Otto Friedrich Karl Deiters (1834-1863).

Otto Deiters, for whom the lateral vestibular nucleus and the supporting cells of the outer auditory hair cells were named, died in 1863 aged 29. He taught in the Bonn Anatomy Department, had an appointment in the University Clinic, and ran a small private practice. He published articles on the cell theory, the structure and development of muscle fibers, the inner ear, leukaemia, and scarlet fever. He was the second of five surviving children in an academic family whose private correspondence revealed him to be a young man with limited social skills and high ambitions to complete a deeply original study of the brainstem and spinal cord. However, first his father and then his younger brother died, leaving him and his older brother responsible for a suddenly impecunious family as he failed to gain academic promotion. Otto died of typhus two years after his younger brother's death, leaving his greatest scientific achievement to be published posthumously. He showed that most nerve cells have a single axon and several dendrites; he recognized the possibility that nerve cells might be functionally polarized and produced the first illustrations of synaptic inputs to dendrites from what he termed a second system of nerve fibers.

Distinct functions for direct and transthalamic corticocortical connections.

Essentially all cortical areas receive thalamic inputs and send outputs to lower motor centers. Cortical areas communicate with each other by means of direct corticocortical and corticothalamocortical pathways, often organized in parallel. We distinguish these functionally, stressing that the transthalamic pathways are class 1 (formerly known as "driver") pathways capable of transmitting information, whereas the direct pathways vary, being either class 2 (formerly known as "modulator") or class 1. The transthalamic pathways provide a thalamic gate that can be open or closed (and otherwise more subtly modulated), and these inputs to the thalamus are generally branches of axons with motor functions. Thus the transthalamic corticocortical pathways that can be gated carry information about the cortical processing in one cortical area and also about the motor instructions currently being issued from that area and copied to other cortical areas.

Branched thalamic afferents: what are the messages that they relay to the cortex?

Many of the axons that carry messages to the thalamus for relay to the cerebral cortex are branched in a pattern long known from Golgi preparations. They send one branch to the thalamus and the other to motor centers of the brainstem or spinal cord. Because the thalamic branches necessarily carry copies of the motor instructions their messages have the properties of efference copies. That is, they can be regarded as providing reliable information about impending instructions contributing to movements that will produce changes in inputs to receptors, thus allowing neural centers to compensate for these changes of input. We consider how a sensory pathway like the medial lemniscus, the spinothalamic tract or the optic tract can also be seen to act as a pathway for an efference copy. The direct connections that ascending and cortical inputs to the thalamus also establish to motor outputs create sensorimotor relationships that provide cortex with a model of activity in lower circuits and link the sensory and the motor sides of behavior more tightly than can be expected from motor outputs with a single, central origin. These transthalamic connectional patterns differ from classical models of separate neural pathways for carrying efference copies of actions generated at higher levels, and introduce some different functional possibilities.

Relating the neuron doctrine to the cell theory. Should contemporary knowledge change our view of the neuron doctrine?

The neuron doctrine, formulated in 1891, attacked in 1906 by Golgi and fiercely defended by Cajal, provided a powerful tool for analyzing the pathways of the brain. It has often been described as though it were merely the cell theory applied to nervous systems. In this essay I show that the neuron doctrine claims more than does the cell theory, and that in many instances, where it goes beyond the cell theory, it can no longer be defended on the basis of contemporary evidence. The neuron doctrine should be seen as a practical tool that is particularly useful for understanding the long pathways of the brain; it cannot be regarded as providing an accurate account of what nerve cells in general are really like.

Anatomical pathways that link perception and action.

