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PubMed1998

Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord.

The development of nicotinic acetylcholine receptors (nAChRs) in brains from human fetuses of 4-12 weeks gestational age was studied. The expression of nAChR subunit mRNAs was analyzed using reverse transcriptase-polymerase chain reaction. Expression of alpha 3, alpha 4, alpha 5, alpha 7, beta 2, beta 3 and beta 4 mRNA were all detected in the prenatal spinal cord, medulla oblongata, pons, cerebellum, mesencephalon, subcortical forebrain and cortex during first trimester development. Relative quantification of mRNA showed that the highest levels for alpha 3, alpha 4 and alpha 7 were expressed in the spinal cord, alpha 5 was most abundant in the cortex and beta 3 was highest in the cerebellum. beta 4 seemed to be equally distributed in all regions whereas beta 2 was high in the cortex and cerebellum. A comparison of expression of nAChR subunit mRNAs in the cortex and cerebellum of prenatal and aged (54-81 years) brain showed that mRNA levels for alpha 4, alpha 5, alpha 7, beta 2 and beta 4 were significantly higher in the prenatal cortex and cerebellum than in aged brain, whereas the level of alpha 3 transcript was similar, and beta 3 significantly higher in aged cortex. Specific binding of [3H]-epibatidine to prenatal brain membranes was detected as early as 4-5 weeks of gestation in the spinal cord, medulla oblongata, pons and subcortical forebrain. A positive correlation between gestational age and [3H]-epibatidine and [3H]-cytisine binding was found in several brain regions. The highest specific binding of [3H]-epibatidine and [3H]-cytisine was detected in the spinal cord, pons and medulla oblongata and the lowest in the cortex. Saturation analysis of [3H]-cytisine binding in both prenatal and aged brain were best fit by a model for a single site, whereas binding data for [3H]-epibatidine revealed two classes of binding sites. The early presence of nAChR proteins and gene transcripts shown in the present study suggests an important role for nAChRs in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development.

Aged↗
PubMed1999

Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study.

Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.

Animals↗
PubMed2001

New molecules for hippocampal development.

Pathfinding by developing axons towards their proper targets is an essential step in establishing appropriate neuronal connections. Recent work involving cell culture assays and molecular biology strategies, including knockout animals, strongly indicates that a complex network of guidance signals regulates the formation of hippocampal connections during development. Outgrowing axons are routed towards the hippocampal formation by specific expression of long-range cues, which include secreted class 3 semaphorins, netrin 1 and Slit proteins. Local membrane- or substrate-anchored molecules, such as ligands of the ephrin A subclass, provide layer-specific positional information. Understanding the molecular mechanisms that underlie axonal guidance during hippocampal development might be of importance in making therapeutic use of sprouting fibers, which are produced following the loss of afferents in CNS lesion.

Animals↗
PubMed2002

Ephrin-As as receptors in topographic projections.

The Eph family of receptor tyrosine kinases and their 'ligands', the ephrins, have been implicated in a large number of developmental processes, such as boundary formation, cell migration, axon guidance and vasculogenesis. A characteristic of the EphB subclass is that both EphBs and transmembrane-anchored ephrin-Bs function as receptors and as ligands, a phenomenon commonly described as 'bi-directional signalling'. Here we review recent data indicating that EphA receptors and glycosylphosphatidylinositol (GPI)-anchored ephrin-As can also mediate bi-directional signalling. Moreover, characterization of the expression of ephrin-As on axons of the retinotectal and vomeronasal projections suggests that the EphA subfamily is involved in both repulsive and attractive guidance mechanisms during establishment of neuronal connections.

Animals↗
PubMed1997

Genetic analysis of axon guidance and mapping in the zebrafish.

