Termination of vestibulospinal fibers arising from the spinal vestibular nucleus in the mouse spinal cord.

The present study investigated the vestibulospinal system which originates from the spinal vestibular nucleus (SpVe) with both retrograde and anterograde tracer injections. We found that fluoro-gold (FG) labeled neurons were found bilaterally with a contralateral predominance after FG injections into the upper lumbar cord. Anterogradely labeled fibers from the rostral SpVe traveled in the medial part of the ventral funiculus ipsilaterally and the dorsolateral funiculus bilaterally in the cervical cord. They mainly terminated in laminae 5-8, and 10 of the ipsilateral spinal cord. The contralateral side had fewer fibers and they were found in laminae 6-8, and 10. In the thoracic cord, fibers were also found to terminate in bilateral intermediolateral columns. In the lumbar and lower cord, fibers were mainly found in the dorsolateral funiculus bilaterally and they terminated predominantly in laminae 3-7 contralaterally. Anterogradely labeled fibers from the caudal SpVe did not travel in the medial part of the ventral funiculus but in the dorsolateral funiculus bilaterally. They mainly terminated in laminae 3-8 and 10 contralaterally. The present study is the first to describe the termination of vestibulospinal fibers arising from the SpVe in the spinal cord. It will lay the anatomical foundation for those who investigate the physiological role of vestibulospinal fibers and potentially target these fibers during rehabilitation after stroke, spinal cord injury, or vestibular organ injury.

Aging-dependent changes in the cellular composition of the mouse brain and spinal cord.

Although the impact of aging on the function of the central nervous system is known, only a limited amount of information is available about accompanying changes affecting the cellular composition of the brain and spinal cord. In the present work we used the isotropic fractionator method to reveal aging-associated changes in the numbers of neuronal and non-neuronal cells harbored by the brain and spinal cord. The experiments were performed on 15-week, 7-month, 13-month, and 25-month-old female mice. The major parts of the brain were studied separately, including the isocortex, hippocampus, cerebellum, olfactory bulb, and the remaining part (i.e., 'rest of brain'). The proliferative capacity of each structure was assessed by counting the number of Ki-67-positive cells. We found no aging-dependent change when the cellular composition of the isocortex was studied. In contrast, the neuronal and non-neuronal cell numbers of the hippocampus decreased in the 7-25-month period. The neuronal cell number of the olfactory bulb showed positive age-dependence between 15 weeks and 13 months of age and presented a significant decrease thereafter. The cerebellum was characterized by an age-dependent decrease of its neuronal cell number and density. In the rest of brain, the non-neuronal cell number increased with age. The neuronal and non-neuronal cell numbers of the spinal cord increased, whereas its neuronal and non-neuronal densities decreased with age. The number of proliferating cells showed a marked age-dependent decrease in the hippocampus, olfactory bulb, and rest of the brain. In contrast, the number of Ki-67-positive cells increased with age in both the cerebellum and spinal cord. In conclusion, aging-dependent changes affecting the cellular composition of the mouse central nervous system are present but they are diverse and region-specific.

Cortical cyto- and chemoarchitecture in three small Australian marsupial carnivores: Sminthopsis macroura, Antechinus stuartii and Phascogale calura.

