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PubMed2005

Timed and targeted differential regulation of nitric oxide synthase (NOS) and anti-NOS genes by reward conditioning leading to long-term memory formation.

In a number of neuronal models of learning, signaling by the neurotransmitter nitric oxide (NO), synthesized by the enzyme neuronal NO synthase (nNOS), is essential for the formation of long-term memory (LTM). Using the molluscan model system Lymnaea, we investigate here whether LTM formation is associated with specific changes in the activity of members of the NOS gene family: Lym-nNOS1, Lym-nNOS2, and the antisense RNA-producing pseudogene (anti-NOS). We show that expression of the Lym-nNOS1 gene is transiently upregulated in cerebral ganglia after conditioning. The activation of the gene is precisely timed and occurs at the end of a critical period during which NO is required for memory consolidation. Moreover, we demonstrate that this induction of the Lym-nNOS1 gene is targeted to an identified modulatory neuron called the cerebral giant cell (CGC). This neuron gates the conditioned feeding response and is an essential part of the neural network involved in LTM formation. We also show that the expression of the anti-NOS gene, which functions as a negative regulator of nNOS expression, is downregulated in the CGC by training at 4 h after conditioning, during the critical period of NO requirement. This appears to be the first report of the timed and targeted differential regulation of the activity of a group of related genes involved in the production of a neurotransmitter that is necessary for learning, measured in an identified neuron of known function. We also provide the first example of the behavioral regulation of a pseudogene.

Animals↗
PubMed2005

A molecular model for axon guidance based on cross talk between rho GTPases.

To systematically understand the molecular events that underlie biological phenomena, we must develop methods to integrate an enormous amount of genomic and proteomic data. The integration of molecular data should go beyond the construction of biochemical cascades among molecules to include tying the biochemical phenomena to physical events. For the behavior and guidance of growth cones, it remains largely unclear how biochemical events in the cytoplasm are linked to the morphological changes of the growth cone. We take a computational approach to simulate the biochemical signaling cascade involving members of the Rho family of GTPases and examine their potential roles in growth-cone motility and axon guidance. Based on the interactions between Cdc42, Rac, and RhoA, we show that the activation of a Cdc42-specific GEF resulted in switching responses between oscillatory and convergent activities for all three GTPases. We propose that the switching responses of these GTPases are the molecular basis for the decision mechanism that determines the direction of the growth-cone expansion, providing a spatiotemporal integration mechanism that allows the growth cone to detect small gradients of external guidance cues. These results suggest a potential role for the cross talk between Rho GTPases in governing growth-cone movement and axon guidance and underscore the link between chemodynamic reactions and cellular behaviors.

Animals↗
PubMed2004

The repair of complex neuronal circuitry by transplanted and endogenous precursors.

During the past three decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of novel approaches has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain, and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis, and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops, as well as to approaches by which transplanted or endogenous precursors might be used to repair the adult brain. For example, recruitment of new neurons can be induced in a region-specific, layer-specific, and neuronal type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow for the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that might not require transplantation of exogenous cells.

Animals↗
PubMed1995

Accumulation of nerve growth factor in cerebrospinal fluid and biological activity following neurosurgery.

Perioperative nerve growth factor (NGF) levels in cerebrospinal fluid (CSF) of patients with acoustic neurinoma (14 cases), tentorial meningioma (1 case), or subarachnoid hemorrhage (1 case) were examined. Preoperative NGF levels in CSF were below the level of detection in all patients. However, NGF was found to accumulate transiently in CSF following neurosurgery. Pre- and postoperative CSF obtained from a patient with acoustic neurinoma enhanced the proliferation of astrocytes in neuronal cell cultures derived from embryonic rat cortex grown in serum-free defined medium, and increased choline acetyltransferase activity of cholinergic neurons derived from embryonic rat septal area and brainstem. The effect of postoperative CSF on septal and brainstem neurons was more potent than that of preoperative CSF. These results indicate that NGF and non-NGF-type neurotrophic activities accumulate in the CSF following neurosurgery. These neurotrophic activities are probably important in the regeneration of damaged neural networks in the central nervous system.

Adult↗
PubMed1977

The ontogeny of swimming behavior in the scyphozoan, Aurelia aurita. I. Electrophysiological analysis.

