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At least 1,063 records · Page 59Linked to original sources
PubMed1986

Reversible embedment cytochemistry (REC): a versatile method for the ultrastructural analysis and affinity labeling of tissue sections.

Reversible embedment cytochemistry (REC) is a new method for revealing cellular ultrastructure and for improving access of intracellular targets to macromolecular affinity labels. Fully polymerized polymethylmethacrylate was dissolved in dichloromethane and infiltrated into fixed tissue-culture cells and tissues. After evaporation of the solvent, samples were left in hard plastic. Samples were thus embedded without exposure to chemical polymerization reactions that might damage tissue ultrastructure or antigenicity. Glass or diamond knives fitted with water troughs were used to cut sections 30-1000 nm thick. Since polymethylmethacrylate is composed of linear polymers that are not covalently crosslinked, the plastic was easily extracted from the sections by immersion in solvent. Subsequently, various preparative methods, including negative staining, critical point-drying, and platinum-carbon rotary shadowing, were used to provide detailed images of well-preserved cell structure for conventional and high-voltage transmission electron microscopy. Fluorescein-conjugated affinity labels were used to obtain subcellular distributions of target molecules in semi-thick sections of cultured cells and tissues for light microscopy. Colloidal gold-labeled antibodies were used to localize microtubules in sections of cultured cells by electron microscopy. REC is a versatile method that should find wide application in many studies of cellular function.

Affinity Labels↗
PubMed1989

Asymmetrical adaptation of human saccades to anisometropic spectacles.

We report the extent to which effective asymmetrical saccadic adaptation was achieved by a myopic subject, who was exposed to "long-term" adaptation as he wore anisometropic corrective spectacles for about 40 years and also the extent of "short-term" adaptation in this subject and two other subjects, who initially made conjugate saccades, when they wore newly fitted anisometropic spectacles for about 8 hr. Two-dimensional binocular eye positions were measured with an accurate and precise revolving magnetic field-sensor coil technique. We found that long-term adaptation of vertical saccades was virtually perfect (almost 100% of the asymmetry introduced by the spectacles was corrected). Long-term adaptation of horizontal saccades was less complete and increased with target separation from about 40% for saccadic amplitudes of 5 degrees to about 75% for amplitudes of 60 degrees. Short-term adaptation of vertical saccades was virtually complete (100%) in one newly fitted subject and only partially complete (40%) in the other two subjects. The persistence of the adaptive asymmetry of saccades during monocular viewing showed that adaptation derived from plasticity in the programming of saccades and not from modification of vergence responses. Without the anisometropic spectacles, 30 min of self-paced, one per second changes in binocular fixation between two targets, which required a version change of 45 degrees in combination with a vergence change of 11 degrees, did not induce any asymmetrical adaptation. This result shows that a specific repeated association of version and vergence eye movements was not sufficient to induce asymmetrical adaptation, leading us to suggest that the transient fixation disparities at saccade-offset might be the necessary stimulus for the asymmetrical saccadic adaptation we observed.

Adaptation, Physiological↗
PubMed1984

Development of synaptic organization in the tangential vestibular nucleus: a quantitative electron microscope study.

The objective of the present study is to quantify the developmental changes in the total synaptic pattern of one part, the soma, of one particular cell type, the principal cells of the tangential vestibular nucleus. The term "synaptic space" is defined and quantified. Intermediate stages in the development of synaptic organization are compared. The findings show that the synaptic space available to the full complement of afferents is constant throughout development, while specific terminals in the afferent population change their synaptic space allotments. The synaptic-junction covering is invariant for small terminals at intermediate stages of development with set proportions between "active" and "non-active" zones of the synaptic surfaces. However, the spoon endings and the postsynaptic target cells are covered by synaptic junctions in variable amounts. The findings are important to the fields of neuroembryology and neural plasticity, for the system provides a useful basis to measure the influence of factors in the local environment and the role of formation of synaptic connections in the competition for synaptic space. This study will assist investigators to probe the mechanisms operating in the selection of competing afferents for the limited amount of surface area available under the changing conditions of maturation and aging in the central nervous system.

Animals↗
PubMed1988

Retinal projections to the superior colliculus and dorsal lateral geniculate nucleus in the tammar wallaby (Macropus eugenii): II. Topography after rotation of an eye prior to retinal innervation of the brain.