The cyto- and chemoarchitecture of the cerebral cortex has been examined in three small (mouse-sized) polyprotodont marsupial carnivores from Australia (the stripe-faced dunnart, Sminthopsis macroura; the brown antechinus, Antechinus stuartii; and the red-tailed phascogale, Phascogale calura) in order to compare the cortical topography of these marsupials with that of diprotodontids, didelphids and eutherians. All three species studied had similar cortical cytoarchitecture. The isocortical surface was dominated by primary somatosensory (S1) and visual (V1) areas. Putative secondary sensory areas (S2, V2M, V2L) were also identified. The primary somatosensory cortex demonstrated clumps of granule cells in the presumptive mystacial field, whereas the primary visual area showed a distinctive chemical signature of intense calbindin immunoreactivity in layer IV. On the other hand, the primary auditory area was small and indistinct, but flanked by a temporal association area (TeA). A cytoarchitecturally distinct primary motor cortex (M1) with prominent pyramidal neurons in layer V and poor layer IV was identified medially to S1, and at rostral levels a putative secondary motor area was identified medial to M1. Transitional areas between isocortex and allocortical regions showed many cyto- and chemoarchitectural similarities to those reported for eutherian (and in particular rodent) cortex. Medially, two cingulate regions were found at rostral levels, with dysgranular and granular 'retrosplenial' areas identified caudally. Laterally, granular and agranular areas surrounded the rostral rhinal fissure, to be replaced by ectorhinal and perirhinal areas caudally. The findings indicate that the cyto- and chemoarchitectural features which characterize the iso- and allocortex in these small marsupial carnivores are similar to those reported in didelphids and eutherians and our findings suggest the existence of putative dedicated motor areas medial to the S1 field.

Development of the human dorsal nucleus of the vagus.

The dorsal nucleus of the vagus nerve plays an integral part in the control of visceral function. The aim of the present study was to correlate structural and chemical changes in the developing nucleus with available data concerning functional maturation of human viscera and reflexes. The fetal development (ages 9 to 26 weeks) of the human dorsal nucleus of the vagus nerve has been examined with the aid of Nissl staining and immunocytochemistry for calbindin and tyrosine hydroxylase. By 13 weeks, the dorsal vagal nucleus emerges as a distinct structure with at least two subnuclei visible in Nissl stained preparations. By 15 weeks, three subnuclei (dorsal intermediate, centrointermediate and ventrointermediate) were clearly discernible at the open medulla level with caudal and caudointermediate subnuclei visible at the level of the area postrema. All subnuclei known to exist in the adult were visible by 21 weeks and cytoarchitectonic differentiation of the nucleus was largely completed by 25 weeks. The adult distribution pattern of calbindin and tyrosine hydroxylase immunoreactive neurons was also largely completed by 21 weeks, although morphological differentiation of labeled neurons continued until the last age examined (26 weeks). The structural development of the dorsal nucleus of the vagus nerve appears to occur in parallel with functional maturation of the cardiovascular and gastric movements, which the nucleus controls.

The pretectal nuclei in two monotremes: the short-beaked echidna (Tachyglossus aculeatus) and the platypus (Ornithorhynchus anatinus).

We have examined the organization of the pretectal area in two monotremes (the short beaked echidna-Tachyglossus aculeatus, and the platypus-Ornithorhynchus anatinus) and compared it to that in the Wistar strain rat, using Nissl staining in conjunction with enzyme histochemistry (acetylcholinesterase and NADPH diaphorase) and immunohistochemistry for parvalbumin, calbindin, calretinin and non-phosphorylated neurofilament protein (SMI-32 antibody). We were able to identify distinct anterior, medial, posterior (now called tectal gray) and olivary pretectal nuclei as well as a nucleus of the optic tract, all with largely similar topographical and chemoarchitectonic features to the homologous regions in therian mammals. The positions of these pretectal nuclei correspond to the distributions of retinofugal terminals identified by other authors. The overall size of the pretectum in both monotremes was found to be at least comparable in size, if not larger than, the pretectum of representative therian mammals of similar brain and body size. Our findings suggest that the pretectum of these two monotreme species is comparable in both size and organization to that of eutherian mammals, and is more than just an undifferentiated area pretectalis. The presence of a differentiated pretectum with similar chemoarchitecture to therians in both living monotremes lends support to the idea that the stem mammal for both prototherian and therian lineages also had a differentiated pretectum. This in turn indicates that a differentiated pretectum appeared at least 125 million years ago in the mammalian lineage and that the stem mammal for proto- and eutherian lineages probably had similar pretectal nuclei to those identified in its descendants.

Precerebellar and vestibular nuclei of the short-beaked echidna (Tachyglossus aculeatus).