1. Electrical correlates of behavioral activity were observed in the lip and tentacles of the polyp, but none were detected during column contraction. The tentacles are the most electrically active tissue, and the potentials are conducted along the length of the tentacle, but conduction to other parts of the animal were not observed. 2. Although the tentacles of the polyp and the rhopalia of the medusa are probably homologous, the development of pacemaker activity during strobilation is not a smooth transition from tentacle contraction potentials (TCPs) to marginal ganglion potentials (MGPs). This result indicates that each pacemaker activity develops de novo. 3. Two types of behavior were observed in the polyp: local responses, and coordinated activity which involved integrated responses in several body parts. The coordinated responses indicate that neurological coordination can take place in the polyp. Furthermore, feeding and spasm in the ephyra are similar to feeding and the protective response in the polyp. This similarity suggests that both coordinated responses in the polyp are coordinated by interneural facilitation in the diffuse nerve net (DNN) as in the ephyra. 4. Swimming in the ephyra is a medusoid behavior but feeding and spasm are coordinated by the DNN and are polypoid responses. Therefore, the ephyra is a mixture of polypoid and medusoid behaviors. As the ephyra matures into an adult medusa both polypoid responses are lost, but the DNN remains to modulate pacemaker output and control marginal tentacle contractions. As development proceeds from polyp, to ephyra, to medusa, each subsequent stage acquires some new behavior while retaining some aspect from the previous stage.

Animals↗
PubMed1980

Effect of cold ischaemic arrest and subsequent coronary reperfusion on the intrinsic adrenergic innervation and neural noradrenaline of the atrial myocardium during aortic valve replacement.

The effect of cold ischaemic arrest (aortic cross-clamping for 50-70 min during general hypothermia of +30 degrees C, associated with local cardiac cooling with +4 degrees C saline solution) and subsequent coronary reperfusion (20-30 min) on the intrinsic adrenergic innervation of the right atrial myocardium, was studied in 10 patients in the course of prosthetic aortic valve replacement using the glyoxylic acid-induced fluorescence histochemical method. No clear changes were observed: (a) the morphological integrity of the intrinsic adrenergic nerve net remained intact, (b) no obvious depletion occurred in the neural noradrenaline level, (c) the procedure did not affect the "droplet fibres" (i.e. huge axonal accumulations of noradrenaline). Thus, the common need for catecholamine support during and after weaning off from cardiopulmonary bypass does not seem to be explained by damage to the adrenergic axons or depletion of the adrenergic neurotransmitter noradrenaline.

Aortic Valve↗
PubMed2002

[A study of human enteric nervous system development in the middle stage of embryogenesis]

OBJECTIVE: To investigate the development of the enteric nervous system(ENS) in the middle stage(the 4th approximate, equals 6th months) of human embryogenesis. METHODS: A histologic evaluation of the clonic enteric nervous system was done using NADPHd histochemistry, PAP immunohistochemistry, with anti-PGP 9.5 and anti-S-100 protein. RESULTS: During this stage of embryology three things were noted. (1)The nerves in the myenteric layer increased markedly. This was shown by the PGP 9.5 immunoreactive nerves spreading out and the S-100 protein immunoreactive nerves forming a "bamboo basket"pattern. (2)The whole myenteric colon showed nitrigeric nerves paralleling the growth of the myofibers in the circular muscle layer. Nitrigeric perikara were rarely found in the extrinsic submucosal layer.(3) In the whole-mounted preparations reactive nerves formed the complex nerve net in the myenteric layer. CONCLUSION: The middle stage of embryogensis is very important to the development of the colon ENS.

Journal Article↗
PubMed1999

Interactions between limbic, thalamo-striatal-cortical, and central autonomic pathways during epileptic seizure progression.

