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At least 865 records · Page 48Linked to original sources
PubMed1998

Postsynaptic pyramidal target selection by descending layer III pyramidal axons: dual intracellular recordings and biocytin filling in slices of rat neocortex.

Paired intracellular recordings in slices of adult rat neocortex with biocytin filling of synaptically connected neurons were used to investigate the pyramidal targets, in layer V, of layer III pyramidal axons. The time-course and sensitivity of excitatory postsynaptic potentials to current injected at the soma, and locations of close appositions between presynaptic axons and postsynaptic dendrites, indicated that the majority of contributory synapses were located in layer V. Within a "column" of tissue, radius < or = 250 microm, the probability that a randomly selected layer III pyramid innervated a layer V pyramid was 1 in 4 if the target cell was a burst firing pyramid with an apical dendritic tuft in layers II/I. If, however, the potential target was a regular spiking pyramid, the probability of connectivity was only 1 in 40, and none of the 13 anatomically identified postsynaptic layer V targets had a slender apical dendrite terminating in layers IV/III. Morphological reconstructions indicated that layer III pyramids select target layer V cells whose apical dendrites pass within 50-100 microm of the soma of the presynaptic pyramid in layer III and which have overlapping apical dendritic tufts in the superficial layers. The probability that a layer V cell would innervate a layer III pyramid lying within 250 microm of its apical dendrite was much lower (one in 58). Both presynaptic layer III pyramids and their large postsynaptic layer V targets could therefore access similar inputs in layers I/II, while small layer V pyramids could not. One prediction from the present data would be that neither descending layer V inputs to the striatum or thalamus, nor transcallosal connections would be readily activated by longer distance cortico-cortical "feedback" connections that terminated in layers I/II. These could, however, activate corticofugal pathways to the superior colliculus or pons, both directly and via layer III.

Animals↗
PubMed2003

Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

Adult↗
PubMed1999

A changing pattern of brain-derived neurotrophic factor expression correlates with the rearrangement of fibers during cochlear development of rats and mice.

The reorganization of specific neuronal connections is a typical feature of the developing nervous system. It is assumed that the refinement of connections in sensory systems requires spontaneous activity before the onset of cochlear function and selective sensory experience during the ensuing period. The mechanism of refinement through sensory experience is currently postulated as being based on the selective reinforcement of active projections by neurotrophins. We studied a presumed role of neurotrophins for rearrangement of afferent and efferent fibers before the onset of sensory function in the precisely innervated auditory end organ, the cochlea. We observed a spatiotemporal change in the localization of brain-derived neurotrophic factor (BDNF) protein and mRNA, which correlated with the reorganization of fibers. Thus, BDNF decreased in target hair cells during fiber retraction and was subsequently upregulated in neurons, target hair cells, and adjacent supporting cells concomitant with the formation of new synaptic contacts. Analysis of the innervation pattern in BDNF gene-deleted mice by immunohistochemistry and confocal microscopy revealed a failure in the rearrangement of fibers and a BDNF dependency of distinct neuronal projections that reorganize in control animals. Our data suggest that, before the onset of auditory function, a spatiotemporal change in BDNF expression in sensory, epithelial, and neuronal cells may guide the initial steps of refinement of the innervation pattern.

Afferent Pathways↗
PubMed2004

Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection.

The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use increase the synthesis, release, or signaling of neurotrophins. Antidepressant drugs increase the synthesis and signaling of brain-derived neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and necessary for the antidepressant-induced behavioral effects. Furthermore, neurotrophins and other neurotrophic factors play a role in the acute and chronic responses produced by addictive drugs. Moreover, several neuroprotective drugs influence neurotrophin synthesis or signaling, although the significance of these effects is still unclear. These findings reveal a wider role for neurotrophic factors in drug action than has previously been expected, and they suggest that neurotrophin-induced trophic responses in neuronal connectivity and plasticity may be involved in the mechanism of action of several classes of CNS drugs. Improved assay systems are needed for the systematic screening of the effects of putative neuroprotective drugs on the synthesis, release, and signaling of neurotrophic factors, and for the evaluation of the functional role of these factors in the action of novel drug candidates.