The monotremes are a unique group of living mammals, which diverged from the line leading to placental mammals at least 125 million years ago. We have examined the organization of pontine, inferior olivary, lateral reticular and vestibular nuclei in the brainstem of the short-beaked echidna (Tachyglossus aculeatus) to determine if the cyto- and chemoarchitecture of these nuclei are similar to that in placental mammals and marsupials. We have used Nissl staining in conjunction with enzyme-histochemistry for acetylcholinesterase, cytochrome oxidase and NADPH diaphorase as well as immunohistochemistry for non-phosphorylated neurofilament protein (SMI-32 antibody) and calcium binding proteins (parvalbumin, calbindin, calretinin). Homologies could be established between the arch shaped inferior olivary complex of the echidna and the principal, dorsal and medial accessory subdivisions of the therian inferior olivary complex. The pontine nuclei of the echidna included basilar and reticulotegmental components with similar cyto- and chemarchitectural features to therians and there were magnocellular and subtrigeminal components of the lateral reticular nucleus, also as seen in therians. Subdivisions and chemoarchitecture of the vestibular complex of the echidna were both similar to that region in rodents. In all three precerebellar nuclear groups studied and in the vestibular nucleus organization, the cyto- and chemoarchitecture of the echidna was very similar to that seen in therian mammals and no "primitive" or "reptilian" features were evident.

Cyto- and chemoarchitecture of the cerebellum of the short-beaked echidna (Tachyglossus aculeatus).

The monotremes (echidnas and platypus) have been claimed by some authors to show 'avian' or 'reptilian' features in the gross morphology and microscopic anatomy of the cerebellum. We have used Nissl staining in conjunction with enzyme histochemistry to acetylcholinesterase and cytochrome oxidase and immunohistochemistry to non-phosphorylated neurofilament protein (SMI-32 antibody), calcium binding proteins (parvalbumin, calbindin and calretinin) and tyrosine hydroxylase to examine the cyto- and chemoarchitecture of the cerebellar cortex and deep cerebellar nuclei in the short-beaked echidna. Immunoreactivity for non-phosphorylated neurofilament (SMI-32 antibody) was found in the deep cerebellar nuclei and in Purkinje cells of most regions except the nodule. Purkinje cells identified with SMI-32 immunoreactivity were clearly mammalian in morphology. Parvalbumin and calbindin immunoreactivity was found in Purkinje cells with some regional variation in staining intensity and in Purkinje cell axons traversing cerebellar white matter or terminating on Lugaro cells. Calbindin immunoreactivity was also present in inferior olivary complex neurons. Calretinin immunoreactivity was found in pontocerebellar fibers and small cells in the deep granule cell layer of the ansiform lobule. We found that, although the deep cerebellar nuclei were much less clearly demarcated than in the rodent cerebellum, it was possible to distinguish medial, interposed and lateral nuclear components in the echidna. As far as we can determine from our techniques, the cerebellum of the echidna shows all the gross and cytological features familiar from the cerebellum of therian mammals.

Development of the human nucleus of the solitary tract: a cyto- and chemoarchitectural study.

The present study investigated the prenatal development of the cyto- and chemoarchitecture of the human nucleus of the solitary tract from 9 to 35 weeks, by using Nissl staining and immunoreactivity to calbindin, calretinin, tyrosine hydroxylase and GAP-43. The nucleus began to gain heterogeneity and show different subnuclei as early as 13 weeks, and approached cytoarchitectural maturation from 21 to 25 weeks. The subnuclear division pattern observed in the fetal nucleus of the solitary tract at 25 weeks was very similar to that of the adult. Neurons immunoreactive to calbindin first appeared in the medial gastrointestinal area of the nucleus at 13 weeks, particularly within a putative gelatinosus subnucleus, while calretinin immunoreactivity during fetal life suggested the possible presence of a central subnucleus. Tyrosine hydroxylase immunoreactive neurons were seen in the medial subdivisions of the nucleus of the solitary tract as early as 13 weeks, but the population continued to increase until 25 weeks. Strong GAP-43 immunoreactivity was also present in the nucleus of the solitary tract at 13 weeks, especially in the dorsolateral and commissural subnuclei, while at 21 weeks there was a significant decline of GAP-43 expression. Results from the chemoarchitectural study showed that the human nucleus of the solitary tract expressed various neurochemical substances at an early developmental age (13 weeks), even before cellular and neuropil maturation was fully attained. Expression of these factors may play an important role in establishment and integration of viscerosensory function in the nucleus.

