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PubMed1999

Rehabilitation of brain damage: brain plasticity and principles of guided recovery.

Rehabilitation of the damaged brain can foster reconnection of damaged neural circuits; Hebbian learning mechanisms play an important part in this. The authors propose a triage of post-lesion states, depending on the loss of connectivity in particular circuits. A small loss of connectivity will tend to lead to autonomous recovery, whereas a major loss of connectivity will lead to permanent loss of function; for such individuals, a compensatory approach to recovery is required. The third group have potentially rescuable lesioned circuits, but guided recovery depends on providing precisely targeted bottom-up and top-down inputs, maintaining adequate levels of arousal, and avoiding activation of competitor circuits that may suppress activity in target circuits. Empirical data are implemented in a neural network model, and clinical recommendations for the practice of rehabilitation following brain damage are made.

Association Learning↗

PubMed2004

Rapid gas chromatography-mass spectrometry screening method for human pharmaceuticals, hormones, antioxidants and plasticizers in water.

A rapid gas chromatography-mass spectrometry (GC-MS) method was developed and validated allowing quantification at the ng/l level of 19 analytes in water including human pharmaceuticals, hormones, antioxidants and a plasticizer. On-line continuous liquid-liquid extraction with dichloromethane of 10-401 unfiltered water samples was used to achieve a 10000-40000-fold concentration factor. No sample cleanup or derivatization was required. Recoveries ranged from 57 to 120%. Application of the method to water recycling plant effluent demonstrated the presence of nearly all targeted compounds at ng/l to microgram/l levels. Screening for nontarget compounds in the treated effluent samples indicated the method could be readily extended to include additional analytes.

Antioxidants↗

PubMed2005

Active listening: task-dependent plasticity of spectrotemporal receptive fields in primary auditory cortex.

Listening is an active process in which attentive focus on salient acoustic features in auditory tasks can influence receptive field properties of cortical neurons. Recent studies showing rapid task-related changes in neuronal spectrotemporal receptive fields (STRFs) in primary auditory cortex of the behaving ferret are reviewed in the context of current research on cortical plasticity. Ferrets were trained on spectral tasks, including tone detection and two-tone discrimination, and on temporal tasks, including gap detection and click-rate discrimination. STRF changes could be measured on-line during task performance and occurred within minutes of task onset. During spectral tasks, there were specific spectral changes (enhanced response to tonal target frequency in tone detection and discrimination, suppressed response to tonal reference frequency in tone discrimination). However, only in the temporal tasks, the STRF was changed along the temporal dimension by sharpening temporal dynamics. In ferrets trained on multiple tasks, distinctive and task-specific STRF changes could be observed in the same cortical neurons in successive behavioral sessions. These results suggest that rapid task-related plasticity is an ongoing process that occurs at a network and single unit level as the animal switches between different tasks and dynamically adapts cortical STRFs in response to changing acoustic demands.

Animals↗

PubMed1996

Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1.

Ca2+ and its ubiquitous intracellular receptor calmodulin (CaM) are required in the nervous system, among a host of cellular responses, for the modulation of several important enzymes and ion channels involved in synaptic efficacy and neuronal plasticity. Here, we report that CaM can be replaced by the neuronal calcium sensor NCS-1 both in vitro and in vivo. NCS-1 is a calcium binding protein with two Ca(2+)-binding domains that shares only 21% of homology with CaM. We observe that NCS-1 directly activates two Ca2+/CaM-dependent enzymes (3':5'-cyclic nucleotide phosphodiesterase and protein phosphatase calcineurin). Co-activation of nitric oxide synthase by NCS-1 and CaM results in a higher activity than with CaM alone. Moreover, NCS-1 is coexpressed with calcineurin and nitric oxide synthase in several neuron populations. Finally, injections of NCS-1 into calmodulin-defective cam1 Paramecium partially restore wildtype behavioral responses. With this highly purified preparation of NCS-1, we have obtained crystals suitable for crystallographic structure studies. NCS-1, despite its very different structure, distribution, and Ca(2+)-binding affinity as compared with CaM, can substitute for or potentiate CaM functions. Therefore, NCS-1 represents a novel protein capable of mediating multiple Ca(2+)-signaling pathways in the nervous system.

Animals↗

PubMed2001

Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain.

