bluuebunny/crossref_metadata_2025 huggingface dataset:
The glial framework of central white matter tracts: Segmented rows of contiguous interfascicular oligodendrocytes and solitary astrocytes give rise to a continuous meshwork of transverse and longitudinal processes in the adult rat fimbria
Authors: Suzuki M. , Raisman G.
Published: January 2005

The cellular skeleton of the adult rat fimbria consists of regularly spaced interfascicular glial rows of considerable length, running in the longitudinal (axonal) axis of the tract.

Each row consists of a series of repeated segments made up of a stretch of interfascicular oligodendrocytes lying in direct contact with each other, and separated from the adjacent segments by usually solitary interfascicular astrocytes. A typical segment would be around 60 μm long, and have an axial core of about eight contiguous oligodendrocytes surrounded by a shell of about 1,200 axons, 70% of which are myelinated. In the transverse plane of the tract, adjacent segments are stacked together with a core‐to‐core distance of around 15 μm.

The interfascicular oligodendrocytes have radial stem processes (in a plane transverse to the axonal axis) which give rise to the longitudinal myelinating (internodal) processes. Both transverse and longitudinal oligodendrocytic processes are longer than the dimensions of the segment (in which their cell bodies lie) and its axonal shell. They thus cooperate in myelinating axons of adjacent segments in both planes.

The interfascicular astrocytes have three distinct types of processes: radial, longitudinal, and vascular (bearing end feet). The radial astrocytic processes are thick and tapering, and the processes of individual astrocytes extend transversely (in the plane of the original embryonic radial glial processes) for a total of at least 100 μm. The considerably more numerous longitudinal astrocytic processes arise from all parts of the cell bodies and radial processes. They are up to at least 30 μm long, thin, untapering, and largely unbranched, and are interdigitated among the fimbrial axons.

In the radial plane, the astrocytic radial processes spread out through a wide swathe of adjacent segments, so that the integrated meshwork of interpenetrating longitudinal processes arising from overlapping radial processes of astrocytes from many different interfascicular rows provides a continuous longitudinal substrate for the fimbrial axons. © 1992 Wiley‐Liss, Inc.
Effect of insulin of glucose and glycogen metabolism and leucine incorporation into protein in cultured mouse astrocytes
Authors: Kum W. , Zhu S. Q. , Ho S. K. S. , Young J. D. , Cockram C. S.
Published: January 2005

Insulin, following binding to its receptor, produces a dose‐ and time‐dependent stimulation of entry of 2‐deoxy‐D‐[U‐14C] glucose and glycogen synthesis from D‐[U‐14C] glucose in cultured mouse astrocytes following differentiation. Maximal stimulation of both glucose entry (217% above basal) and of glycogen synthesis (209% above basal) was observed at an insulin concentration of 1.7 × 10−8 M. Insulin also stimulates the incorporation of leucine into astrocytic proteins with maximal stimulation (156% above basal) at an insulin concentration of 1.7 × 10−7 M, but no effect on leucine uptake was observed at an insulin concentration of 1.7 × 10−6 M. These results, together with a previous demonstration that insulin and certain insulin analogues stimulate pyrimidine nucleoside incorporation into nucleic acid, indicate that insulin has diverse actions on biomacromolecular metabolism in cultured mouse astrocytes. © 1992 Wiley‐Liss, Inc.
Migration of Schwann cells from the distal stump of the sciatic nerve 1 week after transection: The effects of insulin and cytosine arabinoside
Authors: Dubovy P. , Svizenska I.
Published: January 2005

We have examined the migratory capacity of Schwann cells from the distal stump of a 1‐week transected sciatic nerve of adult rat for a distance of 10 mm. The distal stump was introduced into the open end of a silicone chamber packed with artificial fibrin sponge (Gelaspon) soaked in phosphate‐buffered saline (control chambers), cytosine arabinoside (Ara‐C) (0.05 mM), or insulin (40 U/ml). Migrating Schwann cells were distinguished from fibroblasts by the presence of non‐specific cholinesterase (nChE) activity and glial fibrillary acidic protein (GFAP). The cells of distal stumps including Schwann cells accepted Gelaspon as a suitable adhesive substratum. In the chambers filled with Gelaspon soaked in phosphate‐buffered saline alone Schwann cells were outnumbered by fibroblasts. The addition of Ara‐C resulted in greater numbers of Schwann cells, which migrate longer distances into the chambers. The application of insulin enhanced Schwann cell migration as well. These morphologic observations were further supported by biochemical measurements of nChE activity. The results suggest an influence on Schwann cell migration by fibroblasts of connective tissue sheaths and a stimulation of Schwann cell migration by insulin. © 1992 Wiley‐Liss, Inc.
Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease
Authors: Dickson Dennis W. , Lee Sunhee C. , Mattiace Linda A. , Yen Shu‐Hui C. , Brosnan Celia
Published: January 2005

