The role of the dopaminergic projections in MFB self-stimulation

Psychophysical experiments indicate that the first stage of the reward pathway in medial forebrain bundle self-stimulation consists of small myelinated descending axons. Pharmacological experiments show that neuroleptics attenuate or abolish the rewarding effect. This had led to the hypothesis that the descending myelinated axons synapse on an ascending dopaminergic second stage projection. 2-Deoxy-[14C]glucose autoradiography in self-stimulating animals or animals receiving automatically administered rewarding stimulation after treatment with reward-blocking doses of pimozide reveals activation of a descending myelinated system but no stimulation-produced activation of an ascending dopaminergic projection system, even though the autoradiographic method reveals the mild elevations and depressions of activity in dopaminergic terminal fields consequent upon injections of neuroleptics and amphetamine, respectively, and the strong activation of the nigrostriatal projection produced by stimulating directly in the substantia nigra. When the effects of neuroleptics and clonidine are measured by the psychophysical method (that is, by lateral shifts in the rate-frequency function), it is found that both drugs produce only gradual and rather small attenuations of rewarding efficacy up to doses at which it is no longer possible to measure their effects. It is suggested that, for neuroleptics at least, the rewarding effect abruptly fails at these doses. It is further suggested that these drugs do not act on the rewarding pathway itself, but on the process by which the rewarding signal is converted to an enduring rewarding effect.     

Axonal regeneration of descending and ascending spinal projection neurons in spinal cord-transected larval lamprey

The distributions of descending and ascending spinal projection neurons (i.e., spinal neurons with moderate to long axons) were compared in normal larval lamprey and in animals that had recovered for 8 weeks following a complete spinal cord transection at 50% body length (BL, normalized distance from the anterior head). In normal animals, application of HRP to the spinal cord at 60% BL (40% BL) labeled an average of 713.8 +/- 143.2 descending spinal projection neurons (718.4 +/- 108.0 ascending spinal projection neurons) along the rostral (caudal) spinal cord, most of which were unidentified neurons. Some of these neurons project for at least approximately 50-60 spinal cord segments (approximately 36-47 mm in animals with an average length of approximately 90 mm used in the present study). At 8 weeks posttransection, the numbers of HRP-labeled descending or ascending spinal neurons that extended their axons through the transection were about 40% of those in similar areas of the spinal cord in normal animals. Thus, in larval lamprey, axonal regeneration of descending and ascending spinal projection neurons is incomplete, similar to that found for descending brain neurons. The majority of restored projections were from unidentified spinal neurons that have not been documented previously. In contrast to results from several other lower vertebrates, in the lamprey ascending spinal neurons exhibited substantial axonal regeneration. Identified descending spinal neurons, such as lateral interneurons and crossed contralateral interneurons, and identified ascending spinal neurons, such as giant interneurons and edge cells, regenerated their axons at least 9 mm beyond the transection site in animals with an average length of approximately 90 mm, which is appreciably farther than previously reported. In contrast, most dorsal cells, which are centrally located sensory neurons, exhibited very little axonal regeneration.     

A system of rat spinal cord lamina 1 cells projecting through the contralateral dorsolateral funiculus

The aim of these experiments was to sample the properties of lamina I neurones with long ascending projections. Recordings have been made from 136 units at the LA/5 level, with ascending axons reaching C2. More than 80% of the units projected via the contralateral dorsolateral white matter and only 10% via the contralateral ventral quadrant. None projected via the dorsal columns. Receptive fields were typically 1–2 cm² and although a substantial number of units responded to a limited range of intense stim-uli, a greater number of units were fired by both low- and high-threshold stimulation. In contrast to cells of deeper laminae, the majority of units were excited following activation of descending pathways in the dorsolateral funiculus. The functional role of these units is not obvious, but the location of the ascending projection and the influence of descending pathways does not support the notion that the output of lamina 1 constitutes a simple “pain pathway”.     

