external stimuli, and behavioral reactions. In one form, dopamine neurons, norepinephrine neurons, and nucleus basalis neurons broadcast prediction errors as global reinforcement or teaching signals to large postsynaptic structures. In other cases, error signals are coded by selected neurons in the cerebellum, superior colliculus, frontal eye fields, parietal cortex, striatum, and visual system, where they influence specific subgroups of neurons. Prediction errors can be used in postsynaptic structures for the immediate selection of behavior or for synaptic changes underlying behavioral learning. The coding of prediction errors may represent a basic mode of brain function that may also contribute to the processing of sensory information and the short-term control of behavior.

Two fundamental aspects of frequency analysis shape the functional organization of primary auditory cortex. For one, the decomposition of complex sounds into different frequency components is reflected in the tonotopic organization of auditory cortical fields. Second, recent findings suggest that this decomposition is carried out in parallel for a wide range of frequency resolutions by neurons with frequency receptive fields of different sizes (bandwidths). A systematic representation of the range of frequency resolution and, equivalently, spectral integration shapes the functional organization of the iso-frequency domain. Distinct subregions, or “modules,” along the iso-frequency domain can be demonstrated with various measures of spectral integration, including pure-tone tuning curves, noise masking, and electrical cochlear stimulation. This modularity in the representation of spectral integration is expressed by intrinsic cortical connections. This organization has implications for our understanding of psychophysical spectral integration measures such as the critical band and general cortical coding strategies.

The diverse cell types in the nervous system are derived from neural progenitor cells. Neural progenitors can undergo symmetric divisions to expand cell population or asymmetric divisions to generate diverse cell types. Furthermore, neural progenitors must exit the cell cycle in a developmentally regulated manner to allow for terminal differentiation. The patterns of neural progenitor divisions have been characterized in vertebrates and invertebrates. During the course of nervous system development, extrinsic and intrinsic cues dictate the division patterns of neural progenitors by influencing their cell cycle behavior and cellular polarity. The identification in Drosophila of asymmetrically distributed fate determinants, adapter molecules, and polarity organizing molecules that participate in asymmetric neural progenitor divisions should provide points of entry for studying similar asymmetric divisions in vertebrates.

Until recently, most neuroscientists did not regard consciousness as a suitable topic for scientific investigation. This reluctance was based on certain philosophical mistakes, primarily the mistake of supposing that the subjectivity of consciousness made it beyond the reach of an objective science. Once we see that consciousness is a biological phenomenon like any other, then it can be investigated neurobiologically. Consciousness is entirely caused by neurobiological processes and is realized in brain structures. The essential trait of consciousness that we need to explain is unified qualitative subjectivity. Consciousness thus differs from other biological phenomena in that it has a subjective or first-person ontology, but this subjective ontology does not prevent us from having an epistemically objective science of consciousness. We need to overcome the philosophical tradition that treats the mental and the physical as two distinct metaphysical realms. Two common approaches to consciousness are those that adopt the building block model, according to which any conscious field is made of its various parts, and the unified field model, according to which we should try to explain the unified character of subjective states of consciousness. These two approaches are discussed and reasons are given for preferring the unified field theory to the building block model. Some relevant research on consciousness involves the subjects of blindsight, the split-brain experiments, binocular rivalry, and gestalt switching.

The ability of peripheral nervous system (PNS) but not central nervous system (CNS) neurons to regenerate their axons is a striking peculiarity of higher vertebrates. Much research has focused on the inhibitory signals produced by CNS glia that thwart regenerating axons. Less attention has been paid to the injury-induced loss of trophic stimuli needed to promote the survival and regeneration of axotomized neurons. Could differences in the mechanisms that control CNS and PNS neuronal survival and growth also contribute to the disparity in regenerative capacity? Here we review recent studies concerning the nature of the signals necessary to promote neuronal survival and growth, with an emphasis on their significance to regeneration after CNS injury.