Retinal projections to visual centers in a marsupial mammal, the tammar wallaby (Macropus eugenii), have been investigated after an eye rotation prior to retinal innervation of the brain. Retinal topography to the superior colliculus and dorsal lateral geniculate nucleus was mapped by using laser lesions of the retina and horseradish peroxidase histochemistry. Despite the change in orientation of optic axon outgrowth from the developing eye after rotation, retinal ganglion cells made orderly connections in the colliculus and geniculate according to their original retinal position within the eye and not their rotated position. Axons must have corrected their pathways at some point between the back of the eye and their targets. The optic chiasm was one such site. Optic axons from the rotated eye took an abnormal course at the caudal end of the chiasm. Growth of optic axons through aberrant pathways in the brain did not preclude specific innervation of targets. When by chance optic axons entered through the oculomotor nerve root they specifically innervated their correct visual centers, albeit in reduced density, and did not innervate inappropriate targets. These results support the idea of specific interactions between growing axons, the pathways they grow along, and their targets.

Animals↗
PubMed1988

Plasticity of primary afferent acid phosphatase expression following rerouting of afferents from muscle to skin in the adult rat.

We have examined the possibility that reinnervation of a new peripheral target by primary afferent neurones can alter the histochemical properties of those afferents in the adult rat. The hindlimb sural and gastrocnemius nerves largely supply skin and muscle, respectively. In adult animals these nerves were cut and rejoined to either their own distal stumps (self-anastomosis) or that of the other nerve (cross-anastomosis) and allowed to regenerate for 12-16 weeks to reinnervate an appropriate or inappropriate target. Fluoride-resistant acid phosphatase (FRAP) is a chemical marker found in many unmyelinated afferents. We have determined the FRAP expression in normal and regrown nerves and examined its distribution in the dorsal horn of animals with self- and cross-anastomosed nerves. While normal and self-anastomosed sural nerves stained heavily for FRAP, gastrocnemius nerves showed either no staining or only the occasional fibre. Cross-anastomosed gastrocnemius nerves, now innervating the skin, showed a significant increase in staining, in some cases approaching the levels normally seen in sural nerves. Conversely, cross-anastomosed sural nerves (innervating muscle) showed decreased FRAP staining. In the normal dorsal horn the terminals of FRAP containing afferents form a thin band extending throughout the mediolateral extent of lamina II (Devor and Claman: Brain Res. 190:17-28, '80). One week after axotomy of the sural nerve, FRAP is depleted from its terminals and a gap appears in the normal FRAP staining pattern in the lumbar enlargement of the spinal cord. The new expression of FRAP in cross-anastomosed nerves was also seen in their terminals in the dorsal horn.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1990

Competitive and positional cues in the patterning of nerve connections.

The visual system of lower vertebrates has served as an important testing ground for the mechanisms that generate topographic neuronal connections. During both the outgrowth and the regeneration of the optic nerve, a smoothly ordered map of the retina is formed on its major target, the optic tectum (the retinotectal projection). Experiments performed on this projection have offered support for a variety of mechanisms, including the matching of positional cues in the retina and tectum, the guidance of nerve fibers by interactions between fibers, competition for synaptic space, and the refinement of connections based on neuronal activity. Unfortunately, individual experiments that support any one of these mechanisms have been taken at times as evidence against the involvement of any other mechanism; for example, experiments demonstrating the importance of positional cues have been thought mistakenly to indicate that activity-based interactions are unimportant. Computer simulations, in which multiple, somewhat opposed, mechanisms are allowed to operate in concert demonstrate that such a hybrid model is able to generate a full range of experimental results. More importantly, the elimination of any one of the mechanisms renders the model unable to fit entire classes of findings. Thus, the patterning of the retinotectal projection is best viewed as a process in which the optic nerve terminals attempt to satisfy multiple constraints in selecting their target sites.

Animals↗
PubMed2000

INP, a novel N-cadherin antagonist targeted to the amino acids that flank the HAV motif.