Forebrain origins and terminations of the medial forebrain bundle metabolically activated by rewarding stimulation or by reward-blocking doses of pimozide

Using [14C]-2-deoxyglucose autoradiography, we determined which forebrain and diencephalic areas showed metabolic alterations in response to unilateral electrical stimulation of the posterior medial forebrain bundle at parameters chosen to produce a just-submaximal rewarding effect. At these parameters, only a few areas were activated. There was no detectable activation anterior or dorsal to the genu of the corpus callosum. Just anterior to the anterior commissure, there was strong activation of the vertical limb of the diagonal band of Broca, with a focus in the nucleus of the diagonal band. Just posterior to the anterior commissure, there was strong activation of compartment "c" of the medial forebrain bundle (MFB), with weaker activation of the bed nucleus of the stria terminalis and the medial preoptic area. At midhypothalamic levels, the dorsolateral, dorsomedial, and ventral MFB all showed activation. There was bilateral suppression of activity in the lateral habenula. Activation appeared to end in the anterior ventral tegmental area of Tsai. Reward-blocking doses of the neuroleptic pimozide activated the caudate and the lateral habenula but did not alter any of the unilateral effects of stimulation. Using longer pulse durations and/or shifting the site of stimulation to the substantia nigra activated many of the systems not activated in the first experiment, including all of the major dopaminergic projection systems, proving the capacity of the technique to reveal activation of these systems. The results permit one to define a discrete projection system that merits electrophysiological investigation as a likely substrate for the rewarding effect of MFB stimulation. They also suggest that dopaminergic projection systems may not form part of the reward pathway itself.     

Neurotensin, dopamine and mode of action of neuroleptics

It has new been almost ten years since interactions between the neurotensinergic and dopaminergic neuronal systems were first described. These results have now been confirmed on anatomical and biochemical as well as on behavioural grounds. First, we describe experiments showing that ascending dopaminergic pathways control the density of neurotensinergic binding sites in structures such as prefrontal cortex, nucleus accumbens and striatum. Secondly, we attempt to elucidate the consequences that such receptor hetero-regulations, together with the presence of mixed neurotensin/dopamine fibers in the prefrontal cortex, might have on the mode of action of neuroleptic drugs. Indeed, by blocking dopamine receptors, neuroleptics might bring about long-term and heterogeneous changes in the transmission of non dopaminergic systems in those projection areas possessing dopamine receptors. The new functional hierarchies thus produced between dopamine innervated structures might then explain the therapeutic action of neuroleptics.     

The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.     

A light microscopic and electron microscopic study of the superficial layers of the superior colliculus of the tree shrew (Tupaia glis)

Studies on the embryonic spinal cord were extended to include the development of the ascending and descending fibers from the brachial level. This study was designed to correlate morphological development of the intersegmental system with physiological and behavioral observations of early embryonic behavior. Chick embryos were analyzed prior to day 6 of incubation, which is before closure of the reflex arc and arrival of supraspinal inputs to the embryonic spinal cord. Injections of ³H-proline were made in the upper brachial level of chick embryos of stages 27–29 (5–6 days). The location of radioactive label in the marginal zone was analyzed autoradiographically to show the projection of labeled axonal flow from the site of injection. The majority of the labeled axons in the marginal zone was in the first 2–3 segments in both ascending and descending directions from the site of injection. By stage 27 (day 5), ascending labeled axons extended to the upper cervical level and labeled descending axons extended only about 4–5 segments to the upper thoracic level. By stage 29 (day 6) labeled ascending axons extended into the medulla oblongata, and labeled descending axons still extended only 4–5 segments caudally. These studies (Parts I and II) show that at stage 27 (day 5) there was considerable axoplasmic flow of radioactive label in the marginal zone from the lumbar to the brachial plexus but not in the opposite direction from the brachial to the lumbar plexus. Also, axoplasmic flow of label initially extended from the brachial plexus to the medulla oblongata sometime between stages 27–29. It was concluded that the intersegmental system of the embryonic spinal cord is well developed by day 6 of incubation and provides the neuro-anatomical substrate for early embryonic behavior.     