Pathways linking action to perception are generally presented as passing from sensory pathways, through the thalamus, and then to a putative hierarchy of corticocortical links to motor outputs or to memory. Evidence for more direct sensorimotor links is now presented to show that cerebral cortex rarely, if ever, receives messages representing receptor activity only; thalamic inputs to cortex also carry copies of current motor instructions. Pathways afferent to the thalamus represent the primary input to neocortex. Generally they are made up of branching axons that send one branch to the thalamus and another to output centers of the brain stem or spinal cord. The information transmitted through the classical "sensory" pathways to the thalamus represents not only information about the environment and the body, but also about instructions currently on their way to motor centers. The proposed hierarchy of direct corticocortical connections of the sensory pathways is not the only possible hierarchy of cortical connections. There is also a hierarchy of the corticofugal pathways to motor centers in the midbrain, and there are transthalamic corticocortical pathways that may show a comparable hierarchy. The extent to which these hierarchies may match each other, and relate to early developmental changes are poorly defined at present, but are important for understanding mechanisms that can link action and perception in the developing brain.

Observations of synaptic structures: origins of the neuron doctrine and its current status.

The neuron doctrine represents nerve cells as polarized structures that contact each other at specialized (synaptic) junctions and form the developmental, functional, structural and trophic units of nervous systems. The doctrine provided a powerful analytical tool in the past, but is now seldom used in educating neuroscientists. Early observations of, and speculations about, sites of neuronal communication, which were made in the early 1860s, almost 30 years before the neuron doctrine was developed, are presented in relation to later accounts, particularly those made in support of, or opposition to, the neuron doctrine. These markedly differing accounts are considered in relation to limitations imposed by preparative and microscopical methods, and are discussed briefly as representing a post-Darwinian, reductionist view, on the one hand, opposed to a holistic view of mankind as a special part of creation, on the other. The widely misunderstood relationship of the neuron doctrine to the cell theory is discussed, as is the degree to which the neuron doctrine is still strictly applicable to an analysis of nervous systems. Current research represents a 'post-neuronist' era. The neuron doctrine provided a strong analytical approach in the past, but can no longer be seen as central to contemporary advances in neuroscience.

Is postnatal neocortical maturation hierarchical?

To understand the postnatal development of the cerebral cortex we must know how changes in one cortical area depend on inputs from other cortical areas. Do cortical areas serving early stages of processing (primary sensory receiving areas) mature first, passing relatively stable outputs about sensorimotor relationships to cortical areas involved in higher stages of processing that are still developing? And, if some areas mature later than others, do they have functions that can account for aspects of adolescent behavior? Some observations support concurrent maturation in all cortical areas, others support a hierarchical sequence. Here, evidence on this important issue is evaluated, and means of obtaining reliable information are presented.

Branching thalamic afferents link action and perception.

Recent observations of single axons and review of older literature show that axons afferent to the thalamus commonly branch, sending one branch to the thalamus and another to a motor or premotor center of the brain stem. That is, the messages that the thalamus relays to the cerebral cortex can be regarded as copies of motor instructions. This pattern of axonal branching is reviewed, particularly for the somatosensory and the visual pathways. The extent to which this anatomical evidence relates to views that link action to perception is explored. Most pathways going through the thalamus to the cortex are already involved in motor mechanisms. These motor links occur before and during activity in the parallel and hierarchical corticocortical circuitry that currently forms the focus of many studies of perceptual processing.

Structure and connections of the thalamic reticular nucleus: Advancing views over half a century.

The advance of knowledge of the thalamic reticular nucleus and its connections has been reviewed and Max Cowan's contributions to this knowledge and to the methods used for studying the nucleus have been summarized. Whereas 50 years ago the nucleus was seen as a diffusely organized cell group closely related to the brain stem reticular formation, it can now be seen as a complex, tightly organized entity that has a significant inhibitory, modulatory action on the thalamic relay to cortex. The nucleus is under the control, on the one hand, of topographically organized afferents from the cerebral cortex and the thalamus, and on the other of more diffuse afferents from brain stem, basal forebrain, and other regions. Whereas the second group of afferents can be expected to have global actions on thalamocortical transmission, relevant for overall attentive state, the former group will have local actions, modulating transmission through the thalamus to cortex with highly specific local effects. Since it appears that all areas of cortex and all parts of the thalamus are linked directly to the reticular nucleus, it now becomes important to define how the several pathways that pass through the thalamus relate to each other in their reticular connections.

