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Byline: Meghna. Maheshwari, Sadhana. Sanwatsarkar, Milind. Katakwar A child is not a mini adult. They differ from adults in terms of weight, shape, anatomical size and major body systems such [...]

Hippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISC1. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and [...]

Gangliosides are siolic acid-containing glycosphingolipids. Gangliosides are found in human milk; understanding of the potential role of gangliosides in infant development is emerging, with suggested roles in the brain and gut. Ganglioside accretion in the developing brain is highest in utero and in early neonatal life, during the periods of dendritic branching and new synapse formation. Further, brain contains the highest relative ganglioside content in the body, particularly in neuronal cell membranes concentrated in the area of the synaptic membrane. Gangliosides are known to play o role in neuronal growth, migration and maturation, neuritogenesis, synaptogenesis, and myelination. In addition to their roles in development and structure of the brain, gangliosides also play a functional role in nerve cell communication. It is less well known whether dietary gangliosides can influence the development of cognitive function. This review summarizes current knowledge on the role gangliosides play in brain development.

Human learning is distinguished by the range and complexity of skills that can be learned and the degree of abstraction that can be achieved compared with those of other species. Homo sapiens is also the only species that has developed formal ways to enhance learning: teachers, schools, and curricula. Human infants have an intense interest in people and their behavior and possess powerful implicit learning mechanisms that are affected by social interaction. Neuroscientists are beginning to understand the brain mechanisms underlying learning and how shared brain systems for perception and action support social learning. Machine teaming algorithms are being developed that allow robots and computers to learn autonomously. New insights from many different fields are converging to create a new science of learning that may transform educational practices.

Byline: Yasufumi Hayano (Neuroscience Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan); Nobuhiko Yamamoto (Neuroscience Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan, nobuhiko@fbs.osaka-u.ac.jp) Keywords: Axon [...]

Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogenactivated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf-deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data define B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors.

In the neurogenic phase of CNS development, the proliferating progenitors are found medially within the neuroepithelium. The adherens junctions on the apical membrane of proliferating neural progenitors allow for cell-cell adhesion and medial stratification. In contrast, differentiating neuronal precursors delaminate and migrate laterally, establishing the laminar layers. Apical adherens junctions also establish the apical-basal polarity in neural progenitors, which in turn is postulated to lead to asymmetric inheritance of cell fate determinants during neurogenic divisions. The signaling pathways and cellular mechanisms that regulate the assembly and asymmetric localization of adherens junctions in neural progenitors remain elusive. Here we show that atypical PKC[zeta]/[lambda] (aPKC[zeta]/[lambda]) localizes at the apical membrane of proliferating neural stem cells, but not postmitotic neuronal precursors, in the developing chicken neural tube. This precise subcellular compartmentalization of the kinase activity provides an instructive signal for apical assembly of adherens junctions in a PI3K, Rac/Cdc42 signaling-dependent pathway. Apical aPKC[zeta] coordinates neural stem cell proliferation and the overall stratification of cell types within the neural tube. kinase | signaling | neurodevelopment

With aging there is a decline in the number of newly generated neurons in the dentate gyrus of the hippocampus. In rodents and tree shrews, this age-related decrease in neurogenesis is evident long before the animals become aged. No previous studies have investigated whether primates exhibit a similar decline in hippocampal neurogenesis with aging. To investigate this possibility, young to middle aged adult common marmosets (Callithrix jacchus) were injected with BrdU and perfused 3 weeks later. The number of newly generated cells in the subgranular zone/granule cell layer of the dentate gyrus was significantly lower in older animals and decreased linearly with age. A similar age-related decline in new cells was observed in the subventricular zone but not in the hilar region of the dentate gyrus. These data demonstrate that a substantial decrease in neurogenesis occurs before the onset of old age in the adult marmoset brain, suggesting the possibility that similar alterations occur in the human brain. aging | BrdU | dentate gyrus | hippocampus | subventricular zone