Microglia are associated with central nervous system (CNS) pathology of both Alzheimer's disease (AD) and the acquired immunodeficiency syndrome (AIDS). In AD, microglia, especially those associated with amyloid deposits, have a phenotype that is consistent with a state of activation, including immunoreactivity with antibodies to class II major histocompatibility antigens and to inflammatory cytokines (interleukin‐1‐β and tumor necrosis factor‐α). Evidence from other studies in rodents indicate that microglia can be activated by neuronal degeneration. These results suggest that microglial activation in AD may be secondary to neurodegeneration and that, once activated, microglia may participate in a local inflammatory cascade that promotes tissue damage and contributes to amyloid formation. In AIDS, microglia are the primary target of retroviral infection. Both ramified and ameboid microglia, in addition to multinucleated giant cells, are infected by the human immunodeficiency virus (HIV‐1). The mechanism of microglial infection is not known since microglia lack CD4, the HIV‐1 receptor. Microglia display high affinity receptors for immunoglobulins, which makes antibody‐mediated viral uptake a possible mechanism of infection. In AIDS, the extent of active viral infection and cytokine production may be critically dependent upon other factors, such as the presence of coinfecting agents. In the latter circumstance, very severe CNS pathology may emerge, including necrotizing lesions. In other circumstances, HIV infection microglia probably leads to CNS pathology by indirect mechanisms, including release of viral proteins (gp120) and toxic cytokines. Such a mechanism is the best hypothesis for the pathogenesis of vacuolar myelopathy in adults and the diffuse gliosis that characterizes pediatric AIDS, in which very little viral antigen can be detected.
Microglia in degenerative neurological disease
Authors: McGeer Patrick L. , Kawamata Toshio , Walker Douglas G. , Akiyama Haruhiko , Tooyama Ikuo , McGeer Edith G.
Published: January 2005

Microglia express many leukocyte surface antigens which are upregulated in such chronic degenerative neurological diseases as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). These surface antigens include leukocyte common antigen, immunoglobulin Fc receptors, MHC class I and class II glycoproteins, β2‐integrins, and the vitronectin receptor. Ligands for these receptors are also found. They include immunoglobulins, complement proteins of the classical pathway, T lymphocytes of the cytotoxic/suppressor and helper/inducer classes, and vitronectin. T lymphocytes marginate along capillary venules, with some penetrating into the tissue matrix. Immunoglobulins and complement proteins are synthesized locally in brain, although they may also come from the bloodstream if the blood‐brain barrier is compromised. The membrane attack complex, which is formed from C5b‐9, the terminal components of complement, has been identified in AD and multiple sclerosis brain tissue. In addition, proteins designed to defend against bystander lysis caused by the membrane attack complex, including protectin, C8 binding protein, clusterin, and vitronectin, are associated with damaged neuronal processes in AD. Autodestruction may play a prominent part in these 2 diseases.
Characterization of “plasma proteins” secreted by cultured rat macroglial cells
Authors: Zahs Kathleen R. , Bigornia Violeta , Deschepper Christian F.
Published: January 2005

The brain is isolated behind a blood‐tissue barrier that restricts the access of circulating proteins to neural cells. There is evidence that some of these proteins are synthesized within the central nervous system. The present study examines the synthesis and secretion of such proteins by cultured macroglial cells. Primary glial cultures were derived from cortical and subcortical regions of neonatal rat brains, and subsequent secondary cultures were enriched in type‐1 astrocytes, type‐2 astrocytes, or oligodendrocytes. Newly synthesized proteins were immunoprecipitated from the culture media using antisera directed against whole rat serum. All three types of glial cells secreted a range of plasma proteins. In general, type‐1 astrocytes secreted more of these proteins than did type‐2 astrocytes or oligodendrocytes, although the one‐dimensional polyacrylamide gel electrophoresis (PAGE) profiles were specific for each cell type. Antisera directed against specific plasma proteins identified three of the most abundant proteins secreted by type‐1 astrocytes as transferrin, α‐2‐macroglobulin, and ceruloplasmin. Northern blot analysis of cellular RNA confirmed that type‐1 astrocytes contained transferrin mRNA, and that it was more abundant in cultures derived from subcortical regions than from cortical regions. In situ hybridization studies revealed that virtually all type‐1 and type‐2 astrocytes contained transferrin mRNA.

