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PubMed1997

The vulnerability of the fetal sheep brain to hypoxemia at mid-gestation.

Our aim was to test the hypothesis that a brief episode of hypoxemia near mid-gestation in fetal sheep will result in damage to the fetal brain with the extent and type of damage in any particular region being related to the developmental processes occurring at the time of the insult. Hypoxemia was induced, sufficient to reduce arterial O2 content by approximately 50%, by restricting utero-placental blood flow in 14 chronically catheterised fetuses for 6 h or 12 h at 84 days of gestation (term 145-8 days). Age-matched fetuses (n = 14; 4 operated and 10 unoperated) were used as controls. Fetuses were killed 7 days after being exposed to hypoxemia, and brains removed for histological analysis at the light and ultrastructural levels. Body weights of hypoxemic fetuses did not differ significantly from controls but brain weights were significantly reduced both in absolute terms and when expressed in relation to body weight (P < 0.05). Most fetuses exposed to hypoxemia sustained no gross brain damage. However, in one hypoxemic fetus from a multiple pregnancy there was extensive leucomalacia in the cortical white matter; mild focal damage was seen in another 8 hypoxemic fetuses. In the cerebral cortex (frontal lobe) the surface folding index was significantly reduced (P < 0.05) in hypoxemic fetuses compared to controls suggesting that gyral formation had been delayed. In these fetuses there were also degenerating neurons in the deeper cortical layers. In the hippocampus of hypoxemic fetuses there was a delay (P < 0.05), compared to controls, in the migration of cells from the germinal layer to the pyramidal layer in the CA1 region, and decreases (P < 0.05) in the density (area1) of neurons in the pyramidal layer and in the width of stratum oriens. In the cerebellum of hypoxemic fetuses there was a decrease (P < 0.05), compared to controls, in the density (area1) of mitotic bodies in the external granule cell layer. However, there were no significant differences in the number of pyknotic cells in this layer, in the density of Purkinje cells, in their somal area, or in the width of the external granule cell or molecular layers. There was an increase (P < 0.05) in the proportion of the brain parenchyma occupied by blood vessels in both the hippocampus and cortex of hypoxemic fetuses compared to controls. This study has shown that an hypoxemic insult near mid-gestation can result, one week later, in white matter damage and in neuronal death in the hippocampus and to a lesser extent in the cerebral cortex and cerebellum. It can also retard neuronal migration and the growth of neural processes in the hippocampus where development is well established at this age. Such brain damage could result in less than optimal neuronal connectivity and could affect function postnatally.

Animals↗
PubMed1992

Pathobiological reactions of C-fibre primary sensory neurones to peripheral nerve injury.

Mammalian primary sensory neurones display profound anatomical and chemical changes in response to injury of their peripheral processes. Peripheral nerve damage results in transganglionic degeneration of central terminals of A-fibre primary afferent neurones terminating in the deeper layers of the medullary or spinal dorsal horn. The depletion of neuropeptides and other neurone-specific macromolecules from neurones in sensory ganglia and from the superficial dorsal horn, the known central projection area of C-fibre primary afferents, is a salient phenomenon commencing after peripheral nerve lesions. A recently devised new experimental procedure, termed the capsaicin-gap method, permitted evaluation of the transganglionic degenerative phenomena which develop in C-fibre primary sensory neurones after a lesion is inflicted upon their peripheral branches. The experimental findings indicated that C-fibre primary afferent terminals underwent transganglionic degeneration following a perineural treatment with capsaicin, and that this was associated with, and probably resulted from, ganglionic cell degeneration. Studies on the effects of peripheral nerve section yielded similar results. It has therefore been suggested that the observed depletion of specific macromolecules, including sensory peptides, specific glycoconjugates and sensory neurone specific acid phosphatase, may be accounted for, at least in part, by an irreversible loss of sensory ganglion neurones. In contrast, many injured neurones express peptides, including vasoactive intestinal polypeptide, peptide histidine-isoleucine and galanin, which can be demonstrated in only a few neurones under normal conditions. These seem to be involved in dorsal horn regenerative and/or compensatory processes following peripheral nerve damage. There is suggestive evidence that the partial deafferentation caused by the transganglionic degeneration of C-fibre primary afferents creates favourable circumstances for an anatomical rearrangement of neuronal connections within the spinal cord dorsal horn. These changes may provide a morphological substrate of some of the functional alterations demonstrated after peripheral nerve lesions.