Human attentional control is unrivaled. We recently proposed that adults depend on distinct frontoparietal and cinguloopercular networks for adaptive online task control versus more stable set control, respectively. During development, both experience-dependent evoked activity and spontaneous waves of synchronized cortical activity are thought to support the formation and maintenance of neural networks. Such mechanisms may encourage tighter 'integration' of some regions into networks over time while 'segregating' other sets of regions into separate networks. Here we use resting state functional connectivity MRI, which measures correlations in spontaneous blood oxygenation level-dependent signal fluctuations between brain regions to compare previously identified control networks between children and adults. We find that development of the proposed adult control networks involves both segregation (i.e., decreased short-range connections) and integration (i.e., increased long-range connections) of the brain regions that comprise them. Delay/disruption in the developmental processes of segregation and integration may play a role in disorders of control, such as autism, attention deficit hyperactivity disorder, and Tourette's syndrome. attention | connectivity | functional MRI | spontaneous activity development

Both animal and human studies suggest that action goals are defined in external coordinates regardless of their sensory modality. The present study used an auditory-manual task to test whether the default use of such an external reference frame is innately determined or instead acquired during development because of the increasing dominance of vision over manual control. In Experiment I, congenitally blind, late blind, and age-matched sighted adults had to press a left or right response key depending on the bandwidth of pink noise bursts presented from either the left or right loudspeaker. Although the spatial location of the sounds was entirely task-irrelevant, all groups responded more efficiently with uncrossed hands when the sound was presented from the same side as the responding hand ('Simon effect'). This effect reversed with crossed hands only in the congenitally blind: They responded faster with the hand that was located contralateral to the sound source, in Experiment II, the instruction to the participants was changed: They now had to respond with the hand located next to the sound source. In contrast to Experiment I ('Simon-task'), this task required an explicit matching of the sound's location with the position of the responding hand. In Experiment II, the congenitally blind participants showed a significantly larger crossing deficit than both the sighted and late blind adults. This pattern of results implies that developmental vision induces the default use of an external coordinate frame for multisensory action control; this facilitates not only visual but also auditory-manual control. action control | blindness | multisensory | spatial compatibility effects

Byline: T. A. Tsekhmistrenko (1), A. S. Vologirov (1), V. A. Vasil'eva (2), N. S. Shumeiko (2) Keywords: cerebrum; cortex; fibroarchitectonics; postnatal ontogenesis Abstract: Brains from 74 children aged from birth to 12 years were used to study fibroarchitectonic characteristics in topographically and functional diverse cortical zones (the temporal-parietal-occipital subregion, occipital, precentral, postcentral, and frontal areas) of the cerebral cortex children aged up to 12 months were studied on the basis of one-month age intervals. Studies were performed by computer analysis of optical images on frontal sections stained with Nissl cresyl violet and silver nitrate impregnation by the modified Peters method. Data on the rate of increase in the thickness of radial bundles of fibers, the distances between bundles, and the age dynamics of the ratios of the specific volumes of neurons and fibers in fields 3, 4p, 6op, 17, 19, 37ac, 44, and 32/10 were obtained. These measurements showed that age-related transformation of fibroarchitectonics in fields of the sensorimotor, somatosensory, occipital, temporal-parietal-occipital, and frontal areas occurred at different times and with different intensities the most significant changes were seen in the first 2--3 years of life, with changes continuing at a less intense level to age 9--12 years. Author Affiliation: (1) Department of Human Anatomy, Russian University of the Friendship of the Peoples, U.S.A (2) Functional Morphology Laboratory, Institute of Age Physiology, Russian Academy of Education, Moscow Article History: Registration Date: 29/12/2004

The retinotectal map is the best characterized model system to study how axons respond to guidance cues during the formation of the nervous system. Recent studies have shown that the critical event in forming this map is topographic-specific axon branching. To elucidate the in vivo role of the repulsive cue ephrin-A5 in this event, we used chromophore-assisted laser inactivation (CALI) to generate acute loss of ephrin-A5 function in localized areas of the posterior tectum of chick embryos in ovo and analyzed the resulting changes of retinal projections during initial outgrowth (E11) and when retinal axons arborize in the deep layers in the tectum (E12). We confirmed that ephrin-A5 functions to restrict initial axon outgrowth at E11. At E12, CALI of ephrin-A5 did not affect the extent of axon outgrowth on the tectal surface but instead caused ectopic arborization posterior to the topographically correct site in deeper layers of the tectum. This shows that ephrin-A5 restricts arborization during this critical process for developing the retinotopic map. CALI provides an approach to inactivate in vivo function in higher vertebrates with high temporal and spatial specificity that may have wide application.