Pathological pain, consisting of tissue injury-induced inflammatory and nerve injury-induced neuropathic pain, is an expression of neuronal plasticity. One component of this is that the afferent input generated by injury and intense noxious stimuli triggers an increased excitability of nociceptive neurons in the spinal cord. This central sensitization is an activity-dependent functional plasticity that results from activation of different intracellular kinase cascades leading to the phosphorylation of key membrane receptors and channels, increasing synaptic efficacy. Central sensitization is both induced and maintained in a transcription-independent manner. Several different intracellular signal transduction cascades converge on MAPK (mitogen-activated protein kinase), activation of which appears to be a master switch or gate for the regulation of central sensitization. In addition to posttranslational regulation, the MAPK pathway may also regulate long-term pain hypersensitivity, via transcriptional regulation of key gene products. Pharmacological intervention targeted specifically at the signal transduction pathways in nociceptive neurons may provide, therefore, new therapeutic opportunities for pathological pain.

Animals↗

PubMed1999

Identification and transgenic analysis of a murine promoter that targets cholinergic neuron expression.

Choline acetyltransferase (ChAT) is a specific phenotypic marker of cholinergic neurons. Previous reports showed that different upstream regions of the ChAT gene are necessary for cell type-specific expression of reporter genes in cholinergic cell lines. The identity of the mouse ChAT promoter region controlling the establishment, maintenance, and plasticity of the cholinergic phenotype in vivo is not known. We characterized a promoter region of the mouse ChAT gene in transgenic mice, using beta-galactosidase (LacZ) as a reporter gene. A 3,402-bp segment from the 5'-untranslated region of the mouse ChAT gene (from -3,356 to +46, +1 being the translation initiation site) was sufficient to direct the expression of LacZ to selected neurons of the nervous system; however, it did not provide complete cholinergic specificity. A larger fragment (6,417 bp, from -6,371 to +46) of this region contains the requisite regulatory elements that restrict expression of the LacZ reporter gene only in cholinergic neurons of transgenic mice. This 6.4-kb DNA fragment encompasses 633 bp of the 5'-flanking region of the mouse vesicular acetylcholine transporter (VAChT), the entire open reading frame of the VAChT gene, contained within the first intron of the ChAT gene, and sequences upstream of the start coding sequences of the ChAT gene. This promoter will allow targeting of specific gene products to cholinergic neurons to evaluate the mechanisms of diseases characterized by dysfunction of cholinergic neurons and will be valuable in design strategies to correct those disorders.

5' Untranslated Regions↗

PubMed2006

Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders.

The mammalian bombesin (BB)-like peptide gastrin-releasing peptide (GRP) stimulates cell proliferation, displays a range of neuroendocrine activities, and acts as a growth factor in the pathogenesis of several types of human cancer. Several lines of evidence have indicated that GRP and its receptor (GRPR) might also be involved in the neurochemical alterations associated with psychiatric and neurological disorders. GRP and GRPR are distributed throughout the mammalian central nervous system (CNS). Altered levels of BB-like peptides have been found in the CNS of patients with schizophrenia and Parkinson's disease. Dysfunctions in GRPR-induced cellular calcium signaling have been reported in fibroblasts from patients with Alzheimer's disease. A translocation in the GRPR gene has been associated with autism. Pharmacological and genetic studies in rodents have shown that GRPRs in brain areas such as the dorsal hippocampus and amygdala are importantly involved in regulating synaptic plasticity and aspects of behavior that might be altered in disorders such as anxiety, schizophrenia, depression, autism and dementia. Behaviors modulated by the GRPR in rodents include grooming, food intake, stereotypy, social behavior, and emotionally-motivated learning and memory. Together, these findings support the view that the GRPR should be considered a therapeutic target for a subset of CNS diseases.

Animals↗

PubMed2004

The fragile X syndrome: from molecular genetics to neurobiology.

Since the identification of the FMR1 gene basic research has been focused on the molecular characterization of the FMR1 gene product, the fragile X mental retardation protein (FMRP). Recent developments in fragile X research have provided new insights and knowledge about the physiological function of FMRP in the cell and the nerve cell in particular. Currently, compelling evidence suggests a role for FMRP in the transport/translation of dendritically localized mRNAs. In addition, the identification of some of the target mRNAs of FMRP have led to an increased interest in the neurobiology of the syndrome. This review highlights the role of FMRP in dendritic mRNA transport/translation in relation to synaptic plasticity, a molecular mechanism implicated in learning and memory.