Animals↗
PubMed2005

Controlled induction, enhancement, and guidance of neuronal growth cones by use of line optical tweezers.

We report an optical tweezers based approach for efficient and controlled manipulation of neuronal growth cones. The approach exploits asymmetric transverse gradient force created in a line optical tweezers to transport actin monomers in the desired growth direction. With this approach induction of artificial growth cones from the neuronal cell body and enhancement of the growth rate of the natural growth cones have been achieved. The use of this approach to bring two growth cones into close proximity for establishing a neuronal connection is also discussed.

Animals↗
PubMed2006

Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires.

Three closely-linked clusters of protocadherin (Pcdh) genes (alpha, beta, and gamma) encoding more than 50 distinct mRNAs have been identified in humans and mice, and proposed to play important roles in neuronal connectivity in the CNS. The human and mouse Pcdh alpha and gamma clusters each span a region of about 300 kb genomic DNA, and are each organized into a tandem array of more than a dozen highly-similar "variable" exons, and three downstream "constant" exons. Little is known about the expression patterns of the alpha and gamma repertoires in the CNS. Here, we comprehensively analyzed the one megabase rat Pcdh genomic DNA sequences at the nucleotide level using various computational methods. We found that the clustered rat Pcdh genes display strict orthologous relationships with those of mice but not humans. Moreover, each rat Pcdh variable exon is preceded by a distinct promoter. We designed two complete sets of isoform-specific probes and extensively mapped the expression patterns for each member of the alpha and gamma repertoires in the adult rat CNS by non-isotopic in situ hybridization experiments. We found that most alpha and gamma mRNA isoforms are broadly expressed in similar patterns in subsets of cells (with some displaying interesting cortical layer-specific expression) throughout various CNS regions, including the olfactory bulb, cerebral cortex, hippocampus, cerebellum, and spinal cord. The broad expression of most alpha or gamma mRNAs throughout various regions of the CNS is consistent with the hypothesis that these genes may be used for neurons to establish their individuality and also provide the adhesive diversity required for complex synaptic connectivity in the mammalian CNS.

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PubMed1999

Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation.

Neurotrophins have been proposed to participate in activity-dependent modifications of neuronal connectivity and synaptic efficacy. Preferential strengthening of active inputs requires restriction of putative neurotrophin-mediated synaptic potentiation to active synapses. Here we report that potentiation of synaptic efficacy by brain-derived neurotrophic factor (BDNF) is greatly facilitated by presynaptic depolarization at developing neuromuscular synapses. Brief depolarization in the presence of low-level BDNF results in a marked potentiation of both evoked and spontaneous synaptic transmission, whereas exposure to either BDNF or depolarization alone is without effect. This potentiation depends on the relative timing of depolarization and reflects an enhancement of transmitter secretion from the presynaptic neuron. Thus synapses made by active inputs may be selectively strengthened by secreted neurotrophins as part of activity-dependent refinement of developing connections or of mature synapses.

Action Potentials↗
PubMed2001

Development and connectivity of olfactory pathways in the brain of the lobster Homarus americanus.

The main output pathways from the olfactory lobes (primary olfactory centers) and accessory lobes (higher-order integrative areas) of decapod crustaceans terminate within both of the main neuropil regions of the lateral protocerebrum: the medulla terminalis and the hemiellipsoid body. The present study examines the morphogenesis of the lateral protocerebral neuropils of the lobster, Homarus americanus, and the development of their neuronal connections with the paired olfactory and accessory lobes. The medulla terminalis was found to emerge during the initial stages of embryogenesis and to be the target neuropil of the output pathway from the olfactory lobe. In contrast, the hemiellipsoid body is first apparent during mid-embryonic development and is innervated by the output pathway from the accessory lobe. The dye injections used to elucidate these pathways also resulted in the labeling of a previously undescribed pathway linking the olfactory lobe and the ventral nerve cord. To increase our understanding of the morphology of the olfactory pathways in H. americanus we also examined the connectivity of the lateral protocerebral neuropils of embryonic lobsters. These studies identified several interneuronal populations that may be involved in the higher-order processing of olfactory inputs. In addition, we examined the neuroanatomy of ascending pathways from the antenna II and lateral antenna I neuropils (neuropils involved in the processing of chemosensory and tactile inputs). These studies showed that the ascending pathways from these neuropils innervate the same regions of the medulla terminalis and that these regions are different from those innervated by the olfactory lobe output pathway.