We review here factors that control the excitability of the giant neuron-mediated tail-flip escape behavior in crayfish, focusing especially on recent findings concerning serotonergic modulation. Serotonin can either facilitate or inhibit escape depending on concentration and pattern of application. Low concentrations facilitate while high ones inhibit; however, if high concentrations arise gradually they facilitate instead of inhibiting. The effects of serotonin can also be altered by social experience, with application regimens that cause facilitation in social isolates coming to produce inhibition after an extended period of living as a subordinate. Attempts to understand both the possible physiological basis of some of these complexities and their possible function are discussed. Neuroethological investigations indicate that giant neuron-mediated escape is inhibited during the initial fights that establish social relationships and is facilitated in their immediate aftermath. Once the relationship of a pair is well-established, the presence of the dominant tends to suppress giant neuron-mediated escape (but not tail-flip escape mediated by non-giant circuitry) in the subordinate, but the presence of the subordinate has relatively little effect on the dominant. These patterns of modulation can be seen as consistent with the known variations in serotonin's effect as a function of concentration and social experience and may provide a biological reason for these variations.

Programmed cell death (apoptosis) is an important mechanism that determines the size and shape of the vertebrate nervous system. Recent gene-targeting studies have indicated that homologs of the cell-death pathway in the nematode Caenorhabditis elegans have analogous-functions in apoptosis in the developing mammalian brain. However, epistatic genetic analysis has revealed that the apoptosis of progenitor cells during early embryonic development and apoptosis of postmitotic neurons at later stage of brain development have distinct roles and mechanisms. These results provide new insight on the significance and mechanism of neural cell death in mammalian brain development.

XATH-1, a basic/helix-loop-helix transcription factor and a homolog of Drosophila atonal and mammalian MATH-1, is expressed specifically in the dorsal hindbrain during Xenopus neural development. In order to investigate the role of XATH-1 in the neuronal differentiation process, we have examined the effects of XATH-1 overexpression during Xenopus development. XATH-1 induces the expression of neuronal differentiation markers, such as N-tubulin, within the neural plate as well as within nonneural ectodermal progenitor populations, resulting in the appearance of process-bearing neurons within the epidermis. The related basic/helix-loop-helix genes neurogenin-related-1 and neuroD are not induced in response to XATH-1 overexpression within the embryo, suggesting that XATH-1 may activate an alternate pathway of neuronal differentiation. In further contrast to neurogenin-related-1 and neuroD, high-level expression of general neural markers expressed earlier in development, such as N-CAM, is not induced by XATH-1 overexpression. Competent ectodermal progenitors therefore respond to ectopic XATH-1 expression by initiating a distinct program of neuronal differentiation.

Occluding vision through one eye during a critical period in early life nearly abolishes responses to that eye in visual cortex. This phenomenon is mimicked by long-term depression of synaptic transmission in vitro, which may require metabotropic glutamate receptors (mGluRs) and is age-dependent. Peaks in mGluR expression and glutamate-stimulated phosphoinositide turnover during visual cortical development have been proposed as biochemical bases for the critical period. Pharmacological blockade of mGluRs specifically prevented synapse weakening in mouse visual cortical slices but did not alter kitten ocular dominance plasticity in vivo. Thus, a heightened mGluR response does not account for the critical period in development., Connections in the developing vertebrate visual system are sculpted by an activity-dependent competition between inputs for common postsynaptic neurons. Manipulations of visual experience, such as monocular deprivation (MD) during a [...]