Since the proteins identified in this study have been proposed to have a variety of neurotrophic roles in the central nervous system, these data further extend the range of possible functions that glial cells may serve in the CNS.
Stimulation of astrocyte proliferation by purine and pyrimidine nucleotides and nucleosides
Authors: Christjanson Lisa J. , Middlemiss Pamela J. , Rathbone Michel P.
Published: January 2005

Proliferation of brain astrocytes as a result of cell death has been well documented in vivo. Dying cells release purine and pyrimidine nucleosides and nucle‐otides and their deoxy derivatives both from soluble intracellular pools and from DNA and RNA. Previously, we have observed that purine nucleosides and nucleotides stimulate chick astrocyte proliferation in vitro. To further our analysis, we questioned whether pyrimidines or the deoxy derivatives of purine nucleosides and nucleotides might also be astrocyte mitogens. Pyrimidine nucleosides, nucleotides, and their deoxynucleotide derivatives were uniformly inactive. In contrast, deoxyguanosine, deoxyadenosine, and their mono‐, di‐, and triphosphates stimulated thymidine incorporation into astrocytes at concentrations similar to those at which their ribonucleoside and ribonucleotide analogues were active. Inosine, IMP, ITP, and hypoxanthine were active, whereas xanthine and xanthosine were not. However, XMP, XDP, and XTP stimulated thymidine incorporation. The effects of the nucleosides and deoxynucleosides were inhibited by antagonists of adenosine A2 receptors. These data indicate that most purine nucleosides, deoxynucleosides, and their 5′ mono, di‐, and triphosphate derivatives released from damaged cells are capable of stimulating astrocyte proliferation in vitro and may contribute to astrocyte proliferation in vivo following injury to the CNS.
Purinergic P2Y receptors on astrocytes are directly coupled to phospholipase A2
Authors: Bruner Gretchen , Murphy Sean
Published: January 2005

ATP stimulates arachidonic acid mobilization and eicosanoid production in cultured astrocytes via P2Y‐purinergic receptors. To assist in determining the mechanism of phospholipase A2 activation and the role of calcium in eicosanoid production, cultures were pretreated with pertussis toxin (PTx). ATP‐evoked eicosanoid release was inhibited by PTx in a concentration‐dependent fashion. Inositol phospholipid hydrolysis was partially attenuated by PTx, but the concentrations required were approximately 50 times greater than those for inhibition of eicosanoid production, suggesting that phospholipase C activation is not necessary for eicosanoid synthesis. Stimulation of eicosanoid release by other P2Y‐purinergic receptor agonists was also inhibited by PTx; however, PTx had no effect on eicosanoid release evoked by ionomycin or thapsigargin, nor did it affect ATP‐stimulated calcium influx or mobilization from intracellular stores. Increases in intracellular free calcium concentration alone were insufficient to stimulate eicosanoid production, but maximal production was dependent upon the concentration of extracellular calcium. These results suggest that the P2Y‐purinergic receptor is coupled to phospholipase A2 via a guanine nucleotide‐binding protein, and that extracellular calcium may also be involved in the synthesis of eicosanoids by astrocytes.
Distribution of metallothionein in the human central nervous system
Authors: Blaauwgeers H. G. T. , Smitt P. A. E. Sillevis , De Jong J. M. B. V. , Troost D.
Published: January 2005

The distribution of metallothionein (MT), a metal‐binding protein, was examined immunohistochemically in the normal human brain and spinal cord. Paraffinembedded brain tissue from three patients who had died from a non‐neurological disease and were free of histopathological central nervous system alterations were processed. The results of the present study demonstrate that MT is readily detectable in a subgroup of astrocytes in the normal human brain. MT staining is most intense on grey matter astrocytes that bear short stout processes and which probably represent protoplasmic astrocytes.

Using anti‐MT and anti‐glial fibrillary acidic protein immunostaining, we could demonstrate two subpopulations of astrocytes that were mutually exclusive. The functional significance of MT‐expression in protoplasmic astrocytes is not entirely clear. Metal detoxification is only one of the many postulated functions of MT. The finding that staining for MT permits subtyping of astrocytes may be of great importance in glia research and surgical pathology of the human brain. © 1993 Wiley‐Liss, Inc.
Perineuronal nets provide a polyanionic, glia‐associated form of microenvironment around certain neurons in many parts of the rat brain
Authors: Brückner Gert , Brauer Kurt , Härtig Wolfgang , Wolff Joachim R. , Rickmann Michael J. , Derouiche Amin , Delpech Bertrand , Girard Nicole , Oertel Wolfgang H. , Reichenbach Andreas
Published: January 2005