The classical cadherins are homophilic binding molecules that play fundamental roles in several biological processes, including axonal growth and synaptic plasticity. The structures of the amino-terminal homophilic binding domains of N-cadherin and E-cadherin have been resolved. However, the mechanisms that govern cadherin binding and specificity remain contentious. In the present study we have used a peptide competition approach to probe for small linear determinants of cadherin binding. We demonstrate that a linear peptide mimetic of a short sequence in ECD1 of N-cadherin (INPISGQ) functions as a highly specific and potent antagonist of N-cadherin function with an IC(50) value of approximately 15 microM. Peptide mimetics of the corresponding motif in chick R-cadherin also inhibited N-cadherin function, albeit with lower efficacy. In contrast, peptide mimetics of the corresponding motif in E- or P-cadherin failed to inhibit N-cadherin function. A short cyclic peptide that contained only the INP motif from N-cadherin was also a potent N-cadherin antagonist (IC(50) approximately 15 microM). Analysis of existing crystal structures suggests that the peptides are likely to antagonize N-cadherin function by binding to the region that flanks the HAV motif at the adhesion dimer interface.

3T3 Cells↗
PubMed2005

The hippocampus and neurotransplantation.

The present article is a review of our own results from histological and electron microscopic studies of hippocampal neurotransplants with different levels of integration with recipient brains. A model providing complete isolation from the brain was obtained using transplants developing in the anterior chamber of the eye. The growth, development, and cytological composition of transplanted tissue was found to depend on factors such as the age of the donor embryo tissue, the genetic compatibility between the donor and recipient, and the level of integration with the brain. Ultrastructural analysis of intraocular and intracortical transplants showed that overall, nerve and glial cells have the characteristics of highly differentiated, mature elements; the numerical density and structures of synaptic contacts were similar to those in normal conditions. However, transplanted tissues contained morphological features providing evidence of continuing growth of several nerve processes and increases in non-synaptic and transport-metabolic intercellular interactions. The ultrastructural deviations observed here are regarded as the manifestations of compensatory-adaptive changes during the development of tissues in conditions deficient in natural afferent synaptic influences. It is also demonstrated that the axons of transplanted neurons lacking adequate cellular targets can establish functional synaptic contacts with neuronal elements in the recipient brain which are not their normal targets.

Age Factors↗
PubMed1996

Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells.

In addition to their well-established roles as neurotransmitters and neuromodulators, growing evidence suggests that nucleotides and nucleosides might also act as trophic factors in both the central and peripheral nervous systems. Specific extracellular receptor subtypes for these compounds are expressed on neurons, glial and endothelial cells, where they mediate strikingly different effects. These range from induction of cell differentiation and apoptosis, mitogenesis and morphogenetic changes, to stimulation of synthesis or release, or both, of cytokines and neurotrophic factors, both under physiological and pathological conditions. Nucleotides and nucleosides might be involved in the regulation of development and plasticity of the nervous system, and in the pathophysiology of neurodegenerative disorders. Receptors for nucleotides and nucleosides could represent a novel target for the development of therapeutic strategies to treat incurable diseases of the nervous system, including trauma- and ischemia-associated neurodegeneration, demyelinating and aging-associated cognitive disorders.

Central Nervous System↗
PubMed2005

Spatio-temporal expression of immediate early genes in the central nervous system of SJL/J mice.

Gene products of immediate early genes (IEGs) interact with specific binding sites in promoter regions of inducible and constitutively expressed genes. Thereby, they control transcription of down-stream targets, like pro- and anti-apoptotic genes and matrix-metalloproteinases (MMPs), known to play an important role in development, plasticity, response to injury and repair of the central nervous system (CNS). A real-time quantitative RT-PCR and immunohistochemical investigation was performed to study mRNA expression levels and protein distribution patterns of IEGs in cerebrum, cerebellum, and spinal cord of SJL/J mice between postnatal weeks 1 and 40. A down-regulation of c-jun, NF-kappaB1, Max, Ets-1, and p53 mRNA, and an up-regulation of c-fos mRNA was noticed. Down-regulations of Ets-1 and p53 were most prominent between week 1 and 3. The prominent role in CNS development for c-jun, Ets-1 and Max was supported by immunohistochemistry. One-week-old mice were strongly positive for all three proteins in cerebral cortex, medulla oblongata, and gray matter of the spinal cord. A high staining intensity was detected in the developing granule cell layer of the cerebellum for c-jun and Ets-1, and in the Purkinje cell layer of the cerebellum for Max. In addition to the general down-regulation of most mRNAs, minor up-regulations of all IEG proteins could be detected in restricted parts of the CNS indicating regional variations and differential expression and translation during development. Apoptosis was demonstrated using immunohistochemistry for active caspase-3. The expression patterns of IEGs might represent the key to understand the balance of proteolytic activities by MMPs, myelination, and the induction of apoptosis during the development of the CNS.