Systematic genetic screens have been powerful tools in identifying genes responsible for axon guidance in fruitflies and nematodes. This approach has now been extended to the study of axon guidance and the formation of topographic neuronal connections in the vertebrate brain. A systematic genetic screen was used to identify genes responsible for precise axon pathfinding and targeting in the retinotectal system of the zebrafish (Danio rerio). Over 30 genes were found that affect either: (1) retinal axon pathfinding to the contralateral tectal lobe; or (2) the topographic connection between the eye and the tectum. The zebrafish retinotectal mutants represent a new resource for the study of axon guidance in the vertebrate brain.

Animals↗
PubMed1997

Organotypic slice cultures: a technique has come of age.

Slices of CNS tissue prepared from young rodents can be maintained in culture for many weeks to months. The basic requirements are simple: a stable substratum, culture medium, sufficient oxygenation and incubation at a temperature of about 36 degrees C. Under these conditions, nerve cells continue to differentiate and to develop a tissue organization that closely resembles that observed in situ. Several alternative culturing methods have been developed recently. Slices maintained in stationary culture with the interface method are ideally suited for questions requiring a three-dimensional structure, whereas slices cultured in roller-tubes remain the method of choice for experiments that require optimal optical conditions. In this report, three typical experiments are discussed that illustrate the potential of the slice-culture technique. The first example indicates that, due to their high neuronal connectivity, slice cultures provide a very useful tool for studying the properties of synaptic transmission between monosynaptically coupled cell pairs. The other two studies show how long-term application of substances to slice cultures can be used to examine the consequences of epileptic discharges in vitro, as well as the effects of slowly acting clostridial neurotoxins on synaptic transmission.

Animals↗
PubMed2002

Limitations of the sensitive period for sexual imprinting: neuroanatomical and behavioral experiments in the zebra finch (Taeniopygia guttata).

In the course of developmental sensitive periods, an animal receives input from the environment which shapes its behaviour and neuronal connectivity. While normally restricted to early development, it has been shown frequently that an extension of the sensitive period to later ages is possible by sensory deprivation or inadequate stimulation. This raises the question whether sensitive periods can be shifted to any age, or whether a time window exists within which sensitive period shifts are possible. We show here for sexual imprinting that such a time window exists, and we also show that the spine density changes during development in brain areas involved in imprinting predict the limits for sensitive period shifts. Based on these results, we speculate about the mechanisms which may underlay the regulation of spine density and thus the imprinting process.

Aging↗
PubMed1991

Effects of monocular deprivation on the visual fields of squirrel monkeys.

Five squirrel monkeys were monocularly deprived at birth for 3 years. Visual field testing for the deprived eye revealed no responses to visual stimuli at any position, including the monocular segment. These results are similar to those obtained in macaque monkeys after long-term neonatal monocular deprivation and indicate that lack of patterned visual input to an eye during development in primates can produce functional blindness throughout the visual field. Because the monocular segment of the visual field was not spared, binocular competition cannot be the only mechanism underlying this loss. Instead, lack of patterned visual input probably causes improper neuronal connections during development in all segments of the visual cortex resulting in complete loss of form vision.

Animals↗
PubMed1998

Highest trkB mRNA expression in the entorhinal cortex among hippocampal subregions in the adult rat: contrasting pattern with BDNF mRNA expression.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, regulate synaptic functions in the hippocampus of the adult rodent. In previous studies, in situ hybridization methods have been used to evaluate regional differences in BDNF and trkB mRNA expression levels in hippocampal subregions. However, these studies have failed to reach consensus regarding the regional differences in the mRNA expression levels. In the present study, we quantitated mRNA expression levels using two different methods, ribonuclease protection assays and a quantitative reverse-transcription polymerase chain reaction technique, in four hippocampal subregions: the entorhinal cortex, dentate gyrus (DG), CA3 and CA1. These two methods yielded the same results. We found that BDNF and trkB mRNA expression levels did not covary in the four subregions. BDNF and full length trkB (trkB FL) mRNA in the entorhinal cortex and the DG show contrasting expression patterns. The expression level of BDNF mRNA was highest in the DG among the hippocampal subregions and low in the entorhinal cortex and the CA1, whereas the trkB FL mRNA expression level was highest in the entorhinal cortex, low in the DG and lowest in the CA3. These results suggest regional differences in BDNF/TrkB signaling for maintenance and modifiability of neuronal connections in the hippocampal formation.