Animals↗
PubMed1994

Pattern of trkB protein-like immunoreactivity in vivo and the in vitro effects of brain-derived neurotrophic factor (BDNF) on developing cochlear and vestibular neurons.

The cochleo-vestibular ganglion (CVG) contains the neurons connecting the sensory epithelia of the inner ear to the cochlear and vestibular nuclei in the medulla. Expression of trkB protein-like immunoreactivity was studied in the developing CVG, using both Western blot and immunocytochemistry on tissue sections. Specific immunoreactivity was observed in the CVG from the 12th gestation day (gd) to the first postnatal week, reflecting the presence of high-affinity receptors for brain-derived neurotrophic factor (BDNF), a member of the NGF family of neurotrophins. Whole explants and dissociated cell cultures of cochlear (CG) and vestibular ganglion (VG) from mouse embryos and postnatal specimens were grown in neurotrophin-free medium to assay changes in neurite outgrowth and neuronal survival in response to the addition of physiological concentrations (0-5 ng/ml) of BDNF. Exogenous BDNF (2 ng/ml) promoted neurite outgrowth and neuronal survival in explants of both CG and VG, and the effects were stage-dependent. The onset of the response to BDNF occurred at gd 11-12. The response then reached a maximum between 14 and 18 gd and subsequently decreased, although it remained significantly present during the first postnatal week. BDNF-induced response was no longer observed in the mature cochlear and vestibular ganglion (after 30 postnatal days). The effects of BDNF on neuronal differentiation and survival were dose-dependent, starting at 0.5 ng/ml, with saturation at 2 ng/ml and half-maximal effect occurring between 1 and 1.5 ng/ml. On the basis of our results, we propose that BDNF may be physiologically involved in the control of both neuronal differentiation, and central and peripheral target-dependent neuronal death, in the CVG of embryos and early postnatal mice. BDNF may act alone or in cooperation with other neurotrophins to establish the afferent innervation of the inner ear sensory epithelium.

Animals↗
PubMedDate not supplied

Timing of puberty and EEG coherence during photic stimulation.

Selective elimination of a large proportion of cortical synapses constitutes the last major stage in brain development which is linked to sexual maturation. Various neurodevelopmental theories have proposed an association between schizophrenia and late brain maturational events. Based on epidemiological and psychopharmacological data, Saugstad hypothesised a relationship between timing of puberty, synaptic density and psychosis proneness. Early puberty should result in an earlier end to synaptic pruning, a larger number of surviving connections and an increased risk for affective psychosis. In contrast, in late maturers prolonged synapse elimination should lead to lower synaptic density which constitutes a diathesis for schizophrenia. We used EEG coherence as a neurophysiological measure of cortico-cortical connectivity. Late maturers were expected to show higher coherence, especially for short-distance connections where lower synaptic density should lead to decreased local differentiation. EEG was recorded from 12 bipolar derivations in 19 early and 19 late maturing subjects of both sexes under conditions of rest and photic stimulation at different flicker frequencies. Whereas there were no coherence differences between early and late maturers during rest, both groups differed during flicker stimulation. As hypothesised, late maturers were found to have higher short-distance coherence. Late maturers were also found to have higher intrahemispheric long-distance coherence. These findings were restricted to delta, alpha and beta 2 bands and were more pronounced in males. Our findings are interpreted in terms of a structural difference in neuronal connectivity between extreme early and late maturers.