Upon contacting its postsynaptic target, a neuronal growth cone transforms into a presynaptic terminal. A membrane component on the growth cone that facilitates synapse formation was identified by means of a complementary DNA-based screen followed by genetic analysis. The late bloomer (lbl) gene in Drosophila encodes a member of the tetraspanin family of cell surface proteins. LBL protein is transiently expressed on motor axons, growth cones, and terminal arbors. In lbl mutant embryos, the growth cone of the RP3 motoneuron contacts its target muscles, but synapse formation is delayed and neighboring motoneurons display, an increase in ectopic sprouting., As neuronal growth cones encounter a variety of guidance cues, they steer toward attractive signals and away from repulsive ones (1). Ultimately, they reach their targets, shut down their motility [...]

Notch1, a mammalian homolog of the Drosophila melanogaster Notch gene, is asymmetrically localized within dividing progenitor cells and inherited differentially following asymmetric divisions. Asymmetric divisions during mammalian neurogenesis produce basal daughter cells which behave like young migratory neurons and apical daughters that remain within the proliferative zone. Notch1 immunoreactivity prevails asymmetrically in mitotic cells, with Notch1 inherited selectively by the basal daughter cells of horizontal divisions.

The formation of the somatosensory cortex in rats is controlled by a peripheral signal which restrains the spatial distribution of the terminal arbor. Rats subjected to infraorbital nerve section on the day of birth (P0) show wider thalamocortical terminal arbors on the third postnatal day as compared to normal rats. However the number of branches and the length of the arbor are same in both types of rats. Thus, the effect of the signal is rapid and acts on the single thalamic axons.

Developing axons find their targets through direct contact with cues in the extracellular environment and in response to gradients of diffusible factors. The floor plate, a neuroepithelial structure, guides developing commissural axons in the spinal cord by release of chemoattractants. Floor plate cells express neurokinin-1 receptors, and a transiently appearing subpopulation of commissural axons contains substance P, the neuropeptide ligand for this receptor. Substance P increases the amount of axon outgrowth from dorsal horn explants cocultured with floor plate explants. Results of experiments with embryonic rats suggest that substance P released from pioneering neuronal pathways may regulate the release of chemoattractants from floor plate cells., Diffusible factors released by cellular targets support and guide developing neurites. One example of this process occurs in the spinal cord, in which commissural axons are guided by factors released [...]

The formation of specific connections in the developing central nervous system is thought to result from mechanisms that increase the strengths of synapses at which pre- and postsynaptic activity are correlated and decrease it otherwise. in the visual cortex, initially widespread inputs normally sort out into eye-specific patches during early life. If only one eye can see during this period, its patches are much larger than normal, and patches from the occluded eye become much smaller. Anatomical experiments here show that closed-eye inputs expand within a region of cortex that is silenced, establishing that inhibition of common target cells gives less active inputs a competitive advantage., Ocular dominance columns (alternate patches of visual cortex that receive input from the two eyes) form in normal development by a selective loss of the initially widespread and overtapping branches [...]

The fates of cells from the anterior region of the ascidian neural plate are described either as neural or as mixed neural and non-neural. In Ciona intestinalis, all cellular progeny are accounted for until a time 60% between the onset of embryonic development and larval hatching. To resolve the issue of their fates in this species, we have examined the later mitotic history of neural-plate cells. Because cessation of cell division in the neural plate has been claimed to occur at 70% of embryonic development, we need to account for cell production from 60% onward, to determine whether more cells are produced than populate the larval CNS, allowing some to adopt non-neural fates. The embryonic incorporation of bromodeoxyuridine (BrdU), 500 microM in seawater, was monitored in 1-h larvae by anti-BrdU immunocytochemistry. The pattern of incorporations indicates that all larval neurons are born before 70% of embryonic development, but that cell division unexpectedly continues to generate ependymal cells until at least 95%. Divisions in the neuro-hypophysis continue throughout embryonic development. The total number of cells produced appears sufficient only to complete the complement of larval CNS cells, denying non-neural fates for anteriorly migrating neural plate cells, and indicating a general absence of cell death. Consistent numbers of incorporations after the same exposure in different larvae provide evidence for determinacy of neural plate lineages. The last three conclusions confirm those reached previously (Nicol and Meinertzhagen, 1988b).

An experiment conducted to study skeletal muscle development in the mouse mutant peroneal muscular atrophy (pma) muscular indicate that the formation of secondary myotubes is not nerve-dependent. A higher ratio of secondary to primary myotubes was recorded in the pma as compared to normal strains. Furthermore, no difference was observed between aneural and normal muscles in terms of myotube ratio. These results, along with similar studies conducted on chicks, indicate that innervation doe not directly affect secondary myotube formation.