Animals↗
PubMed2001

Predictive learning of temporal sequences in recurrent neocortical circuits.

When a spike is initiated near the soma of a cortical pyramidal neuron, it may back-propagate up dendrites toward distal synapses, where strong depolarization can trigger spike-timing dependent Hebbian plasticity at recently activated synapses. We show that (a) these mechanisms can implement a temporal-difference algorithm for sequence learning, and (b) a population of recurrently connected neurons with this form of synaptic plasticity can learn to predict spatiotemporal input patterns. Using biophysical simulations, we demonstrate that a network of cortical neurons can develop direction selectivity similar to that observed in complex cells in alert monkey visual cortex as a consequence of learning to predict moving stimuli.

Action Potentials↗
PubMed2005

Novel calretinin and reelin expressing neuronal population includes Cajal-Retzius-type cells in the neocortex of adult pigs.

Cajal-Retzius cells and their secreted product reelin are essential for the lamination of the cerebral cortex. In all species studied to date Cajal-Retzius cells form a transient neuronal population that almost completely disappears from the neocortex postnatally. Recently, in the hippocampal formation of adult domestic pig, we have found a large calretinin- and reelin-immunoreactive cell population that morphologically corresponded to Cajal-Retzius cells. In the present study, we examined calretinin- and reelin-immunoreactive neurons in layer I of the prefrontal, temporal, parietal and occipital neocortical areas of newborn, young adult and adult domestic pigs. Large numbers of bipolar or fusiform calretinin-positive cells were found in the upper half of layer I in all examined age groups. The morphology of these neurons resembled that of the Cajal-Retzius cells. Layer I was occupied by a dense calretinin-positive axonal plexus that was similar to the previously described axons of Cajal-Retzius cells in other species. In a similar location, where calretinin-positive cells occurred in layer I, large numbers of reelin-immunoreactive cells were found in all examined age groups. In addition, reelin colocalized with calretinin in layer I neurons. The number of calretinin and reelin-positive neurons decreased from 1 day to one year, but calretinin-positive Cajal-Retzius-type cells still comprised a remarkable large population in 12-month-old animals. Correlated light and electron microscopic examination of calretinin-labeled Cajal-Retzius-type cells indicated that these cells are integrated in the synaptic circuitry of the neocortex. Our results suggest that Cajal-Retzius cells do not disappear inevitably from the mature neocortex in all mammalian species. The function of this cell type is not known, but late persisting Cajal-Retzius-type cells in the domestic pig provide an opportunity to study their neuronal connections and the possible role of reelin in plasticity and regeneration of neocortex.

Aging↗
PubMed2000

Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice.

Neural activity is crucial for cell survival and fine patterning of neuronal connectivity during neurodevelopment. To investigate the role in vivo of sodium channels (NaCh) in these processes, we generated knockout mice deficient in brain NaChalpha(II). NaChalpha(II)(-/-) mice were morphologically and organogenically indistinguishable from their NaChalpha(+/-) littermates. Notwithstanding, NaChalpha(II)(-/-) mice died perinatally with severe hypoxia and massive neuronal apoptosis, notably in the brainstem. Sodium channel currents recorded from cultured neurons of NaChalpha(II)(-/-) mice were sharply attenuated. Death appears to arise from severe hypoxia consequent to the brainstem deficiency of NaChalpha(II). NaChalpha(II) expression is, therefore, redundant for embryonic development but essential for postnatal survival.

Animals↗
PubMed1998

Striation is the characteristic neuritic abnormality in Alzheimer disease.

In this study, we found that neuropil threads of Alzheimer disease, rather than being continuous filaments along cell processes, show multiple interruptions. They are segmental in nature and therefore appear as striations rather than continuous filaments along the length of the neurite. Neuritic striation is not an artifact of section thickness since the majority of abnormal filament accumulations are extremely short. The dominance of short striations demonstrates that argyrophilic grains, rather than being distinct structures, simply represent a short variant of striation and that longer striations are arbitrarily considered neuropil threads. Ultrastructural examination showed that the intervals between striations lack a cytoskeleton. We suggest that neuritic striations may interrupt the microtubule system functionally blocking fast neuritic transport as well as playing a role in loss of neuronal connectivity.

Aged↗
PubMed2002

Developmental changes in ionotropic glutamate receptors: lessons from hippocampal synapses.