Adult↗
PubMed2000

Molecular mechanisms associated with long-term consolidation of the NMDA signals.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the mammalian brain plays a central role in synaptic plasticity underlying refinement of neuronal connections during development, or processes like long-term potentiation (LTP), learning and memory. On the other hand, over-activation of glutamate receptors leading to neurodegeneration has been implicated in major areas of brain pathology. Any sustained effect of a transient NMDA receptor activation is likely to involve signaling to the nucleus and coordinated changes in gene expression. Classically, a set of immediate-early genes is induced first; some of them are themselves transcription factors that control expression of other target genes. This review deals with the induction of Fos, Jun and Egr (Krox) transcription factors in response to NMDA or non-NMDA (AMPA/kainate) ionotropic receptor agonists in vivo or in neuronal cultures in vitro. In addition, the mechanism of induction of a model immediate-early gene c-fos in response to Ca2+ influx through activated NMDA receptors or voltage-sensitive calcium channels is discussed. Both modes of calcium entry induce c-fos via activation of multiple signaling pathways that converge on constitutive transcription factors cAMP-response element-binding protein (CREB), serum response factor (SRF) and a ternary complex factor (TCF), such as Elk-1. In contrast to the traditional view of the NMDA receptor as a ligand-gated calcium channel, whose activation leads to calcium influx and activation of Ca2+/calmodulin-dependent kinases, recent evidence highlights involvement of the Ras/ mitogen-activated protein kinase (MAPK) pathway in the NMDA signaling to the nucleus.

Animals↗
PubMed1983

Functional impairment of the primary nociceptive analyser in the course of transganglionic degenerative atrophy.

Latency to the hind-paw lick in the hot-plate test (54 degrees C) is significantly increased (P less than 0.001) in the course of transganglionic degenerative atrophy of central terminals of primary sensory neurons. This was induced by a 30 min perineural application of 10(-8) mol Formyl-Leurosin, which results in the blockade of retrograde axoplasmic transport without Wallerian degeneration of the peripheral nerve. Values of latency return to normal in the course of synaptoneogenetic restoration of neuronal connectivity in the upper dorsal horn. The results are compatible with the working hypothesis that the beneficial effect of chronic pain therapy with Vinca alkaloid iontophoresis might be due to the fact that transganglionic degenerative atrophy is followed by the establishment of a sound, normal wiring in the upper dorsal horn in the course of restorative synaptoneogenesis.

Acid Phosphatase↗
PubMed2005

Mosaic analysis with double markers in mice.

We describe a method termed MADM (mosaic analysis with double markers) in mice that allows simultaneous labeling and gene knockout in clones of somatic cells or isolated single cells in vivo. Two reciprocally chimeric genes, each containing the N terminus of one marker and the C terminus of the other marker interrupted by a loxP-containing intron, are knocked in at identical locations on homologous chromosomes. Functional expression of markers requires Cre-mediated interchromosomal recombination. MADM reveals that interchromosomal recombination can be induced efficiently in vivo in both mitotic and postmitotic cells in all tissues examined. It can be used to create conditional knockouts in small populations of labeled cells, to determine cell lineage, and to trace neuronal connections. To illustrate the utility of MADM, we show that cerebellar granule cell progenitors are fated at an early stage to produce granule cells with axonal projections limited to specific sublayers of the cerebellar cortex.

Animals↗
PubMed2000

Plasticity and primary motor cortex.

One fundamental function of primary motor cortex (MI) is to control voluntary movements. Recent evidence suggests that this role emerges from distributed networks rather than discrete representations and that in adult mammals these networks are capable of modification. Neuronal recordings and activation patterns revealed with neuroimaging methods have shown considerable plasticity of MI representations and cell properties following pathological or traumatic changes and in relation to everyday experience, including motor-skill learning and cognitive motor actions. The intrinsic horizontal neuronal connections in MI are a strong candidate substrate for map reorganization: They interconnect large regions of MI, they show activity-dependent plasticity, and they modify in association with skill learning. These findings suggest that MI cortex is not simply a static motor control structure. It also contains a dynamic substrate that participates in motor learning and possibly in cognitive events as well.