Doubt and certainty in counting.

Some of the methods used for counting objects in histological sections are discussed. The method best suited for any particular counting program depends on many variables, which include the level of accuracy required, the type of preparation available for study, the size of the objects to be counted, the thickness of the sections that can be used, the equipment available and the amount of labor that can reasonably be invested. For light and electron microscopy, profile counts are simple and quick for objects that are small relative to section thickness and whose dimensions are readily defined. The 'physical disector' is particularly useful where objects to be counted are large relative to sections thickness, or where their dimensions are unknown or highly variable. For light microscopy, the optical disector is often easier to use. However, it makes more assumptions than the physical disector; some of these can introduce serious bias in the counts, and they are explored. Electron microscopy raises some special problems that relate to the depth of focus, the relatively very thin sections, and the tendency for thin structures that do not span the full thickness of a section to be lost or unrecognizable in some section planes. The importance of recognizing the assumptions that underlie any method of counting and its interpretation is stressed.

On counting and counting errors.

Counting objects in histological sections is often a necessary, sometimes an unexpected part of a research project. The recent literature shows that the subject of counting is of particular interest to readers of the Journal of Comparative Neurology but that it is also contentious and difficult. Even a brief review of past issues of the Journal shows that there are many misconceptions about counting and that there remain issues that have received little or no attention. Counts are subject to many errors. Some reports include readily recognizable errors, others fail to include all of the information that is needed for an evaluation of their accuracy. This review is above all a plea for adequate information about the methods used for counts in all publications. It serves to help those who are new to quantitative methods in histology; it considers some of the basic issues arising for anyone undertaking counts, or reviewing manuscripts that include counts. In particular, it considers recently introduced or re-introduced counting methods that depend on accurate measures along the axis perpendicular to the plane of the sections, and looks at the difficulties inherent in these measures.

Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system.

All neocortical areas receive thalamic inputs. Some thalamocortical pathways relay information from ascending pathways (first order thalamic relays) and others relay information from other cortical areas (higher order thalamic relays), thus serving a role in corticocortical communication. Most, possibly all, afferents reaching thalamus, ascending and cortical, are branches of axons that innervate lower (motor) centers, so that thalamocortical pathways can be viewed generally as monitors of ongoing motor instructions. In terms of numbers, the thalamic relay is dominated by synapses that modulate the relay functions. One of the roles of these modulatory pathways is to change the transfer of information through the thalamus, in accord with current attentional demands. Other roles remain to be explored. These modulatory functions can be expected to act on corticocortical communication in addition to their action on ascending pathways.

The role of the thalamus in the flow of information to the cortex.

The lateral geniculate nucleus is the best understood thalamic relay and serves as a model for all thalamic relays. Only 5-10% of the input to geniculate relay cells derives from the retina, which is the driving input. The rest is modulatory and derives from local inhibitory inputs, descending inputs from layer 6 of the visual cortex, and ascending inputs from the brainstem. These modulatory inputs control many features of retinogeniculate transmission. One such feature is the response mode, burst or tonic, of relay cells, which relates to the attentional demands at the moment. This response mode depends on membrane potential, which is controlled effectively by the modulator inputs. The lateral geniculate nucleus is a first-order relay, because it relays subcortical (i.e. retinal) information to the cortex for the first time. By contrast, the other main thalamic relay of visual information, the pulvinar region, is largely a higher-order relay, since much of it relays information from layer 5 of one cortical area to another. All thalamic relays receive a layer-6 modulatory input from cortex, but higher-order relays in addition receive a layer-5 driver input. Corticocortical processing may involve these corticothalamocortical 're-entry' routes to a far greater extent than previously appreciated. If so, the thalamus sits at an indispensable position for the modulation of messages involved in corticocortical processing.

The thalamus as a monitor of motor outputs.