Aging↗
PubMed2005

Neuronal BC1 RNA: microtubule-dependent dendritic delivery.

RNA localization is an important means of post-transcriptional regulation of gene expression in many eukaryotic cell types. In neurons, select RNAs are delivered to postsynaptic dendritic microdomains, a mechanism that is considered a key underpinning in the administration of long-term synaptic plasticity. BC1 RNA is a small untranslated RNA that interacts with translation initiation factors and functions as a translational repressor by targeting assembly of 48S initiation complexes. BC1 RNA is specifically and rapidly transported to dendrites where it is found concentrated in postsynaptic microdomains. The cytoskeletal infrastructure underlying dendritic localization of BC1 RNA has not been investigated. We now report that the dendritic delivery of BC1 RNA is dependent on intact microtubules. In two neuronal cell types, hippocampal neurons and sympathetic neurons in primary culture, disruption of microtubules abolished dendritic localization of BC1 RNA. In contrast, disruption of actin filaments had no significant effect on the somatodendritic distribution of BC1 RNA. It is concluded that the long-range dendritic delivery of BC1 RNA is supported by microtubules. At the same time, a role for actin filaments, while unlikely for long-range BC1 delivery, is not ruled out for short-range local translocation and anchoring at dendritic destination sites.

Animals↗
PubMed2003

Heat shock proteins in mammalian development.

Mammalian development follows a defined but adjustable program, depending on the plasticity of embryonic cells 'response to environmental changes. Heat shock proteins (Hsp) are integral part of this developmental program and gene targeting experiments have started to unravel developmental processes, which exhibit specific requirements for Hsps (e.g. Hsp70.2 for spermatogenesis). In the present paper, we will review available data on Hsp function and discuss the roles of heat shock factors (HSF), their major regulators, in mammalian development.

Animals↗
PubMed2026

AAV-mediated CBLN1 replacement rescues hereditary ataxia caused by bi-allelic CBLN1 variants.

Cbln1 is a secreted synaptic organizer required for parallel fiber-Purkinje cell (PF-PC) synapse integrity, climbing fiber (CF) refinement, and cerebellar motor learning but has not previously been implicated in human disease. We identified bi-allelic CBLN1 missense variants (A63P and Y112C) in two unrelated families with early-onset cerebellar ataxia accompanied by oculomotor abnormalities, cerebellar atrophy, and variable cognitive delay. In heterologous cells, both variants showed reduced steady-state protein abundance, impaired maturation through the early secretory pathway, and little or no detectable secretion, resulting in markedly reduced extracellular CBLN1 availability. Consistently, cerebellar granule cells expressing CBLN1-Y112C failed to induce excitatory synapses onto glutamate receptor δ2 (GluD2)-expressing cells in vitro. A knockin mouse harboring Y112C lacked synaptic Cbln1 and recapitulated key features of Cbln1 deficiency, including disrupted PF-PC synapse organization, persistent CF multi-innervation, impaired PF-PC transmission, and long-term depression, and deficits in motor coordination and oculomotor learning. Notably, systemic delivery of an astrocyte-targeted adeno-associated virus expressing wild-type CBLN1 in adult mutant mice restored synaptic CBLN1 localization, cerebellar synaptic function, plasticity, and behavior. These findings establish CBLN1 deficiency as a cause of hereditary ataxia and identify extracellular CBLN1 replacement as a therapeutic strategy for a reversible cerebellar synaptopathy.

CBLN1↗
PubMed2003

Pro-region of neurotrophins: role in synaptic modulation.

Neurotrophins are synthesized first as precursors, followed by maturation through proteolytic removal of the "pro" region. Since pro- and mature neurotrophins elicit opposite functional effects by differential interactions with Trks and p75 receptors, extracellular cleavage represents a new way to control the synaptic functions of neurotrophins. A single nucleotide mutation in the pro-region appears to affect synaptic targeting and activity-dependent secretion of BDNF in hippocampal neurons. These results demonstrate new mechanisms by which neurotrophins regulate synaptic plasticity and memory function.