Animals↗
PubMed1985

The vestibuloocular reflex of the adult flatfish. I. Oculomotor organization.

The flatfish species constitute a natural paradigm for investigating adaptive changes in the vertebrate central nervous system. During metamorphosis all species of flatfish experience a 90 degree change in orientation between their vestibular and extraocular coordinate axes. As a result, the optic axes of both eyes maintain their orientation with respect to earth horizontal, but the horizontal semicircular canals become oriented vertically. Since the flatfish propels its body with the same swimming movements when referenced to the body as a normal fish, the horizontal canals are exposed to identical accelerations, but in the flatfish these accelerations occur in a vertical plane. The appropriate compensatory eye movements are simultaneous rotations of both eyes forward or backward (i.e., parallel), in contrast to the symmetric eye movements in upright fish (i.e., one eye moves forward, the other backward). Therefore, changes in the extraocular muscle arrangement and/or the neuronal connectivity are required. This study describes the peripheral and central oculomotor organization in the adult winter flounder, Pseudopleuronectes americanus. At the level of the peripheral oculomotor apparatus, the sizes of the horizontal extraocular muscles (lateral and medial rectus) were considerably smaller than those of the vertical eye muscles, as quantified by fiber counts and area measurements of cross sections of individual muscles. However, the spatial orientations and the kinematic characteristics of all six extraocular muscles were not different from those described in comparable lateral-eyed animals. There were no detectable asymmetries between the left and the right eye. Central oculomotor organization was investigated by extracellular horseradish peroxidase injections into individual eye muscles. Commonly described distributions of extraocular motor neurons in the oculomotor, trochlear, and abducens nuclei were found. These motor neuron pools consisted of two contralateral (superior rectus and superior oblique) and four ipsilateral populations (inferior oblique, inferior rectus, medial rectus, and lateral rectus). The labeled cells formed distinct motor neuron populations, which overlapped little. As expected, the numbers of labeled motoneurons differed in horizontal and vertical eye movers. The numerical difference was especially prominent in comparing the abducens nucleus with one of the vertical recti subdivisions. Nevertheless, there was bilateral symmetry between the motoneurons projecting to the left and right eyes.(ABSTRACT TRUNCATED AT 400 WORDS)

Abducens Nerve↗
PubMed1983

Amyotrophic lateral sclerosis: alterations in neurotransmitter receptors.

Loss of motor neurons is the primary pathological hallmark of amyotrophic lateral sclerosis. Drug and neurotransmitter receptors are neuronal markers and can be indicators of neuronal connectivity. Knowledge of alterations in receptors in amyotrophic lateral sclerosis should contribute to our understanding of normal spinal cord neurotransmitter systems as well as of the pathophysiology of amyotrophic lateral sclerosis. We therefore used a sensitive, light microscopic in vitro labeling receptor autoradiographic technique to map and quantitate muscarinic cholinergic, glycinergic, and benzodiazepine receptors in three levels of spinal cord from six patients with amyotrophic lateral sclerosis and six age- and sex-matched control patients. In control tissues, the receptor distributions were similar in the three levels of spinal cord and also similar to those found in previous studies with animals. In amyotrophic lateral sclerosis, major reductions in receptor densities were noted in Rexed layer IX, the region containing motor neurons. Reductions were noted in other laminae as well, particularly for muscarinic receptors. The changes in muscarinic receptors were caused solely by changes in high-affinity agonist sites. Reductions in glycine and muscarinic receptors were highly correlated with the degree of motor neuron loss found in the amyotrophic lateral sclerosis patients. The findings in this study point out the usefulness of this receptor mapping technique in understanding the changes in neuronal populations that occur in the degenerative neurological diseases.

Adult↗
PubMed2004

A biophysical model of vertebrate olfactory epithelium and bulb exhibiting gap junction dependent odor-evoked spatiotemporal patterns of activity.

