Summary Cajal-Retzius (CR) cells play a fundamental role in the development of the mammalian cerebral cortex. They control the formation of cortical layers by regulating the migration of pyramidal cells through the release of Reelin. The function of CR cells critically depends on their regular distribution throughout the surface of the cortex, but little is known about the events controlling this phenomenon. Using time-lapse video microscopy in vivo and in vitro, we found that movement of CR cells is regulated by repulsive interactions, which leads to their random dispersion throughout the cortical surface. Mathematical modeling reveals that contact repulsion is both necessary and sufficient for this process, which demonstrates that complex neuronal assemblies may emerge during development through stochastic events. At the molecular level, we found that contact repulsion is mediated by Eph/ephrin interactions. Our observations reveal a novel mechanism that controls the even distribution of neurons in the developing brain.
The distribution of glycinergic cells in the brain of nonmammalian vertebrates is still unknown. Lampreys are the most primitive extant vertebrates, and they may provide important data on the phylogeny of this system. Here, we studied for the first time the distribution of glycine immunoreactivity in the sea lamprey brain and compared it with gamma-aminobutyric acid (GABA)-ergic populations. Most glycine-immunoreactive neurons were found at midbrain and hindbrain levels, and most of these cells did not exhibit GABA immunoreactivity. We describe glycine-immunoreactive cell populations in the olfactory bulbs, the preoptic nucleus, and the thalamus of the sea lamprey, which is in striking contrast to their lack in the mammalian forebrain. We also observed glycine-immunoreactive populations in the optic tectum, the torus semicircularis and the midbrain tegmentum, the isthmus, the octavolateral area, the dorsal column nucleus, the abducens nucleus, the trigeminal motor nucleus, the facial motor nucleus, and the rhombencephalic reticular formation. In these populations, colocalization with GABA was observed in only some cells of the tegmental M5 nucleus, ventral isthmus, medial octavolateral nucleus, dorsal column nucleus, and lateral reticular region. The present results allow us to conclude that the distribution of glycine-immunoreactive cells changed notably from lamprey to mammals, with a decrease in glycinergic populations in the forebrain and a specialization of brainstem cell groups. Although knowledge of the glycinergic populations in lampreys is important for understanding the early evolution of this system, there is a notable gap of information regarding its organization in brains of other nonmammalian vertebrates.
The neurochemistry of the retina of the larval and postmetamorphic sea lamprey was studied via immunocytochemistry using antibodies directed against the major candidate neurotransmitters [glutamate, glycine, gamma-aminobutyric acid (GABA), aspartate, dopamine, serotonin] and the neurotransmitter-synthesizing enzyme tyrosine hydroxylase. Immunoreactivity to rod opsin and calretinin was also used to distinguish some retinal cells. Two retinal regions are present in larvae: the central retina, with opsin-immunoreactive photoreceptors, and the lateral retina, which lacks photoreceptors and is mainly neuroblastic. We observed calretinin-immunostained ganglion cells in both retinal regions; immunolabeled bipolar cells were detected in the central retina only. Glutamate immunoreactivity was present in photoreceptors, ganglion cells, and bipolar cells. Faint to moderate glycine immunostaining was observed in photoreceptors and some cells of the ganglion cell/inner plexiform layer. No GABA-immunolabeled perikarya were observed. GABA-immunoreactive centrifugal fibers were present in the central and lateral retina. These centrifugal fibers contacted glutamate-immunostained ganglion cells. No aspartate, serotonin, dopamine, or TH immunoreactivity was observed in larvae, whereas these molecules, as well as GABA, glycine, and glutamate, were detected in neurons of the retina of recently transformed lamprey. Immunoreactivity to GABA was observed in outer horizontal cells, some bipolar cells, and numerous amacrine cells, whereas immunoreactivity to glycine was found in amacrine cells and interplexiform cells. Dopamine and serotonin immunoreactivity was found in scattered amacrine cells. Amacrine and horizontal cells did not express classical neurotransmitters (with the possible exception of glycine) during larval life, so transmitter-expressing cells of the larval retina appear to participate only in the vertical processing pathway.
Glutamate is the major excitatory neurotransmitter in vertebrates, and glutamatergic cells probably represent a majority of neurons in the brain. Physiological studies have demonstrated a wide presence of excitatory (glutamatergic) neurons in lampreys. The present in situ hybridization study with probes for the lamprey vesicular glutamate transporter (VGLUT) provides an anatomical basis for the general distribution and precise localization of glutamatergic neurons in the sea lamprey brainstem. Most glutamatergic neurons were found within the periventricular gray layer throughout the brainstem, with the following regions being of particular interest: the optic tectum, torus semicircularis, isthmus, dorsal and medial nuclei of the octavolateral area, dorsal column nucleus, solitary tract nucleus, motoneurons, and reticular formation. The reticular population revealed a high degree of cellular heterogeneity including small, medium-sized, large, and giant glutamatergic neurons. We also combined glutamate immunohistochemistry with neuronal tract-tracing methods or γ-aminobutyric acid (GABA) immunohistochemistry to better characterize the glutamatergic populations. Injection of Neurobiotin into the spinal cord revealed that retrogradely labeled small and medium-sized cells of some reticulospinal-projecting groups were often glutamate-immunoreactive, mostly in the hindbrain. In contrast, the large and giant glutamatergic reticulospinal perikarya mostly lacked glutamate immunoreactivity. These results indicate that glutamate immunoreactivity did not reveal the entire set of glutamatergic populations. Some spinal-projecting octaval populations lacked both VGLUT and glutamate. As regards GABA and glutamate, their distribution was largely complementary, but colocalization of glutamate and GABA was observed in some small neurons, suggesting that glutamate immunohistochemistry might also detect non-glutamatergic cells or neurons that co-release both GABA and glutamate.
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