We used immunocytochemistry to determine the regional and temporal distribution of Fos protein expression in awake and unrestrained rats after a unilateral stereotaxic microinjection of a cholinergic agonist, carbachol, in the thalamic ventroposterolateral and reticular nuclei, previously shown to cause limbic and generalized convulsive seizures. The microinjection of carbachol elicits behavioral alterations including immobilization, staring, facial and jaw clonus, rearing, and falling, followed by recurrent generalized convulsive seizures, and a pattern of c-fos expression throughout the brain. In addition to the hypothalamic paraventricular and supraoptic nuclei, the initial induction of c-fos expression was observed as early as 15 minutes after the carbachol microinjection, in the piriform and entorhinal cortices, the thalamic paraventricular, the supramammilary, the lateral parabrachial nuclei, and the central gray. From 30 minutes to 2 hours, corresponding to the occurrence of motor expression of limbic and recurrent generalized convulsive seizures, Fos immunoreactivity was seen in a number of functionally related brain regions including the hippocampus, the amygdala, and the anterior thalamic nucleus (limbic system); the thalamus, the basal ganglia, and the cortex (thalamo-striatal-cortical system); and the hypothalamus, the central nucleus of the amygdala, the pons, and the medulla (central autonomic system). On the basis of the present results showing regional and temporal c-fos expression and well known neuroanatomical connections, we have constructed a neural network relating the limbic, thalamo-striatal-cortical, and central autonomic systems. This analysis provides, for the first time, neuronal circuits and pathways relating epilepsy-elicited behavioral expression of convulsive seizures and adaptive homeostatic responses and could serve as a basis for studying central autonomic regulation during epileptic disorders.

Acetylcholine↗
PubMed2000

[Developmental disorders and their responsible genes; the genes involved in neuronal positioning].

The mammalian neocortex is a highly ordered structure with different classes of neurons aligning in an organized radial array of six cellular layers ranging from the pial surface to the white matter. Positioning of a particular neuron at the particular cortical layer is an essential step in forming an elaborate neuronal network in the neocortex. It is important to study the molecular mechanism how neuroblasts produced reach to a particular position in the laminated structure of the brain. We took advantage of reeler mutant mouse in which the position of the neurons is abnormal. We obtained an antibody against reeler gene product which we named CR-50, by immunizing wild type embryonic brains to reeler mice. CR50 blocked neuronal positioning in the cerebellum, hippocampus and cerebral cortex. CR-50 reacted with the product of the reelin gene, which was cloned as the responsible gene for the reeler mutant. Cajal-Retzius neurons secrete CR-50 antigen/Reelin and play an important role for neuroblasts to settle to their proper position in the brain. The mutant mouse missing "disabled 1", called yotari mouse, shows similar phenotypes in both morphology and behavior to those of reeler. The information of CR-50 antigen/Reelin is considered to be transmitted inside the neuroblasts to the "disabled 1", which is an adaptor protein to Src, Fyn, Abl tyrosine kinase.

Animals↗
PubMed2000

Behavioral recovery after transplantation into a rat model of Huntington's disease: dependence on anatomical connectivity and extensive postoperative training.

Rats were trained to perform a conditioned stimulus-response task known to be sensitive to striatal damage, after which they received unilateral excitotoxic striatal lesions. The subsequent implantation of graft tissue into the lesioned striatum was either immediate (9 days) or substantially delayed (70 days). When retested 14 weeks later, all graft and lesion rats were equally impaired initially and biased their responding toward the ipsilateral side. Graft-associated recovery was evident with repeated postoperative testing, but only in rats that had received transplants 9 days postlesion. It is suggested that this training-dependent, graft-associated recovery is mediated specifically by the restored host-graft connections.

Animals↗
PubMed2000

Neuroglycan C, a neural tissue-specific transmembrane chondroitin sulfate proteoglycan, in retinal neural network formation.

PURPOSE: Neuroglycan C (NGC) is a transmembrane chondroitin sulfate proteoglycan present exclusively in central nervous system tissues. In the current study the expression pattern and characterization of NGC during the development of the retina were investigated. METHODS: Expressional changes of NGC mRNAs during rat retinal development were examined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). The localization and characterization of NGC core proteins were investigated by immunoblot analysis and immunohistochemistry using an anti-NGC antibody. RESULTS: Immunohistochemical analysis revealed that NGC was highly expressed in the nerve fiber layer (NFL) and inner plexiform layer (IPL) in rat postnatal developing retina. At embryonal stages, NGC immunoreactivities were faint. In contrast, at postnatal developmental stages (approximately postnatal day [P]7), intense immunoreactivity was observed in the NFL and IPL, where active dendrite branching was observed, and conventional synapses began to be formed. As retinal layer differentiation proceeded (from P14 to P42), immunoreactivities in the inner retinal layers gradually became fainter. Immunoblot and semiquantitative RT-PCR analyses showed that the peak level of NGC expression occurred on approximately P7 and P14. Glycosylation of the NGC core protein changed as the retinal layers matured. In immunoelectron microscopic analysis, NGC immunoreactivity was located on the axonal membranes of neuronal cells in the postnatal retina, whereas immunoreactivity was reduced on membranes at the adult stage. In retinal ganglion cells in vitro, NGC was highly localized in their spiny budding neurites. CONCLUSIONS: The results show spatiotemporal expression patterns of NGC, and suggest that it plays a role in the formation of neural networks in retinal development.