Glutamatergic synapses are the primary source of excitatory transmission in the central nervous system (CNS), and their formation is critical in the establishment of neuronal connections. The refinement of these connections occurs during development and also it is postulated during learning and memory. Recent progress in understanding the molecular components of synaptic junctions, together with advances in imaging techniques, has started to offer new insights into the development of excitatory synapses. Studies performed on low-density primary neuronal cultures have enabled dissection of the temporal sequence of events, which have lead to the differentiation of pre- and postsynaptic components. A central feature of the development of excitatory synapses is the accumulation of glutamatergic receptors (GluRs) at the postsynaptic site. These receptors need to be localized and fixed opposite nerve terminals that release glutamate. But for this to occur, neurons require intracellular anchoring molecules, as well as mechanisms that ensure the efficient turnover and transport of receptor proteins. This review focuses on some of the developmental changes observed in the subcellular distribution and molecular organization of AMPA and NMDA type ionotropic GluRs (iGluRs), which mediate the majority of fast excitatory neurotransmission in the CNS.

Animals↗
PubMed2004

Transient microcircuits formed by subplate neurons and their role in functional development of thalamocortical connections.

Subplate neurons are a transient population of neurons in the brain forming one of the first functional cortical circuits. Past experiments have demonstrated their importance in growth of thalamocortical afferents into the cortical plate and later segregation of thalamocortical afferents. Recently, subplate neurons have been shown to be required for the functional maturation of both thalamocortical connections and mature visual responses in visual cortex. These findings suggest that thalamocortical afferents might not segregate properly in the absence of subplate neurons because the thalamocortical synapse does not mature. Subplate neurons are unique in that they form a circuit that appears to promote synaptic scaling and maturation. Although the precise contribution of subplate neurons within the context of cortical development is unknown, they might play an early role in providing thalamic input to cortex that then interacts with learning rules governing synaptic strengthening at the thalamocortical synapse. Because they appear to play multiple key roles at different stages of development, subplate neurons might also play a role in the pathology of developmental disorders, such as epilepsy and schizophrenia.

Animals↗
PubMed2002

DN-cadherin is required for spatial arrangement of nerve terminals and ultrastructural organization of synapses.

We studied roles of DN-cadherin, the Drosophila major neuronal cadherin, in neuronal connections in the visual system. In DN-cadherin mutants, axon terminals of a large subset of photoreceptor cells reached and associated with their target interneurons, but their characteristic spatial arrangement was disrupted as synaptogenesis proceeded. Although synapses were formed at contact sites between the axon terminals and target neurons, underlying cytoplasmic structures were not fully specialized at both pre- and postsynaptic terminals and synaptic vesicles appeared to accumulate at the presynapses. These results suggest that the cadherin adhesion system is required for interaction between pre- and postsynaptic terminals and for generation of the mature synaptic structures.

Animals↗
PubMed1997

Neuronal activation in the forebrain following electrical stimulation of the cuneiform nucleus in the rat: hypothalamic expression of c-fos and NGFI-A messenger RNA.

Forebrain neuronal connections associated with the cardiovascular response to unilateral, low-intensity, electrical stimulation of the mesencephalic cuneiform nucleus were examined in the halothane-anesthetized and paralysed rat by in situ hybridization histochemistry using specific 35S-labelled oligonucleotides for detection of c-fos and nerve growth factor inducible-A gene (NGFI-A) messenger RNAs. Stimulation of the cuneiform nucleus led to increases in mean arterial pressure and heart rate, whereas no cardiovascular response was observed in animals stimulated in the inferior colliculus or in sham-operated animals [see concurrent mid- and hindbrain study [Lam W. et al. (1996) Neuroscience 71, 193-211]. Cuneiform nucleus stimulation was associated with increased c-fos and NGFI-A messenger RNA levels bilaterally in the ventromedial, dorsomedial and lateroanterior hypothalamic nuclei, lateral and anterior hypothalamic areas, and ipsilaterally in the medial amygdaloid nucleus, at levels significantly greater than those in inferior colliculus-stimulated, sham-operated and naive, unoperated animals. C-fos, but not NGFI-A, messenger RNA expression was increased bilaterally in the piriform cortex and subparafascicular thalamic nucleus. These results are consistent with the existence of direct and indirect projections between the cuneiform nucleus and the aforementioned activated areas, the functions of which may include the control of reproduction and metabolism, as well as cardiovascular regulation. The ipsilateral nature of responses in certain brain areas may be explained by the absence of decussating pathways and/or the presence of multisynaptic connections which attenuate bilateral signal transmission. The existence of structures that are known to receive afferent projections from the cuneiform nucleus, but that were not activated, may be explained by synaptic depolarization not reaching the threshold for immediate early gene expression or by a net inhibitory effect on innervated neurons. Characterization of these activated forebrain regions using other compatible labelling techniques should further elucidate the mechanisms by which these central nervous system structures are integrated in the response to stimulation of the cuneiform nucleus.