Biochemical mechanism of action of neuroleptics (author's transl)

This review is devoted to the analysis of the mechanism of action of neuroleptics. The effects of these compounds on cerebral dopaminergic transmission and on the metabolism of various neurotransmitters are reviewed. Ample evidence derived from behavioral, clinical and biochemical studies indicates that a diminution of cerebral dopaminergic transmission (due to a blockade of dopaminergic receptors) probably accounts for the therapeutic activity (as well as some side effects) of neuroleptics. The tubero-infundibular dopaminergic system appears to play a major role in the neuroendocrine side effects of neuroleptics. Blockade of striatal dopaminergic transmission may probably be accounted for the extrapyramidal side effects induced by these drugs. As suggested by various biochemical data obtained in both animals and humans, the meso-cortico-limbic dopaminergic system appears to be the anatomical substrate of the antipsychotic action of neuroleptics. Recent results also suggest a modulatory influence of the frontal cortex on neuroleptic-induced extrapyramidal side effects. Finally, other cerebral neurotransmitters (noradrenaline, neuropeptides) might be involved in the mechanism of action of neuroleptic agents.     

The tegmental pedunculopontine nucleus: a brain-stem output of the limbic system critical for the conditioned place preferences produced by morphine and amphetamine

The potent reinforcing properties of psychoactive drugs have been attributed to the activation of motivational processes localized to the limbic system. We investigated the role of 2 specific outputs of the forebrain limbic system, the tegmental pedunculopontine nucleus (TPP) and the periacqueductal gray (PAG) of the pons-midbrain, in the positive motivational effects of morphine and amphetamine. We now report that the TPP, but not the PAG nor other nearby regions, is a critical site in the neural system subserving the rewarding effects of both opiates and stimulants. Bilateral ibotenic acid lesions of the TPP blocked the positive reinforcing effects of both morphine and amphetamine in naive rats as measured in a conditioned place preference paradigm. However, TPP lesioned animals were still capable of acquiring a conditioned place preference to an environment paired with the peripheral opiate antagonist methylnaltrexone. This suggested that TPP lesions did not cause nonspecific deficits in the basic learning mechanisms underlying conditioned place preferences. Furthermore, while the TPP was critical for the acquisition of a conditioned preference to an environment paired with morphine in naive rats, rats that had acquired a morphine conditioned place preference prior to the lesions were capable of retaining and demonstrating these place preferences after lesions of the TPP. This again demonstrates that TPP lesions are producing an unconditioned deficit in motivation rather than a deficit in learning or memory. Finally, direct comparisons of the place preference data of individual animals with their correspondent TPP lesion sites indicated that the most effective lesions overlapped to a greater degree TPP perikarya with descending, rather than ascending, axons. This suggests that motivational information generated by drug stimuli acting at "upstream" neural structures flows in a descending direction through the TPP region of the brain stem. These results suggest that opiates and stimulants must ultimately activate a single brain-stem substrate in order to have a positive motivational impact. It is hypothesized that the neural circuits mediating the rewarding effects of drug stimuli acting at forebrain sites exit the limbic system in the TPP region of the brain stem, where motivation may ultimately influence or be isomorphic with the elicitation of motor responses subserving approach and exploration.     

Myelinated axons and the pyramidal cell modules in monkey primary visual cortex

In addition to the horizontal bands of myelinated axons that produce the line of Gennari and the inner band of Baillarger, the macaque primary visual cortex contains prominent vertical bundles of myelinated axons. In tangential sections through layer IVC, these axon bundles are regularly arranged. They have a mean center-to-center spacing of about 23 μm, and each one contains an average of 34 (S.D. ± 13) myelinated axons. These bundles seem to be largely composed of efferent fibers, because in material in which pyramidal cells have been labelled in layer II/III and in layers IVA and IVB the axons of these neurons descend towards the white matter in bundles. However, it is doubtful whether all of the descending myelinated axons from the superficial layers emerge from the cortex, since counts show that the bundles contain maximum numbers of myelinated axons at the level of layer IVC, and that in layers V and VI their number is reduced by about 30%. Perhaps some of the axons enter the line of Baillarger, in layer V. When the bundles of myelinated axons and the clusters of apical dendrites of the layer V pyramidal cells are visualized simultaneously within layer IVC in electron microscopic preparations, it is apparent that their center-to-center spacing is similar, namely, about 23 μm and that a bundle of axons has a cluster of apical dendrites lying adjacent to it. Because of this association, and because axons from layer III pyramidal cells have been shown to enter the bundles, it is suggested that the myelinated axon bundles contain the efferent axons from the projection neurons in the individual pyramidal cell modules. However, in addition to the myelinated axons, the bundles contain unmyelinated axons, so that they also probably serve as the conduits for axons forming connections between layers. It is proposed that the pyramidal cell modules are the basic, functional neuronal units of the visual cortex, and since the neurons within a particular module can be expected to have slightly different inputs and response properties from those in neighboring modules, the individual axon bundles that emerge from each module would be expected to carry a unique set of efferent information. © 1996 Wiley-Liss, Inc.     