This work describes a biophysical model of the initial stages of vertebrate olfactory system containing structures representing the olfactory epithelium and bulb. Its main novelty is the introduction of gap junctions connecting neurons both in the epithelium and bulb, and of biologically detailed dendrodendritic synapses between granule and mitral cells in the bulb. The model was used to simulate the effect of an odor presentation on the neural activity pattern in the epithelium and bulb. During the time for which an odor is presented with a constant concentration, there are spatiotemporal patterns in the epithelium and bulb generated by the couplings due to the gap junctions and/or dendrodendritic synapses. A study varying the strength of the gap junction coupling shows that the spatiotemporal patterns, both in the epithelium and bulb, are dependent of the coupling strength. It is also shown that the olfactory bulb's spatiotemporal pattern depends on the existence of the dendrodendritic connections between mitral and granule cells. If these spatiotemporal patterns really exist in the early processing stages of the olfactory system they may be used for odor coding and the gap junctions and dendrodendritic synapses might have a role on it.

Animals↗
PubMed2000

Deafferentation-induced apoptosis of neurons in thalamic somatosensory nuclei of the newborn rat: critical period and rescue from cell death by peripherally applied neurotrophins.

This study shows that unilateral transection of the infraorbital nerve (ION) in newborn (P0) rats induces apoptosis in the contralateral ventrobasal thalamic (VB) complex, as evidenced by terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) and electron miscroscopy. Double-labelling experiments using retrograde transport of labelled microspheres injected into the barrel cortex, followed by TUNEL staining, show that TUNEL-positive cells are thalamocortical neurons. The number of TUNEL-positive cells had begun to increase by 24 h postlesion, increased further 48 h after nerve section, and decreased to control levels after 120 h. Lesion-induced apoptosis in the VB complex is less pronounced if ION section is performed at P4, and disappears if the lesion is performed at P7. This time course closely matches the critical period of lesion-induced plasticity in the barrel cortex. Nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), applied on the ION stump alone or in combination, are able to partially rescue thalamic neurons from apoptosis. Total cell counts in the VB complex of P7 animals that underwent ION section at P0 confirm the rescuing effect of BDNF and NGF. Blockade of axonal transport in the ION mimics the effect of ION section. These data suggest that survival-promoting signals from the periphery, maybe neurotrophins, are required for the survival of higher-order neurons in the somatosensory system during the period of fine-tuning of neuronal connections. We also propose that anterograde transneuronal degeneration in the neonatal rat trigeminal system may represent a new animal model for studying the pathways of programmed cell death in vivo.

Animals↗
PubMed2000

Brain plasticity and stroke rehabilitation. The Willis lecture.

Neuronal connections and cortical maps are continuously remodeled by our experience. Knowledge of the potential capabilityof the brain to compensate for lesions is a prerequisite for optimal stroke rehabilitation strategies. Experimental focal cortical lesions induce changes in adjacent cortex and in the contralateral hemisphere. Neuroimaging studies in stroke patients indicate altered poststroke activation patterns, which suggest some functional reorganization. To what extent functional imaging data correspond to outcome data needs to be evaluated. Reorganization may be the principle process responsible for recovery of function after stroke, but what are the limits, and to what extent can postischemic intervention facilitate such changes? Postoperative housing of animals in an enriched environment can significantly enhance functional outcome and can also interact with other interventions, including neocortical grafting. What role will neuronal progenitor cells play in future rehabilitation-stimulated in situ or as neural replacement? And what is the future for blocking neural growth inhibitory factors? Better knowledge of postischemic molecular and neurophysiological events, and close interaction between basic and applied research, will hopefully enable us to design rehabilitation strategies based on neurobiological principles in a not-too-distant future.

Age Factors↗
PubMed1989

Localization of the growth-associated phosphoprotein GAP-43 (B-50, F1) in the human cerebral cortex.