Central vagal sensory and motor connections: human embryonic and fetal development.

The embryonic and fetal development of the nuclear components and pathways of vagal sensorimotor circuits in the human has been studied using Nissl staining and carbocyanine dye tracing techniques. Eight fetal brains ranging from 8 to 28 weeks of development had DiI (1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate) inserted into either the thoracic vagus nerve at the level of the sternal angle (two specimens of 8 and 9 weeks of gestation) or into vagal rootlets at the surface of the medulla (at all other ages), while a further five were used for study of cytoarchitectural development. The first central labeling resulting from peripheral application of DiI to the thoracic vagus nerve was seen at 8 weeks. By 9 weeks, labeled bipolar cells at the ventricular surface around the sulcus limitans (sl) were seen after DiI application to the thoracic vagus nerve. Subnuclear organization as revealed by both Nissl staining and carbocyanine dye tracing was found to be advanced at a relatively early fetal age, with afferent segregation in the medial Sol apparent at 13 weeks and subnuclear organization of efferent magnocellular divisions of dorsal motor nucleus of vagus nerve noticeable at the same stage. The results of the present study also confirm that vagal afferents are distributed to the dorsomedial subnuclei of the human nucleus of the solitary tract, with particular concentrations of afferent axons in the gelatinosus subnucleus. These vagal afferents appeared to have a restricted zone of termination from quite early in development (13 weeks) suggesting that there is no initial exuberance in the termination field of vagal afferents in the developing human nucleus of the solitary tract. On the other hand, the first suggestion of afferents invading 10N from the medial Sol was not seen until 20 weeks and was not well developed until 24 weeks, suggesting that direct monosynaptic connections between the sensory and effector components of the vagal sensorimotor complex do not develop until this age.

In vitro autoradiographic localization of calcitonin and amylin binding sites in monkey brain.

Calcitonin (CT) and amylin are related peptides with potent central actions, including suppression of appetite and gastric acid secretion. Little is known about the distribution and binding characteristics of amylin receptors in species other than rat; therefore, in this study, by using in vitro autoradiography, we have mapped the distribution of 125I-rat amylin binding sites in the monkey brain and compared this distribution to that of binding sites for 125I-salmon CT (125I-sCT). Highest densities of 125I-amylin binding were in the hypothalamus, including the arcuate nucleus and parts of the ventromedial hypothalamic nuclei, and the solitary nucleus. Rostrally, moderate to high density binding was present in parts of the preoptic area, bed nucleus of the stria terminalis, amygdala and accumbens nucleus (Acb). Caudally, binding of amylin was more restricted, with moderate to high density binding present only in dorsal raphe, and area postrema. The primary visual cortex displayed strong and periodic CT binding in layer 4. The subcortical pattern of distribution of amylin and CT receptors in the monkey was similar to that seen previously in the rat, although the relative densities of binding to different brain structures were not always conserved. As with rat, monkey amylin receptors were a subset of the sites labeled with 125I-sCT. Analysis of receptor specificity indicated a greater relative potency of CT peptides in competing for 125I-amylin binding in monkey, when compared to rat, while, there was a decrease in the relative potency of CT gene-related peptides, potentially due to differences the level of receptor activity modifying proteins (RAMPs) in monkey versus rat brain. Amylin receptors in primates are likely to perform a similar role to those in rats; however, the interaction of the receptors with related peptides may differ.

The anatomy of the cerebral cortex of the echidna (Tachyglossus aculeatus).