Animals↗
PubMed2000

Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder.

Functional neuroimaging studies have advanced the understanding of the brain mediation of OCD by orbitofrontal-subcortical circuitry, but much is still unknown. Phenotypic heterogeneity could account for many of the inconsistencies among previous neuroimaging studies of OCD. Current studies are seeking to find the neurobiological basis of OCD symptom subtypes and predictors of treatment response. Future studies combining genetics and basic neuroanatomic research with neuroimaging may clarify the cause and pathophysiology of OCD. Although many lines of evidence point to dysfunction of orbitofrontal-subcortical circuitry in patients with OCD, many questions remain unanswered. Some have suggested that orbitofrontal-subcortical hyperactivity in OCD may be the result of abnormal neuroanatomic development of these structures or a failure of pruning of neuronal connections between them, as occurs in normal development, but no postmortem neuroanatomic studies of OCD exist to delineate its pathophysiology. Interventions that directly alter the indirect-direct pathway balance within frontal-subcortical circuits will allow for direct testing of the pathophysiologic hypotheses presented here. The roles of various neurochemical systems in OCD are similarly unclear. Although an abundance of indirect evidence suggests serotonergic abnormalities in patients with OCD, no direct evidence demonstrates what those abnormalities are or whether they are primary or secondary phenomena in patients with OCD. Ongoing studies of 5-HT synthesis in the brains of patients with OCD may shed light on this question.

Brain↗
PubMed2000

Neural mechanism of the antisecretory effect of peptide YY in the rat colon in vivo.

The purpose of this work was to determine the mechanism of the antisecretory effect of peptide YY in the rat colon and whether this effect is physiological. In this prospect, doses of exogenous peptide YY producing physiological and supraphysiological plasma levels were intravenously infused in rats provided with colonic and jejunal ligated loops in vivo, under secretory stimulation by vasoactive intestinal peptide. Peptide YY decreased the secretory effect of VIP in a dose-related fashion. The effect of peptide YY was blocked or strongly decreased by tetrodotoxin, hexamethonium, idazoxan, haloperidol, and the sigma antagonist BMY 14, 802 in both the colon and jejunum. We conclude that peptide YY decreases water and electrolyte secretion in the colonic mucosa by a complex neural mechanism involving at least two neurons connected through a nicotinic synapse, alpha-2 adrenoceptors and sigma receptors, and that this effect can occur with physiological doses of peptide YY.

Adrenergic alpha-Antagonists↗
PubMed1998

The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling.

The increased expression and/or abnormal processing of the amyloid precursor protein (APP) is associated with the formation of amyloid plaques and cerebrovascular amyloid deposits, which are one of the major morphological hallmarks of Alzheimer's disease (AD). Among the processes regulating APP metabolism, the proteolytic cleavage of APP into amyloidogenic or nonamyloidogenic fragments is of special interest. The cleavage of the APP by the alpha-secretase within the beta-amyloid sequence generates nonamyloidogenic C-terminal APP fragments and soluble APPs alpha, which has neurotrophic and neuroprotective activities. Proteolytic processing of APP by beta-secretase, on the other hand, exposes the N-terminus of beta-amyloid, which is liberated after gamma-secretase cleavage at the variable amyloid C-terminus. The resulting 39-43 amino acid beta-amyloid may be neurotoxic and disrupt neuronal connectivity after its accumulation in senile plaques. In this review, we discuss evidence derived from in vitro experiments, suggesting that the stimulation of protein kinase C (PKC)-coupled M1/M3 muscarinic acetylcholine receptors increases the nonamyloidogenic, secretory pathway of APP processing. It has also been shown in animal models that under conditions of reduced M1/M3 muscarinic acetylcholine receptor stimulation the secretory pathway of APP processing is inhibited and that constitutive upregulation of M1/M3-associated PKC increases APP secretion. Thus, the cortical cholinergic hypoactivity characteristic of AD may inhibit the nonamyloidogenic APP processing pathway and lead to increased beta-amyloid generation. It has been shown in vitro that nerve growth factor (NGF)-associated signaling also influences the expression and catabolism of APP. Recent experiments with NGF-responsive cells revealed a specific role for the high-affinity NGF receptor, TrkA, in the increases in secretory APP processing and a role for the low-affinity neurotrophin receptor, p75NTR, in the transcriptional regulation of APP. Therefore, treatments with NGF could ameliorate cortical cholinergic dysfunction in AD. These findings may influence the design of therapeutic strategies aimed at stimulating cholinergic function and at increasing nonamyloidogenic APP processing without elevating APP expression.