The growth-associated phosphoprotein GAP-43 is a component of the presynaptic membrane that has been linked to the development and functional modulation of neuronal connections. A monospecific antibody raised against rat GAP-43 was used here to study the distribution of the protein in cortical and subcortical areas of the human brain. On Western blots, the antibody recognized a synaptosomal plasma membrane protein that had an apparent molecular weight and isoelectric point similar to GAP-43 of other species. In brain tissue reacted with the antibody, the heaviest immunoreactivity was found in associative areas of the neocortex, particularly within layers 1 and 6, in the molecular layer of the dentate gyrus, the caudate putamen, and the amygdala. In contrast, primary sensory or motor regions of the cortex, portions of dorsal thalamus, and cerebellum showed only light staining. Staining was generally confined to the neuropil, which showed punctate labeling, whereas most neuronal somata and fiber bundles were unreactive. The pronounced variations in GAP-43 immunostaining among various areas of the human brain may reflect different potentials for functional and/or structural remodeling.

Cerebral Cortex↗
PubMedDate not supplied

Parvalbumin immunoreactivity in the lateral geniculate nucleus of rhesus monkeys raised under monocular and binocular deprivation conditions.

Newborn rhesus monkeys were raised under monocular (lid suture, aphakia, aphakia corrected optically with contact lenses, and occlusion with opaque occluder lenses) and under binocular visual deprivation conditions (aphakia combined with occlusion or optical undercorrection of the fellow eye). Routine immunohistochemical methods with an antibody to the calcium-binding protein paravalbumin (PV) were used to examine the distribution of PV+ neurons and PV+ processes in the LGN of these monkeys. Under all rearing conditions, we found no obvious difference in PV density in neurons in any lamina, although in all monocularly deprived and in two of the three binocularly deprived monkeys neurons connected to the deprived eye were of reduced size. Furthermore, PV-immunoreactive processes in the neuropil of deprived laminae were as numerous and of the same morphologies as those in nondeprived laminae or as in normal controls. Thus, in the LGN of rhesus monkeys, the calcium-binding protein paravalbumin is resistant to monocular as well as binocular visual deprivation during the postnatal maturation process of the visual system.

Animals↗
PubMed2002

A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons.

The neural cell adhesion molecule (NCAM) plays a key role in morphogenesis of the nervous system and in remodeling of neuronal connections accompanying regenerative and cognitive processes. Recently, a new synthetic ligand of NCAM, the C3-peptide, which binds to the NCAM IgI module, has been identified by means of combinatorial chemistry (Rønn, L. C. B, Olsen, M., Ostergaard, S., Kiselyov, V., Berezin, V., Mortensen, M. T., Lerche, M. H., Jensen, P. H., Soroka, V., Saffell, J. L., Doherty, P., Poulsen, F. M., Bock, E., Holm, A., and Saffells, J. L. (1999) Nat. Biotechnol. 17, 1000-1005). In vitro, the dendrimeric form of C3, termed C3d, disrupts NCAM-mediated cell adhesion, induces neurite outgrowth, and triggers intracellular signaling cascades similar to those activated by homophilic NCAM binding. The peptide may therefore be expected to regulate regeneration and synaptic plasticity. Here we demonstrate that in primary cultures of hippocampal neurons: 1) C3d induces a sustained neuritogenic response, the neuritogenic activity of the compound being dependent on the dose, starting time, and duration of peptide application; 2) the peptide triggers the neuritogenic response by forming an adhesive substratum necessary for NCAM-mediated neurite formation and elongation; 3) C3d promotes synapse formation; and 4) C3d modulates the presynaptic function, causing a transient increase of the function at low (2 and 5 microm) doses and a reduction when applied at a higher concentration (10 microm). The effect of the peptide is dependent on the activation of the fibroblast growth factor receptor. We suggest that C3d may constitute a useful lead for the development of compounds for treatment of various neurodegenerative disorders.

Animals↗