The cerebral cortex of the echidna is notable for its extensive folding and the positioning of major functional areas towards its caudal extremity. The gyrification of the echidna cortex is comparable in magnitude to prosimians and cortical thickness and neuronal density are similar to that seen in rodents and carnivores. On the other hand, many pyramidal neurons in the cerebral cortex of the echidna are atypical with inverted somata and short or branching apical dendrites. All other broad classes of neurons noted in therian cortex are also present in the echidna, suggesting that the major classes of cortical neurons evolved prior to the divergence of proto- and eutherian lineages. Dendritic spine density on dendrites of echidna pyramidal neurons in somatosensory cortex and apical dendrites of motor cortex pyramidal neurons is lower than that found in eutheria. On the other hand, synaptic morphology, density and distribution in somatosensory cortex are similar to that in eutheria. In summary, although the echidna cerebral cortex displays some structural features, which may limit its functional capacities (e.g. lower spine density on pyramidal neurons), in most structural parameters (e.g. gyrification, cortical area and thickness, neuronal density and types, synaptic morphology and density), it is comparable to eutheria.

Conditioned changes in ultrasonic vocalizations to an aversive olfactory stimulus are lateralized in 6-day-old rats.

Using a soft rubber plug to block airflow in one naris, Kucharski, Johanson, and Hall (1986) found that some forms of olfactory memory (e.g., odor preferences) were lateralized in young rats while other forms (e.g., conditioned activation and mouthing) were not. The present experiments extended that research by showing that conditioned increases in ultrasonic vocalizations were also lateralized. That is, when exposed to an odor that was previously paired with footshock, 6-day-old rats significantly increased their rate of vocalizing. This response only occurred, however, when the naris open at training was also open at test. The use of the developing rat as a natural split-brain preparation appears to be an effective procedure with which to broaden current approaches to the analysis of learning, memory, and emotion.

The distribution of the neurokinin B receptor in the human and rat hypothalamus.

The neurokinin B receptor (NK3) is an element of the hypothalamic neuronal circuitry regulating blood pressure in rats. The present study used immunohistochemistry to reveal the distribution of NK3 in the human hypothalamus. The strongest NK3-like immunoreactivity in the human hypothalamus was found in neurons of the paraventricular nucleus, specifically in the parvicellular and posterior paraventricular subnuclei. Another prominent population of NK3-positive cells in the human hypothalamus was found in the perifornical nucleus. The present study also showed two previously unreported populations of NK3-positive neurons in the rat periventricular nucleus and medial magnocellular paraventricular subnucleus. It is concluded that there is a large degree of similarity in the distribution of NK3 in the human and rat hypothalamus.

Organization of the human paraventricular hypothalamic nucleus.

The cyto- and chemoarchitecture of the human paraventricular hypothalamic nucleus (Pa) was studied with the aid of three-dimensional computer reconstruction. The adult human Pa is a vertically elongated structure that abuts the wall of the third ventricle (3V) medially and is indented dorsolaterally by the descending fornix. Chemoarchitecture revealed the following five subnuclei in the human Pa. The most prominent of these is the magnocellular subnucleus (PaM) occupying the ventrolateral quadrant of the Pa and comprised of a concentration of large arginin-vasopressin (AVP)- and acetylcholinesterase (AChE)-positive cells, and small calbindin (Cb)-positive neurons. Rostrally, the PaM is succeeded by the small anterior parvicellular subnucleus (PaAP), which contains small AChE-, AVP- and tyrosin hydroxylase (TH)-positive cells. Dorsal to the PaM is found the dorsal subnucleus (PaD), containing large spindle-shaped TH-, oxytocin (OXY)-, and AChE-positive cells, as well as a population of small Cb-positive neurons. Abutting the wall of the 3V and medial to PaM and PaD is the parvicellular subnucleus (PaP). The PaP contains small cells immunoreactive for corticotropin-releasing factor (CRF), neuromedin K receptor (NK3), and nonphosphorylated neurofilament protein (SMI32). The posterior subnucleus (PaPo) is situated posterior to the descending column of the fornix; it replaces all above-mentioned subdivisions caudally, and is a chemoarchitectonic amalgam that includes dispersed large AChE-, OXY-, AVP- and TH-positive cells, as well as small NK3-, CRF-, SMI32- and Cb-immunoreactive neurons. The present findings suggest that the human PaM and PaD are homologues to the magnocellular subnuclei of the rat Pa, whereas the human PaP and PaPo correspond to the rat medial parvicellular and posterior subnuclei, respectively.