Many of the ascending pathways to the thalamus have branches involved in movement control. In addition, the recently defined, rich innervation of 'higher' thalamic nuclei (such as the pulvinar) from pyramidal cells in layer five of the neocortex also comes from branches of long descending axons that supply motor structures. For many higher thalamic nuclei the clue to understanding the messages that are relayed to the cortex will depend on knowing the nature of these layer five motor outputs and on defining how messages from groups of functionally distinct output types are combined as inputs to higher cortical areas. Current evidence indicates that many and possibly all thalamic relays to the neocortex are about instructions that cortical and subcortical neurons are contributing to movement control. The perceptual functions of the cortex can thus be seen to represent abstractions from ongoing motor instructions.

Edward George Gray, 11 January 1924 - 14 August 1999.

George Gray was an early contributor to our knowledge of the electron microscopic appearance of the central nervous system. He was skillful with the difficult techniques for preparing the tissues, worked rapidly, and was an astute observer. Sitting with him in the dark, staring at a dim image that George was moving rapidly as he searched for significant detail, could be an exciting experience. He had clear ideas about features that mattered and could quickly relate the two-dimensional electron microscopic images to the three-dimensional neural structures under investigation. He is best known for his detailed and perspective description of synaptic junctions in the mammalian neocortex, and his name is still linked to two distinct junctional types (Gray's type 1 and Gray's type 2), now recognized as generally distinguishing excitatory from inhibitory junctions. He studied a wide range of neural tissues, played a significant role in the early isolation of 'synaptosomes', contributed greatly to the rapid advance of knowledge that accompanied the early application of the electron microscope to neural tissues, and influenced a great many later fine-structural studies of the nervous system.

Connections of higher order visual relays in the thalamus: a study of corticothalamic pathways in cats.

Axonal markers injected into layers 5 and 6 of cortical areas 17, 18, or 19 labeled axons going to the lateral geniculate nucleus (LGN), the lateral part of the lateralis posterior nucleus (LPl), and pulvinar (P). Area 19 sends fine axons (type 1, Guillery [1966] J Comp Neurol 128:21-50) to LGN, LPl, and P, and thicker, type 2 axons to LPl and P. Areas 17 and 18 send type 1 axons to LGN, and a few type 1, but mainly type 2 axons to LPl and P. Type 1 and 2 axons from a single small cortical locus distribute to distinct, generally nonoverlapping parts of LP and P; type 1 axons have a broader distribution than type 2 axons. Type 2 axons, putative drivers of thalamic relay cells (Sherman and Guillery [1998] Proc Natl Acad Sci USA 95:7121-7126; Sherman and Guillery [2001] Exploring the thalamus. San Diego: Academic Press), supply small terminal arbors (100- to 200-microm diameter) in LPl and P, and then continue into the midbrain. Each thalamic type 2 arbor contains two terminal types. One, at the center of the arbor, is complex and multilobulated; the other, with a more peripheral distribution, is simpler and may contribute to adjacent arbors. Type 2 arbors from a single injection are scattered around and along "isocortical columns" in LPl, (i.e., columns that represent cells having connections to a common cortical locus). Evidence is presented that the connections and consequently the functional properties of cells in LP change along these isocortical columns. Type 2 driver afferents from a single cortical locus can, thus, be seen as representing functionally distinct, parallel pathways from cortex to thalamus.

Professor Edward George Gray, FRS (1924-1999).

Professor George Gray, who died in August 1999, had a notable career as a pioneer electron microscopist of neural tissues. His name is still attached to synapses, which can be classified as Gray type 1 (symmetric) or type 2 (asymmetric), and in addition he made a number of other profound contributions to our knowledge of synaptic structures.He started his academic career late, having worked before the second World War as a bank clerk, and then serving in the Navy, patrolling for U-boats in the North Sea and Atlantic for 4 years during the latter part of the war. He had an early interest in zoology, particularly in marine biology and microscopy and when he left the Navy he took the opportunity to work for a degree in Zoology at the University of Wales in Aberystwyth. A first class honours degree was followed by a PhD on melanophores in teleosts. It was fortunate that the external examiner for the thesis was J. Z. Young, who was impressed by the work and by George, and who invited George to work as his assistant in the preparation of The Life of the Mammals in the Anatomy Department at University College London.