Animals↗

PubMed1993

Enhanced in vitro hair growth at the air-liquid interface: minoxidil preserves the root sheath in cultured whisker follicles.

Inasmuch as hair follicles are difficult to maintain in culture, the study of hair biology using cultured hair follicles has met with only limited success. In our attempts to solve the problem of follicle degeneration, we cultured follicles at the air-surface interface on a modified collagen matrix (Gelfoam). In follicles cultured at the air-surface or submerged, we examined follicular morphology, hair shaft growth, sulfotransferase levels, cysteine incorporation, an expression of a tissue inhibitor of metalloproteinase (TIMP), and ultra-high sulfur keratin (UHSK). Follicles cultured at the air-liquid interface produced a 2.7-fold increase in hair growth and maintained an anagen-like morphology. Substrates such as nylon mesh seeded with fibroblasts, Full Thickness Skin, or 5-microns polycarbonate filter also supported hair growth, whereas Gelfilm, GF-A glass filter, filter paper, or 1-micron polycarbonate filter did not. The UHSK expression was significantly higher in the air-liquid interface cultures compared to the submerged culture. Several potassium channel openers, including minoxidil, a minoxidil analog, and the pinacidil analog (P-1075), all stimulated significant cysteine incorporation in follicles. Minoxidil and its analog specifically preserved the follicular root sheath, in contrast to P-1075 which did not, indicating a difference in the two drug types. The preservation of the root sheath was measured by increased TIMP expression and sulfotransferase activity and indicates that the root sheath is a target tissue for minoxidil. Our results show that follicles cultured at the air-liquid interface maintain a better morphology and produced greater hair growth than follicles cultured on tissue culture plastic.

Air↗

PubMed1981

Some characteristics of natural cytostatic mouse splenocytes.

Murine B16 melanoma cells and metastasis variants of this tumor are resistant to NK activity mediated by normal splenocytes. The B16 cells are, however, sensitive to splenocyte-mediated cytostasis. Cytostasis was measured by a [125I]UDR incorporation-inhibition [(125I]UDR I-I) assay. The main characteristics of the [125I[UDR I-I assay and of the cells mediating it are as follows: The activity is mediated by splenocytes but not by thymocytes, it is not syngeneically restricted and it does not decrease with age. The presence of effector cells is required as splenocyte supernatants or supernatants of effector-target cell mixtures do not cause [125I]UDR I-I. The activity is probably mediated by at least 2 populations of non-phagocytic splenocytes. The first population adheres to plastic surfaces and to Sephadex G-10 columns while the other does not. The sensitivity to [125I]UDR I-I of the high metastasis B16 variant was similar to that of the low metastasis variant.

Animals↗

PubMed1988

IgM anti-erythrocyte autoantibodies specific for buried and neo-antigens using cellular-ELISA assays.

The aim was to develop a cellular-ELISA assay to detect natural autoantibodies specific for bromelain-treated mouse red blood cells (BrMRBC). High, unexpected IgM titres against normal mouse red blood cells (NMRBC) were detected in day 7-14 sera of CBA mice treated with E. coli lipopolysaccharide (LPS). These "autoantibodies" bound to normal mouse red blood cells in the presence or absence of commonly used c-ELISA adhering agents. Such high reactivity to NMRBC was never detected using complement dependent haemolytic assays in earlier work in this system. The question whether these IgM alpha-NMRBC molecules were binding nonspecifically (via Fc) or specifically (via Fab) was answered indirectly by comparing the binding titres of LPS-stimulated serum and several purified IgM antibody preparations (alpha-PC, alpha-KLH, MOPC 104E) on the same antigen coated plates. The observed binding ratios (titre on antigen X: titre on NMRBC) varied widely between different antibody sources, indicative of specific binding. In addition no significant unequivocal binding against NMRBC could be detected in vivo (LPS-stimulated mice) nor could bound IgM antibody be detected in a suspension-c-ELISA assay (high binding titres to BrMRBC could be detected in the latter test system). In conventional c-ELISA assays, modification of normal erythrocyte by adhesion to plastic microtitre plates appears to expose or create "neoantigens" on NMRBC which are not encountered in suspension-type c-ELISA, nor in lytic or agglutination assays where the erythrocyte targets are in suspension at physiological pH and isotonicity.