Architectonic analysis of the human retrosplenial cortex.

The architecture of the macaque retrosplenial cortex, including its posteroventral extension around and below the splenium of the corpus callosum, was recently characterized (Morris et al. [1999a] Eur. J. Neurosci. 11:2506-2518.). This analysis was made possible by sectioning the posterior cingulate gyrus radially, i.e., in planes that were orthogonal to its line of curvature and that, therefore, preserved the laminar organization of this region. The aim of the present study was to examine the architecture and the limits of the human retrosplenial cortex. Cross sections through the entire posterior cingulate gyrus were obtained by applying the sectioning technique developed in the monkey, so that an explicit comparison could be made between the architecture of the human and the monkey retrosplenial cortex. The present analysis revealed that, as is the case in the macaque brain, the human retrosplenial cortex is composed of granular areas 29a-c and d, and dysgranular/agranular area 30. The human retrosplenial cortex, like that of the macaque monkey, runs, as an arch, around the splenium of the corpus callosum. In the macaque brain, the retrosplenial cortex remains buried within the callosal sulcus throughout its entire course around the splenium. In the human brain, however, the posteroventral segment of the retrosplenial cortex extends on the medial wall of the cerebral hemisphere to encompass most of the cortical region commonly referred to as the "isthmus of the cingulate gyrus."

The ontogeny of conditioned odor potentiation of startle.

During development, conditioned responses usually occur first to olfactory, then to auditory, and finally to visual cues. The authors of the present study report that fear potentiation of startle to an olfactory conditioned stimulus emerges relatively late in development (i.e., at 23 days of age; Experiments 1 and 2). The failure to observe conditioned odor potentiation of startle (OPS) in younger rats was not due to a failure to either acquire or remember the odor-shock association (Experiment 3). Surprisingly, the authors also found that rats trained at 16 but tested at 23 days of age failed to exhibit the OPS effect even though they did exhibit pronounced odor avoidance (Experiment 4). The results are discussed in terms of (a) sensory-specific sequential emergence of learned fear, (b) the neural circuit involved in fear potentiation of startle, and (c) the concept that conditioned responding is appropriate to the animal's age at the time of training rather than its age at testing.

Distribution of angiotensin IV binding sites (AT4 receptor) in the human forebrain, midbrain and pons as visualised by in vitro receptor autoradiography.

Angiotensin IV and other AT4 receptor agonists, improve memory retention and retrieval in the passive avoidance and swim maze learning paradigms. Angiotensin IV binding sites (also known as the AT4 receptors) are widely distributed in guinea pig and monkey (Macaca fascicularis) brains where high densities of the binding sites have been detected in the hippocampus, neocortex and motor nuclei. However, the distribution of the binding sites in the human brain is not known. We have recently localised the angiotensin IV binding sites (AT4 receptors) in post-mortem human brain using iodinated Nle-angiotensin IV, a higher affinity and more stable analogue of angiotensin IV. This radioligand bound with relatively high affinity and specificity to angiotensin IV binding sites. In competition studies on consecutive sections through the prefrontal cortex and claustrum, angiotensin IV, Nle-angiotensin IV and LVV-hemorphin 7 competed for the binding of 125I[Nle]-angiotensin IV with nanomolar affinities. Angiotensin II and the AT1 and AT2 receptor antagonists were ineffective in competing for the binding at concentrations of up to 10 microM. We found high densities of 125I[Nle]-angiotensin IV binding sites throughout the cerebral cortex including the insular, entorhinal, prefrontal and cingulate cortices. Very high densities of the binding sites were observed in the claustrum, choroid plexus, hippocampus and pontine nucleus. Some thalamic nuclei displayed high densities of binding including the anteroprincipal, ventroanterior, anteromedial, medial dorsal and ventrolateral nuclei. The caudate nucleus, putamen, many amygdaloid nuclei and the red nucleus all displayed moderate densities of binding with a higher level detected in the substantia nigra pars compacta. In the hypothalamus, high densities binding sites were found in the ventromedial nucleus with lower levels in the dorsomedial and paraventricular nuclei. The distribution of 125I[Nle]-angiotensin IV binding sites in the human brain is similar to that found in other species and supports multiple roles for the binding sites in the central nervous system, including facilitation of memory retention and retrieval.