The mouse mutants peroneal muscular atrophy and muscular dysgenesis were used to study the effects of muscle innervation, electrical activity and contraction on the development of myotubes during embryonic development. During embryonic day 15, the ratio of secondary to primary myotubes was three times greater than normal. Furthermore, administration of tetrodoxin to induce paralysis significantly reduced the number of secondary myotubes and resulting in a smaller ratio. These results indicate that secondary myotube formation depends on the electrical activity produced by primary myotubes.

An experiment was conducted to test whether the formation of secondary myotubes in aneural fetal muscles is dependent on the presence of primary myotubes or on innervation. Attempts to suppress secondary myotube formation using the neurotoxic agent Beta-bungarotoxin (Beta-BTX) indicated that the influence of Beta-BTX is dependent on the timing of injection. Results provided evidence for the hypothesis that secondary myotube formation is nerve-dependent.

Suckling and adult opossums were utilized in the investigation of gamma amino butyric acid (GABA) mediation of changes in respiratory pattern with maturation. GABA and bicuculline, a GABA antagonist, were injected in the respiratory centers of the subjects and the effects were monitored. No significant differences was demonstrated in the responses of adult and sucklingopossums to bicuculline. On the other hand, the magnitude of animal responses to GABA exhibited positive correlation with age. However, recovery of neuronal functions upon cessation of treatment reveal that GABA is not a mediator in theage-related alteration in respiratory pattern.

The neural activity-dependent and activity-independent mechanisms that generate precision of neuronal connections during development are reviewed. These two mechanisms act in concert to regulate the formation of precise patterns of neural connections. Activity-independent mechanisms usually operate during pathway and target recognition, while activity-dependent mechanisms are responsible for the refinement and remodelling of these initial coarse patterns of synaptic connections. These mechanisms are illustrated by comparing and contrasting the connections between motoneurons and muscles and between the thalamus and cortex.

The mammalian neocortex consists of a mosaic of columnar units whose development is poorly understood. Optical recordings of brain slices labeled with the fluorescent calcium indicator fura-2 revealed that the neonatal rat cortex was partitioned into distinct domains of spontaneously coactive neurons. In tangential slices, these domains were 50 to 120 micrometers in diameter; in coronal slices they spanned several cortical layers and resembled columns found in the adult cortex. In developing somatosensory cortex, domains were smaller than, and distinct from, the barrels, which represent sensory input from a single vibrissa. The neurons within each domain were coupled by gap junctions. Thus, nonsynaptic communication during cortical development defines discrete multicellular patterns that could presage adult functional architecture., In mammalian neocortex, local circuits are preferentially organized in a radial direction, forming a modular architecture of columnar units [1]. At least two possible developmental mechanisms, not mutually exclusive, could [...]

Anatomical development of the third-order giant axons was studied in conjunction with ontogeny of the escape response and the underlying neural control. Stimulated escape jetting appears at stage 26 (Segawa et al., 1988); such responses are driven solely by a small axon motor system. Giant axons become morphologically identifiable in the more posterior stellar nerves that effect jetting by stage 28, and electrical activity in the stellate ganglia associated with the giant axons is first recordable at this time. Maturation of the giant axons is accompanied by a marked improvement in temporal aspects of escape behavior up to the time of hatching. In embryonic and hatchling Loligo, all escape responses, regardless of the mode of stimulation, are fast-start responses with latencies less than the minimum value displayed by adults (50 ms). Giant axon activity recorded in the stellate ganglion always precedes small axon motor activity; this is not true for adults which display two distinct modes of giant axon use. Both giant and non-giant motor systems are thus functional in embryonic and hatchling squid, and both contribute to escape jetting. However, these animals do not yet display the concerted interplay of the two motor systems characteristic of adults.

The floor plate is a specialized group of midline neuroepithelial cells that appears to regulate cell differential and axonal growth in the developing vertebrate nervous system. A floor plate-specific chemorattractant [...]