Animals↗

PubMedDate not supplied

GDNF mRNA expression in normal postnatal development, aging, and in Weaver mutant mice.

Glial cell line-derived neurotrophic factor (GDNF) has been demonstrated to enhance the survival and process outgrowth of mesencephalic dopamine neurons. A nuclease protection assay was utilized to determine whether GDNF mRNA is expressed in the ventral mesencephalon and/or striatum during normal mouse postnatal development. While no GDNF mRNA was detected in the ventral mesencephalon, expression was detected in the striatum throughout postnatal development and maturity with the peak of expression being in the second postnatal week. In the process of normal aging, no change in the levels of GDNF mRNA was observed in the striatum, while a 10-fold increase in glial fibrillary acid protein (GFAP) mRNA was detected in 24-month-old relative to either 4.5- or 11-month-old mice. Further analysis addressed whether there are changes in GDNF gene expression associated with the neurodegeneration of dopamine neurons that occurs in the weaver mutant mouse. A transient 65% increase in the expression of GDNF mRNA was observed in weaver mutant striatum on postnatal day 22. The results of this study suggest that GDNF could provide target derived of dopaminergic neurotrophic support and stimulate fiber outgrowth during development and that decreased levels of GDNF expression are not responsible for either aging-associated decreases in dopaminergic neuronal plasticity or neurodegeneration in the weaver mutant mouse.

Age Distribution↗

PubMed2006

Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: potential implications for Rett syndrome.

In addition to their prominent role as survival signals for neurons in the developing nervous system, neurotrophins have established their significance in the adult brain as well, where their modulation of synaptic transmission and plasticity may participate in associative learning and memory. These crucial activities are primarily the result of neurotrophin regulation of intracellular Ca(2+) homeostasis and, ultimately, changes in gene expression. Outlined in the following review is a synopsis of neurotrophin signaling with a particular focus upon brain-derived neurotrophic factor (BDNF) and its role in hippocampal synaptic plasticity and neuronal Ca(2+) homeostasis. Neurotrophin signaling through tropomyosin-related kinase (Trk) and pan-neurotrophin receptor 75 kD (p75(NTR)) receptors are also discussed, reviewing recent results that indicate signaling through these two receptor modalities leads to opposing cellular outcomes. We also provide an intriguing look into the transient receptor potential channel (TRPC) family of ion channels as distinctive targets of BDNF signaling; these channels are critical for capacitative Ca(2+) entry, which, in due course, mediates changes in neuronal structure including dendritic spine density. Finally, we expand these topics into an exploration of mental retardation (MR), in particular Rett Syndrome (RTT), where dendritic spine abnormalities may underlie cognitive impairments. We propose that understanding the role of neurotrophins in synapse formation, plasticity, and maintenance will make fundamental contributions to the development of therapeutic strategies to improve cognitive function in developmental disorders associated with MR.

Animals↗

PubMed2000

Distinct expression patterns of eph receptors and ephrins relate to the structural organization of the adult rat peripheral vestibular system.

Eph receptors and their ligands, termed ephrins, have been implicated in axon guidance, neuron-target interactions, regional compartmentalization, and synaptic functions in nervous systems. These activities of the Eph family molecules prompted us to investigate whether these molecules play roles in the maintenance, regeneration and plasticity in the mature peripheral vestibular system. Using reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunocytochemical analyses, we identified distinct and reciprocal expression patterns of full-length isoforms of EphA5, EphA6, EphA7, EphB1, ephrin-A2 and ephrin-B1 that correlated with structural features of the peripheral vestibular system in adult rats. All of the Eph receptors and ephrins examined were localized in the cell bodies of vestibular ganglion neurons in vivo and in vitro, and were readily detected in their outgrowing neurites in vitro. In the utricle, these molecules were localized in distinct cellular and subcellular compartments corresponding to discrete features of utricular afferent innervation, e.g. defasciculation, branching and synapse formation. Taken together, these results identify the Eph receptors and ephrins as candidate molecular substrates for defining some aspects of the structural organization of the adult peripheral vestibular system.