Performance deficit induced by low doses of dopamine agonists in rats. Toward a model for approaching the neurobiology of negative schizophrenic symptomatology?

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.     

Periaqueductal gray afferents synapse onto dopamine and GABA neurons in the rat ventral tegmental area

The midbrain central gray (periaqueductal gray; PAG) mediates defensive behaviors and is implicated in the rewarding effects of opiate drugs. Projections from the PAG to the ventral tegmental area (VTA) suggest that this region might also regulate behaviors involving motivation and cognition. However, studies have not yet examined the morphological features of PAG axons in the VTA or whether they synapse onto dopamine (DA) or GABA neurons. In this study, we injected anterograde tracers into the rat PAG and used immunoperoxidase to visualize the projections to the VTA. Immunogold‐silver labeling for tyrosine hydroxylase (TH) or GABA was then used to identify the phenotype of innervated cells. Electron microscopic examination of the VTA revealed axons labeled anterogradely from the PAG, including myelinated and unmyelinated fibers and axon varicosities, some of which formed identifiable synapses. Approximately 55% of these synaptic contacts were of the symmetric (presumably inhibitory) type; the rest were asymmetric (presumably excitatory). These findings are consistent with the presence of both GABA and glutamate projection neurons in the PAG. Some PAG axons contained dense‐cored vesicles indicating the presence of neuropeptides in addition to classical neurotransmitters. PAG projections synapsed onto both DA and GABA cells with no obvious selectivity, providing the first anatomical evidence for these direct connections. The results suggest a diverse nature of PAG physiological actions on midbrain neurons. Moreover, as both the VTA and PAG are implicated in the reinforcing actions of opiates, our findings provide a potential substrate for some of the rewarding effects of these drugs. © 2009 Wiley‐Liss, Inc.     

The dopamine hypothesis of reward: past and current status.

Mesolimbic dopaminergic neurons are thought to serve as a final common neural pathway for mediating reinforcement processes. However, several recent findings have challenged the view that mesolimbic dopamine has a crucial role in the maintenance of reinforcement processes, or the subjective rewarding actions of natural rewards and drugs of abuse. Instead, there is growing evidence that dopamine is involved in the formation of associations between salient contextual stimuli and internal rewarding or aversive events. This evidence suggests that dopaminergic-neuron activation aids the organism in learning to recognize stimuli associated with such events. Thus, mesolimbic dopaminergic neurons have an important function in the acquisition of behavior reinforced by natural reward and drug stimuli. Furthermore, long-lasting neuroadaptive changes in mesolimbic dopamine-mediated transmission that develop during chronic drug use might contribute to compulsive drug-seeking behavior and relapse.     