Selective right parietal lobe activation during mental rotation: a parametric PET study.

Regional cerebral blood flow (rCBF) was measured with PET in seven healthy subjects while they carried out a mental rotation task in which they decided whether alphanumeric characters presented in different orientations were in their canonical form or mirror-reversed. Consistent with previous findings, subjects took proportionally longer to respond as characters were rotated further from the upright, indicating that they were mentally rotating the characters to the upright position before making a decision. We used a parametric design in which we varied the mental rotation demands in an incremental fashion while keeping all other aspects of the task constant. In four different scanning conditions, 10, 40, 70 or 100% of the stimuli presented during the scan required mental rotation while the rest were upright. The statistical parametric mapping technique was used to identify areas where changes in rCBF were correlated with the rotational demands of the task. Significant activation was found in only one area located in the right posterior parietal lobe, centred on the intraparietal sulcus (Brodmann area 7). The experimental literature on monkeys and humans suggests that this area is involved in a variety of spatial transformations. Our results contribute evidence that such transformations are recruited during mental rotation and add to a body of evidence which suggests that the right posterior parietal lobe is important for carrying out visuospatial transformations.

Regional distribution of low affinity kainate receptors in brain of Macaca fascicularis determined by autoradiography using [3H](2S,4R)-4-methylglutamate.

Binding of [3H](2S,4R)-4-methylglutamate, a novel low affinity kainate receptor agonist, was studied in brain sections of a Macaca fascicularis monkey. In cerebellar sections, [3H](2S,4R)-4-methylglutamate bound to a single population of sites (KD = 20 nM) and was inhibited by various glutamate receptor ligands: kainate > 6-cyano-7-nitroquinoxaline-2,3-dione > L-glutamate >> AMPA. (S)-5-lodowillardiine and (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA), drugs selective for the GluR5 subunit, displaced 50% and 40% of binding, respectively. Autoradiography revealed topographic binding of [3H](2S,4R)-4-methylglutamate. Binding in cortex was highest in layer 5 and restricted to CA2/3 in hippocampus. Levels of binding were high in septum and hypothalamus. Moderate densities of binding were found in caudate-putamen, cerebellar granular layer, nucleus tractus solitarius, cuneate nucleus and area postrema. Binding in spinal cord was concentrated in dorsal horn. [3H](2S,4R)-4-Methylglutamate shows differential binding throughout primate brain and is a valuable new ligand for low affinity kainate receptors.

EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract.

Members of the Eph family of tyrosine kinase receptors have been implicated in the regulation of developmental processes and, in particular, axon guidance in the developing nervous system. The function of the EphA4 (Sek1) receptor was explored through creation of a null mutant mouse. Mice with a null mutation in the EphA4 gene are viable and fertile but have a gross motor dysfunction, which is evidenced by a loss of coordination of limb movement and a resultant hopping, kangaroo-like gait. Consistent with the observed phenotype, anatomical studies and anterograde tracing experiments reveal major disruptions of the corticospinal tract within the medulla and spinal cord in the null mutant animals. These results demonstrate a critical role for EphA4 in establishing the corticospinal projection.