Amino Acid Sequence↗

PubMed2001

Development of a new operating rectal tube with a side window for transanal endoscopic surgery.

The authors describe a new rectal tube for use in transanal endoscopic surgery. The tube is a transparent plastic sheath with its forward end closed, measuring 40 mm in diameter and 150 mm in insert length. It has a window, measuring 40 mm in diameter, on its side. The target lesion, captured within the side window, prolapses into the rectal tube and is excellently visualised without positive pressure gas insufflation. This paper gives details of the tube and reports on a sessile rectal tumour successfully treated using the new system.

Journal Article↗

PubMed2004

Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants.

Acute stress inhibits long-term potentiation (LTP) at synapses from the hippocampus to prefrontal cortex in the rat, a model of the dysfunction in the anterior cingulate/orbitofrontal cortices which has been observed in human depression. We demonstrate that the antidepressants tianeptine and, to a lesser extent, fluoxetine, are able to reverse the impairment in LTP, a measure of frontal synaptic plasticity, caused by stress on an elevated platform. LTP was induced by stimulation of hippocampal outflow. Beneficial effects on neuronal plasticity, defined as a reversal of the effects of stress in this paradigm, can be considered as a new animal model for the impact of stress on hippocampal/frontal circuits, a key target in psychiatric diseases.

Acute Disease↗

PubMed2000

Pain: neuroanatomy, chemical mediators, and clinical implications.

Most pain information begins at simple, naked nerve endings called nociceptors that form a functional pain unit with nearby tissue capillaries and mast cells. Tissue injury causes these nerve terminals to depolarize, an event that is propagated along the entire afferent fiber eventuating in sensory impulses reaching the spinal cord. This firing of primary afferent fibers at the site of tissue injury causes axonal release of vesicles containing neuropeptides such as substance P, which acts in an autocrine and paracrine manner to sensitize the nociceptor and increase its rate of firing. Cellular damage and inflammation increase concentrations of other chemical mediators such as histamine, bradykinin, and prostaglandins in the area surrounding functional pain units. These additional mediators act synergistically to augment the transmission of nociceptive impulses along sensory afferent fibers. Primary fibers travel from the periphery to the dorsal horn where they synapse on secondary neurons and interneurons. When activated, interneurons exert inhibitory influences on further pain signal trafficking. Efferent supraspinal influences, in turn, determine the activity of interneurons by releasing a variety of neurotransmitter substances, thus resulting in a high degree of modulation of nociception within the dorsal horn. Events occurring in the periphery and in the dorsal horn can cause a dissociation of pain perception from the presence or degree of actual tissue injury. These phenomena involve many chemical mediators and receptor systems, and can increase pain experience qualitatively, quantitatively, temporally, and spatially. The complexity and plasticity of the nociceptive system can make clinical management of pain difficult. Undestanding the structure and chemical signals associated with this system can improve the use of existing analgesics and provide targets for development of newer and more specific pain-fighting drugs.

Afferent Pathways↗

PubMed2006

From blue states to up states: a regional view of NMDA-ethanol interactions.

This article summarizes the proceedings of a symposium at the 2005 Research Society on Alcoholism Meeting in Santa Barbara, California, organized and cochaired by John J. Woodward and Dorit Ron. The purpose of the symposium was to discuss recent findings that extend our understanding of the importance of the N-methyl-D-aspartate (NMDA) receptor as a target for ethanol action in the brain. These receptors are ligand-gated ion channels that are activated by the neurotransmitter glutamate and are critically involved in many forms of synaptic plasticity including those associated with learning and memory. In the first presentation, Dorit Ron presented data showing how activation of Fyn or Src tyrosine kinases differentially regulated the cell surface expression and activity of NR2A and NR2B containing NMDA receptors. Danny Winder discussed the effects of ethanol on NMDA receptor-dependent long-term potentiation in the bed nucleus of the stria terminalis (BNST), a brain region associated with the interaction between stress and drug/alcohol use. In the third presentation, Marisa Roberto described adaptations in the expression and function of NMDA receptors in the central nucleus of the amygdala following chronic exposure to ethanol. Finally, John Woodward described the effects of ethanol on the activity of neurons in deep layers of the prefrontal cortex using a novel slice coculture preparation.

Alcoholism↗