Acetylcholine↗
PubMedDate not supplied

Some thoughts about neural coding and spike trains.

This communication introduces the topic. Foundations: Core concepts: Codings are relations summarized by rules or 'codes'. Special codings are 'neural', 'natural' (in everyday life), 'experimental' (in laboratories), 'conditional' (to partner restrictions). etc. Partial aspects are mechanisms, what partners say about each other, etc. Critical experimental issues: Trains are evaluated by when spikes occur: i.e. as point processes and timings. Trains and point process representations become synonyms. Any code must: (i) be a 'number (rate) code' and an 'interval code'; and (ii) include 'referent, train' covariations involving steady states with overall averages and fluctuations with patterns (dispersions, sequences). Seminal findings. Early data proved trains participated in codings; this is accepted unanimously. Inevitably, though accepted less readily, codings included rates, intervals, averages and patterns. Literature highlights. (1) Confirmed the seminal finding (2.2.) over vast domains; (2) Demonstrated both general and synaptic codings (referents, respectively, sensory, states, etc. and trains in directly connected neurons); (3) Revealed overlap between general and synaptic coding features. Overlap allows train participation in network dynamics; (4) Introduced natural formal contexts. (Point Process Mathematics, Communication. Information and Dynamical Systems Theories); (5) Includes confused opinions: (i) Opposition between rates and intervals; (ii) claims that averages are meaningful but patterns irrelevant. Both, overlooking foundations and evidence, are untenable.

Action Potentials↗
PubMed2003

Hippocampal synaptophysin immunoreactivity is reduced during natural hypothermia in ground squirrels.

Natural hypothermia during hibernation results in physiological and behavioral deficits. These changes may be traced at the level of hippocampal signal transduction. We investigated synaptophysin immunoreactivity (SYN-ir) in the hippocampus after short and long periods of hypothermia and short and long periods of euthermy in hibernating ground squirrels. SYN-ir in the stratum lucidum of the hippocampus was transiently reduced during natural hypothermia. Natural hypothermia thus reduces synaptic efficacy. This may play a role in the reduced neuronal connectivity of CA3 pyramidal cell dendrites observed in hibernating ground squirrels.

Animals↗
PubMed1996

Abnormal, ubiquitinated cortical neurites in patients with diffuse Lewy body disease.

Although it is known that the severity of dementia in patients with diffuse Lewy body disease is related to cortical Lewy body density, the morphological substrate of dementia in these patients is poorly understood. Vibratome sections processed free-floating for ubiquitin immunohistochemistry in three patients with the common form and one patient with the pure form has shown the presence of large numbers of abnormal, ubiquitinated neurites in the cerebral cortex, mainly cingulate cortex, entorhinal cortex and temporal lobe, and hippocampal complex, regions in which, precisely, Lewy bodies are most abundant. Abnormal neurites are a consistent change which results in abnormal neuronal connectivity. Abnormal cortical neurites, rather than cortical Lewy bodies, may play a significant role in the development and progression of cognitive deficits in patients with diffuse Lewy body disease.