Animals↗
PubMed2000

Multicolor "DiOlistic" labeling of the nervous system using lipophilic dye combinations.

We describe a technique for rapid labeling of a large number of cells in the nervous system with many different colors. By delivering lipophilic dye-coated particles to neuronal preparations with a "gene gun," individual neurons and glia whose membranes are contacted by the particles are quickly labeled. Using particles that are each coated with different combinations of various lipophilic dyes, many cells within a complex neuronal network can be simultaneously labeled with a wide variety of colors. This approach is most effective in living material but also labels previously fixed material. In living material, labeled neurons continue to show normal synaptic responses and undergo dendritic remodeling. This technique is thus useful for studying structural plasticity of neuronal circuits in living preparations. In addition, the Golgi-like labeling of neurons with many different colors provides a novel way to study neuronal connectivity.

Animals↗
PubMed1987

Anatomy and electrophysiology of neurons terminating in the corpora allata of the cockroach Diploptera punctata.

Intracellular recording and dye injection were used to study the structure and electrophysiological properties of individual neurons that project to the corpora allata of the cockroach, Diploptera punctata. Neurons in the pars intercerebralis generate long-duration, tetrodotoxin-sensitive action potentials. Dye injection revealed two cell types. One type extends axons to the contralateral nervi corporis cardiaci I, some of which innervate the corpora allata, and another type extends a major axon down each of the circumoesophageal connectives. Neurons in the pars lateralis also generate long-duration action potentials. These neurons extend axons to the ipsilateral nervi corporis cardiaci II, which continue on to terminate in the corpora cardiaca and the corpora allata. Small groups of all the above neuronal types are dye and electrically coupled. Penetration and dye injection into nerve terminals in the corpora allata and corpora cardiaca confirmed the innervation of the corpora allata by neurons located in the pars intercerebralis and pars lateralis and revealed a third class of neurons that have terminals in the corpora allata: intrinsic neurons of the corpora cardiaca.

Action Potentials↗
PubMed1998

Genetic analysis of Drosophila larval optic nerve development.

To identify genes necessary for establishing connections in the Drosophila sensory nervous system, we designed a screen for mutations affecting development of the larval visual system. The larval visual system has a simple and stereotypic morphology, can be recognized histologically by a variety of techniques, and is unnecessary for viability. Therefore, it provides an opportunity to identify genes involved in all stages of development of a simple, specific neuronal connection. By direct observation of the larval visual system in mutant embryos, we identified 24 mutations affecting its development; 13 of these are larval visual system-specific. These 13 mutations can be grouped phenotypically into five classes based on their effects on location, path or morphology of the larval visual system nerves and organs. These mutants and phenotypic classifications provide a context for further analysis of neuronal development, pathfinding and target recognition.

Animals↗
PubMed2002

Calcium-binding proteins: intracellular sensors from the calmodulin superfamily.

In all eukaryotic cells, and particularly in neurons, Ca(2+) ions are important second messengers in a variety of cellular signaling pathways. In the retina, Ca(2+) modulation plays a crucial function in the development of the visual system's neuronal connectivity and a regulatory role in the conversion of the light signal received by photoreceptors into an electrical signal transmitted to the brain. Therefore, the study of retinal Ca(2+)-binding proteins, which frequently mediate Ca(2+) signaling, has given rise to the important discovery of two subfamilies of these proteins, neuronal Ca(2+)-binding proteins (NCBPs) and calcium-binding proteins (CaBPs), that display similarities to calmodulin (CaM). These and other Ca(2+)-binding proteins are integral components of cellular events controlled by Ca(2+). Some members of these subfamilies also play a vital role in signal transduction outside of the retina. The expansion of the CaM-like protein family reveals diversification among Ca(2+)-binding proteins that evolved on the basis of the classic molecule, CaM. A large number of NCBP and CaBP subfamily members would benefit from their potentially specialized role in Ca(2+)-dependent cellular processes. Pinpointing the role of these proteins will be a challenging task for further research.

Animals↗