Medullary and cerebellar projections of the statoacoustic nerve of the dogfish,Scyliorhinus canicula

The statoacoustic nerve of the dogfish, Scyliorhinus canicula, was transected medial to the ganglion for the purpose of elucidating its central pathways and terminal fields. Following two to six weeks postoperative survival times, transverse, horizontal, and sagittal sections of the brain stem were stained by the Fink-Heimer silver-impregnation method to reveal degenerating axons and terminals. Fragmented axons enter the medulla and give rise to medial, descending, and ascending pathway. Fibers of the medial pathway terminate about the soma and lateral dendrites of the large cells that comprise nucleus magnocellularis; descending and ascending flbers terminate on the dendrites of the cells of ventral and superior nuclei respectively. In addition, fibers emanate from fascicles of the descending pathway to form a large field of degenerating axons and terminals within the ventromedial part of the medulla, and a substantial proportion of the fibers of the ascending pathway continues beyond the superior nucleus to terminate among the granule cells of the medial part of the vestibulolateral lobe of the cerebellum. No fragmented axons are traceable to the lateral part (auricles) of the vestibulolateral lobe, cerebellar nucleus or corpus, or those nuclei associated with the lateral-line lobes. It appears therefore that octavus terminal fields are separate from those of the lateral line at both cerebellar and medullary levels, at least at the level of the first-order neuron.     

Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals

Dopaminergic neurons from the ventral mesencephalon/diencephalon (mesodiencephalon) form vital pathways constituting the majority of the brain's dopamine systems. Mesodiencephalic dopaminergic (mdDA) neurons extend longitudinal projections anteriorly through the diencephalon, ascending toward forebrain targets. The mechanisms by which mdDA axons initially navigate through the diencephalon are poorly understood. Recently the Slit family of secreted axon guidance proteins, and their Robo receptors, have been identified as important guides for descending longitudinal axons. To test the potential roles of Slit/Robo guidance in ascending trajectories, we examined tyrosine hydroxylase-positive (TH+) projections from mdDA neurons in mutant mouse embryos. We found that mdDA axons grow out of and parallel to Slit-positive ventral regions within the diencephalon, and that subsets of the mdDA axons likely express Robo1 and possibly also Robo2. Slit2 was able to directly inhibit TH axon outgrowth in explant co-culture assays. The mdDA axons made significant pathfinding errors in Slit1/2 and Robo1/2 knockout mice, including spreading out in the diencephalon to form a wider tract. The wider tract resulted from a combination of invasion of the ventral midline, consistent with Slit repulsion, but also axons wandering dorsally, away from the ventral midline. Aberrant dorsal trajectories were prominent in Robo1 and Robo1/2 knockout mice, suggesting that an aspect of Robo receptor function is Slit-independent. These results indicate that Slit/Robo signaling is critical during the initial establishment of dopaminergic pathways, with roles in the dorsoventral positioning and precise pathfinding of these ascending longitudinal axons.     

Failure of amygdaloid lesions to increase the threshold for self-stimulation of the lateral hypothalamus and ventral tegmental area

It has been proposed that the directly stimulated axons underlying the rewarding effect of medial forebrain bundle (MFB) stimulation originate in the forebrain and descend at least as far as the ventral tegmentum. However, little is known about the location of the somata that give rise to these axons. Among the nuclei that contribute fibers to the descending component of the MFB and project past the lateral hypothalamus (LH) and ventral tegmental area (VTA) are cell groups within the amygdaloid complex. In this study, the rewarding effectiveness of stimulating the LH and VTA was measured before and after the amygdaloid complex was damaged by electrolytic lesions. Changes in rewarding effectiveness were inferred from shifts in the frequency required to sustain a half-maximal rate of lever-pressing at each of 3 currents. Following the lesions, there was no clear evidence of substantial, sustained decreases in rewarding effectiveness at the 14 stimulation sites, although one subject ceased to self-stimulate reliably. Given that the lesions damaged the principal amygdaloid sources of descending MFB fibers, these results suggest that the amygdaloid complex is not a major source of the directly activated fibers responsible for the rewarding effect of MFB stimulation.     

Regeneration of ascending spinal axons in goldfish

Regeneration of descending spinal cord tracts occur spontaneously in adult goldfish. Very little information is available regarding the fate of ascending fibers. Using Dextran amines as a tracer, we studied the normal and regenerated ascending axonal projection patterns in adult goldfish brain nuclei. Present study includes spinal projections to torus semicircularis, hypothalamus, thalamus and the telencephalon. Regenerated fibers had finer caliber axons and the terminal axonal arbors covered a larger area than the corresponding normal ones.     