Animals↗
PubMed2000

Pattern formation in the cerebellar cortex.

The cerebellar cortex is subdivided rostrocaudally and mediolaterally into a reproducible array of zones and stripes. This makes the cerebellum a valuable model for studying pattern formation in the vertebrate central nervous system. The structure of the adult mouse cerebellar cortex and the series of embryological events that generate the topography are reviewed.

Adult↗
PubMed2000

[Morphogenesis and formation of a pattern in hydra. I. Distribution of morphogenetic potential].

True multicellularity is characterized by complex interactions between individual cells of the organism as well as by organization of cell masses into spatially and functionally determined structures promoting the exchange of information. Morphogenetic processes--genetically programmed generation of structures--always correlate with determination and maintenance of a pattern, i.e. a system of spatial relationships between them. Hydroid polyps provide a wide variety of approaches to study morphogenesis and patterning. Being comparatively simply organized, these animals have nevertheless certain developed mechanisms underlaying such processes as regeneration of missing structures, recovery of normal pattern after dissociation of polyps into single cells, tissue transdifferentiation in non-complementary chimaeras. An important feature of regeneration of hydroid polyps is its independence of the nerve net elements; the basis for regeneration is rather stored in epithelial cells and in their interactions. Phenomenological data, provided in the XVIII-XX centuries, allowed to propose several theoretical models of pattern regulation in hydra. The main goal of this paper is to review contemporary models of morphogenesis and patterning in the hydroid polyps.

Animals↗
PubMed2001

On-line measurement of human CNS re-organization.

Based on measurements of relative phase and frequency coordination of time-space distributed firing of neurons in the human nervous system, methods have been developed with which it is possible to functionally re-organize the lesioned or not optimally functioning human central nervous system (CNS) and to measure on-line the organization (the coordination dynamics) of the CNS non-invasively. By measuring the present coordination dynamics at different times with ongoing coordination dynamic therapy when exercising on a special coordination dynamic therapy device, the progress in re-organization of the lesioned CNS can be quantified. The coordination dynamic recording method is derived from measurements of natural firing patterns of single neurons in the human CNS. The method is explained with load changes in the healthy CNS and with essential improvement in CNS organization following coordination dynamic therapy in traumatic brain lesion, spinal cord lesion, stroke, cerebral palsy, and myelomeningocele. Evaluations of CNS re-organization are discussed with respect to usefullness and ethics.

Adult↗
PubMed2001

Synchronous oscillatory activity in immature cortical network is driven by GABAergic preplate neurons.

Neurons dissociated from embryonic cerebral rat cortex form a differentiated network of synaptic connections and develop synchronous oscillatory network activity with the beginning of the second week in culture. During an initial phase lasting 3-4 d, synchronous calcium transients can be blocked completely by either CNQX or bicuculline, showing that both glutamatergic and GABAergic neurons are required for the generation of this form of activity. By manipulating dissociation and growth conditions, cultures containing different populations of GABAergic neurons were obtained. These cultures revealed that a distinct population of large GABAergic neurons is a key element in the generation of synchronous oscillatory network activity. A minimal number of two large GABAergic neurons per square millimeter are required for the occurrence of synchronous activity. Changes in the density of all other types of GABAergic or non-GABAergic neurons has no influence on the synchronous activity. Electron microscopic analysis shows that the large GABAergic neurons form an interconnected network. Exceptionally high somatodendritic innervation and extended axonal arborization enable these neurons to collect electric network activity and to distribute it effectively throughout the neuronal network. Additional experiments indicated that most neurons developing in culture to large GABAergic neurons are derived from the primordial plexiform layer and reside in the subplate at the time of birth. We suggest that they function as an integrating element that synchronizes neuronal activity during early cortical development by collecting incoming extrinsic and intrinsic signals and distributing them effectively throughout the developing cortical plate.

Animals↗