Adult↗
PubMed1998

Humoral signals mediate the circadian expression of rat period homologue (rPer2) mRNA in peripheral tissues.

Northern blot analysis revealed the circadian expression of rat period homologue (rPer2) mRNA in peripheral mononuclear leukocytes that have no neuronal connections. The mRNA expression in the suprachiasmatic nucleus (SCN), peripheral mononuclear leukocytes, and other peripheral tissues exhibited prominent, synchronous circadian oscillation with peaks at early night. As we have previously shown the peripheral circadian expression of rPer2 mRNA is abolished in SCN-lesioned rats [Sakamoto, K., Nagase, T. Fukui, H., Horikawa, K., Okada, T., Tanaka, H., Sato, K., Miyake, Y., Ohara, O., Kako, K. and Ishida, N., J. Biol. Chem., 273 (1998) 27039-27042], our findings suggest that some humoral signals, driven by the SCN, mediate the circadian expression of mammalian per homologues in peripheral tissues.

Animals↗
PubMed2003

A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum.

Pattern of activity during development is important for the refinement of the final architecture of the brain. In the cerebellar cortex, the regression from multiple to single climbing fiber innervation of the Purkinje cell occurs during development between postnatal days (P) 5 and 15. However, the regression is hampered by altering in various ways the morpho-functional integrity of the parallel fiber input. In rats we disrupted the normal activity pattern of the climbing fiber, the terminal arbor of the inferior olive neurons, by administering harmaline for 4 days from P9 to P12. At all studied ages (P15-87) after harmaline treatment multiple (double only) climbing fiber EPSC-steps persist in 28% of cells as compared with none in the control. The ratio between the amplitudes of the larger and the smaller climbing fiber-evoked EPSC increases in parallel with the decline of the polyinnervation factor, indicating a gradual enlargement of the synaptic contribution of the winning climbing fiber synapse at the expense of the losing one. Harmaline treatment had no later effects on the climbing fiber EPSC kinetics and I/V relation in Purkinje cells (P15-36). However, there was a rise in the paired-pulse depression indicating a potentiation of the presynaptic mechanisms. In the same period, after harmaline treatment, parallel fiber-Purkinje cell electrophysiology was unaffected. The distribution of parallel fiber synaptic boutons was also not changed. Thus, a change in the pattern of activity during a narrow developmental period may affect climbing fiber-Purkinje cell synapse competition resulting in occurrence of multiple innervation at least up to 3 months of age. Our results extend the current view on the role of the pattern of activity in the refinement of neuronal connections during development. They suggest that many similar results obtained by different gene or receptor manipulations might be simply the consequence of disrupting the pattern of activity.

Aging↗
PubMed2002

Evidence that toxicity of lipopolysaccharide upon cholinergic basal forebrain neurons requires the presence of glial cells in vitro.

The cholinergic system of the basal forebrain is affected in brains of dementia patients and during neuroinflammation. The aim of this study was to establish a method to cultivate basal forebrain cholinergic neurons in dissociated, pure neuronal cultures and to apply this method to study the effect of acute and chronic experimentally-induced inflammation using lipopolysaccharide. Purity of the cultures, degrees of neuronal dissociation, connectivity and neuronal survival were investigated by immunocytochemistry for microtubule-associated protein-2 (neurons), glial fibrillary acidic protein (astroglia), complement receptor 3 (microglia), choline acetyltransferase and the neurotrophin receptor p75 (cholinergic neurons). Neuronal cultures only contained <7% astrocytes and <1% microglia when using a "sandwich-technique". Acute (1, 10 microg/ml) as well as chronic (0.1, 1 microg/ml) treatment with lipopolysaccharide did neither affect total number of neurons, nor number of p75-positive neurons or enhance expression of major histocompatibility complex I or II. Our results suggest that lipopolysaccharide-induced degeneration of both microtubule-associated protein-2-like immunoreactive as well as specific killing of cholinergic forebrain neurons in vitro are mediated by glial cells.

Age Factors↗