Axonal growth cones in the developing amphibian spinal cord

Axonal growth cones in the spinal cord of embryonic and larval Xenopus (stages 24-48) were filled with the anatomical tracer horseradish peroxidase (HRP). Growth cones of lateral and ventral marginal zones, including those of descending spinal and supraspinal pathways, were labeled by application of tracer to the caudal medulla or to one of several levels of the spinal cord. Central axons of sensory neurons were filled via their peripheral processes. Growth cone configuration varied widely but fell into five general categories: complex with both filopodia and veils, filopodia only, lamellipodia only, clavate, and fusiform. Several general patterns emerged from the distribution of these various configurations. Growth cones of younger animals generally were more complex than those of older ones. Growth cones closer to the leading edge of descending fiber bundles were more elaborate than those that followed. Growth cones of the dorsolateral fascicle, which carries ascending central processes of Rohon-Beard and sensory ganglion neurons, were very simple and followed a straight course rostrally, whereas those of descending axons of the lateral fiber areas were more complex and sometimes spread over almost the entire lateral marginal zone. Growth cones of Rohon-Beard central ascending axons were fusiform or clavate, while those of sensory ganglion axons showed several fine filopodia at their tips. Growth cones of both types of sensory axons change configuration as they approached the hindbrain, becoming more complex. This study demonstrates that the configurations of growth cones belonging to the same axonal pathway vary with age and with position along their routes, and that growth cones of different neuron classes exhibit characteristic ranges of morphological variation.     

The spinal terminations of single, physiologically characterized axons originating in the pontomedullary raphe of the cat

Single myelinated axons were recorded in the dorsolateral funiculus of the cat and physiologically characterized as descending from the midline medulla or midline pons. Following further physiological characterization (e.g., conduction velocity, adequate stimulus, receptive field, activation by stimulation of periaqueductal gray), the axons were labeled with horseradish peroxidase that was iontophoretically ejected from the recording micropipette. Histochemical reaction allowed visualization of the stained axons and their arborizations in the spinal gray matter. The conduction velocities of the sampled axons ranged from 7.3 to 117.2 m/second with a mean of 35.5 m/second. However, unmyelinated axons could not be sampled with the technique employed here. Descending axons could be divided into two groups: (1) those which terminated in laminae I, II, V, and X, and (2) those which terminated in laminae V, VII, and X. Axons from both groups had myelinated parent axons, were activated by periaqueductal gray stimulation, and responded to noxious pinch of their receptive field. Terminal collaterals from both groups of axons were generally transversely oriented. These results suggest heterogeneous functions for these descending axons which may include modulation of nociceptive input to higher centers.     

Early pattern of neuronal differentiation in the Xenopus embryonic brainstem and spinal cord

Wholemount antibody labeling techniques and horseradish peroxidase backfilling were used to analyze the pattern of neuronal differentiation in the embryonic Xenopus central nervous system between stages 22 and 35/36. In the spinal cord, the first neurons to differentiate are the Rohon-Beard neurons; they are followed by ventral neurons with descending axons (descending interneurons, motoneurons) and lateral interneurons with commissural axons. The somata and axons of these primary neurons form dorsal, ventral, and lateral columns, respectively; the ventral and lateral columns uninterruptedly continue forward into the brainstem. The distribution and projection patterns of spinal neurons were analyzed quantitatively. Rohon-Beard neurons, commissural interneurons, and primary motoneurons vary in number from segment to segment. Thus, these neurons are not distributed in a segmental pattern. In each segment, neurons of a given type project axons whose length varies over a wide range. The numerical distribution of length of axons formed by a population of neurons of a given type was calculated and expressed as the projection profile of these neurons. For each type of neuron and spinal segment, the projection profile is different. Furthermore, the projection profiles change in a systematic way along the spinal cord. For example, the fraction of Rohon-Beard neurons with long ascending axons steadily increases if one moves towards caudal spinal levels. The findings suggest that suprasegmental cues with a graded distribution along the spinal cord determine the number and projection profile of a particular cell type in a given segment. © 1993 Wiley-Liss, Inc.