Brain-Derived Neurotrophic Factor↗
PubMed1998

Intrinsic controls of intracellular calcium and intercellular communication in the regulation of neuroendocrine cell activity.

1. The magnocellular hypothalamoneurohypophysial system, consisting chiefly of the supraoptic and paraventricular nuclei and their axonal projections to the pituitary neural lobe, has become a model for the study of neuroendocrine cell morphology, function, and plasticity. 2. Decades of research have produced a wealth of knowledge about the physiological conditions that activate this system, the peripheral target tissues affected by its outputs, and its capacity to undergo use-dependent, reversible reorganization. 3. Earlier research on the neural control of this system concentrated largely on the synaptic inputs that influence the activity of these magnocellular neurons and, while that task is still far from completed, methods have now been developed that permit insights to be gained into the control exercised by intrinsic cellular and molecular mechanisms. 4. This article reviews the current state of knowledge of roles played by these intrinsic mechanisms, including influences of intracellular calcium buffering, calcium release from internal stores and intercellular communication through gap junctions, in the control of neuroendocrine cell activity.

Animals↗
PubMed2006

Role of voltage-gated L-type Ca2+ channel isoforms for brain function.

Voltage-gated LTCCs (L-type Ca2+ channels) are established drug targets for the treatment of cardiovascular diseases. LTCCs are also expressed outside the cardiovascular system. In the brain, LTCCs control synaptic plasticity in neurons, and DHP (dihydropyridine) LTCC blockers such as nifedipine modulate brain function (such as fear memory extinction and depression-like behaviour). Voltage-sensitive Ca2+ channels Cav1 .2 and Cav1.3 are the predominant brain LTCCs. As DHPs and other classes of organic LTCC blockers inhibit both isoforms, their pharmacological distinction is impossible and their individual contributions to defined brain functions remain largely unknown. Here, we summarize our recent experiments with two genetically modified mouse strains, which we generated to explore the individual biophysical features of Cav1.2 and Cav1.3 LTCCs and to determine their relative contributions to various physiological peripheral and neuronal functions. The results described here also allow predictions about the pharmacotherapeutic potential of isoform-selective LTCC modulators.

Animals↗
PubMed1997

The interactive language of the hypothalamus for the gonadotropin releasing hormone (GNRH) system.

The enormous diversity in neurochemical signals employed within the network of afferents to GnRH neurons is well-documented. An examination of novel and accumulating knowledge on the operation of these messengers indicates the presence of an interactive language governing GnRH secretion. The basic operational structures identified to date to affirm this interactive form of communication summarized in this review are the following: (i) the demonstration of interconnections within various components of the afferent network; (ii) coexistence and possible co-release of excitatory and inhibitory neurotransmitters/neuromodulators; (iii) co-action of various messengers at synaptic targets, and (4) modulation by gonadal steroids of the synthesis and release of signals and their receptors, and induction of synaptic plasticity for the timely relay of signals for GnRH secretion. Unraveling the molecular sequelae that promote this interactive communication to elicit periodic GnRH secretion is now a new challenge.

Afferent Pathways↗
PubMed2005

Generalized Bienenstock-Cooper-Munro rule for spiking neurons that maximizes information transmission.

Maximization of information transmission by a spiking-neuron model predicts changes of synaptic connections that depend on timing of pre- and postsynaptic spikes and on the postsynaptic membrane potential. Under the assumption of Poisson firing statistics, the synaptic update rule exhibits all of the features of the Bienenstock-Cooper-Munro rule, in particular, regimes of synaptic potentiation and depression separated by a sliding threshold. Moreover, the learning rule is also applicable to the more realistic case of neuron models with refractoriness, and is sensitive to correlations between input spikes, even in the absence of presynaptic rate modulation. The learning rule is found by maximizing the mutual information between presynaptic and postsynaptic spike trains under the constraint that the postsynaptic firing rate stays close to some target firing rate. An interpretation of the synaptic update rule in terms of homeostatic synaptic processes and spike-timing-dependent plasticity is discussed.

Action Potentials↗