The nature and function of previously described perineuronal nets are still obscure. In the present study their polyanionic components were demonstrated in the rat brain using colloidal iron hydroxide (CIH) staining. In subcortical regions, such as the red nucleus, cerebellar, and vestibular nuclei, most neurons were ensheathed by CIH‐binding material. In the cerebral cortex perineuronal nets were seen around numerous nonpyramidal neurons. Biotinylated hyaluronectin revealed that hyaluronan occurs in perineuronal nets. Two plant lectins [Wisteria floribunda agglutinin (WFA) and Vicia villosa agglutinin (VVA)] with affinity for N‐acetylgalactosamine visualized perineuronal nets similar to those rich in anionic components. Glutamic acid decarboxylase (GAD)‐immunoreactive synaptic boutons were shown to occupy numerous meshes of perineuronal VVA‐positive nets. Electron microscopically, VVA binding sites were scattered throughout perisynaptic profiles, but accumulated at membranes and in the extra‐cellular space except not in synaptic clefts. To investigate the spatial relationship between glial cell processes and perineuronal nets, two astrocytic markers (S100‐protein and glutamine synthetase) were visualized at the light and electron microscopic level. Two methods to detect microglia by the use of Griffonia simplicifolia agglutinin (GSA I‐B4) and the monoclonal antibody, OX‐42, were also applied. Labelled structures forming perineuronal nets were observed with both astrocytic, but not with microglial, markers. It is concluded that perineuronal nets are composed of a specialized type of glia‐associated extracellular matrix rich in polyanionic groups and N‐acetylgalactosamine. The net‐like appearance is due to perisynaptic arrangement of the astrocytic processes and these extracellular components. Similar to the ensheathment of nodes of Ranvier, perineuronal nets may provide a special ion buffering capacity required around various, perhaps highly active, types of neurons. © 1993 Wiley‐Liss, Inc.
Insulin‐like growth factor I: A mitogen for rat schwann cells in the presence of elevated levels of cyclic AMP
Authors: Jung‐Testas Ingrid , Robel Paul , Baulieu Etienne‐Emile , Schumacher Michael
Published: January 2005

To develop effective procedures for improving the regeneration of peripheral nerves and for preventing the formation of neurofibromas, it is necessary to identify the different mitogens that stimulate the proliferation of Schwann cells. Insulinlike growth factor I (IGF‐I), which is a potent autocrine growth factor in many tissues, is synthesized by proliferating Schwann cells. However, the role of IGF‐I in stimulating their division is still uncertain. Here we show that nanomolar concentrations of IGF‐I stimulate the growth of Schwann cells in primary culture. IGF‐I alone was uneffective but in the presence of forskolin (5 μM) or dibutyryl cyclic AMP (dbcAMP, 10 μM), it became a potent mitogen. Neither IGF‐II nor epidermal growth factor (EGF) were effective, even in the presence of forskolin. Insulin also stimulated Schwann cell proliferation in the presence of forskolin, but only at micromolar concentration.

Receptors for IGF‐I were visualized on the Schwann cell surface by indirect immunofluorescence staining using anti‐human IGF‐I receptor antibodies. Their presence was also assessed by binding assays using [125I]‐IGF‐I as a ligand. Scatchard analysis showed a single class of high‐affinity receptors (Kd = 1.5 nM). Competition studies with unlabeled IGF‐I or insulin indicated a half‐maximal displacement of [125I]‐IGF‐I by IGF‐I at about 5 nM, while insulin was about 500‐fold less effective. The number of binding sites for IGF‐I was increased by exposing cells for 3 days to forskolin (‐ forskolin: about 5,100; + forskolin: about 12,200 binding sites/cell). These results suggest that forskolin increases available receptors for IGF‐I, which is consistent with the synergism between cAMP and IGF‐I in stimulating Schwann cell growth. © 1993 Wiley‐Liss, Inc.
Development of radial glia and astrocytes in the spinal cord of the north american opossum (Didelphis virginiana): An immunohistochemical study using anti‐vimentin and anti‐glial fibrillary acidic protein
Authors: Ghooray Ganesh T. , Martin George F.
Published: January 2005

We have shown previously that rubrospinal axons grow around a lesion of their pathway in developing opossums and that a critical period exists for that plasticity. As a first step toward addressing the possibility that glial maturation and/or the development of an astrocytic response to lesioning contribute to loss of rubrospinal plasticity, we have studied the normal development of radial glia and astrocytes in the spinal cord of the opossum by immunostaining for vimentin (Vim) and glial fibrillary acidic protein (GFAP). Vim‐like immunoreactivity (Vim‐LI) was present in radial glia throughout the spinal cord at birth (12 days after conception), whereas GFAP‐like immunoreactivity (GFAP‐LI) was limited to cells of comparable morphology in the ventral part of the cervical cord. The subsequent appearance of GFAP‐LI followed ventral to dorsal and rostral to caudal gradients and by postnatal day (PD) 15, it was found in radial glia throughout the cord. At the same age, processes immunostained by either antibody had lost their radial orientation in the ventral horn of the cervical cord. The subsequent transformation from radial glia to astrocytes also followed ventral to dorsal and rostral to caudal gradients. By PD30, mature appearing astrocytes were immunostained by both antibodies at thoracic levels of the spinal cord, the levels lesioned in the plasticity experiments referred to above, and by PD41, they were found at all levels of the cord. Since rubral axons are able to grow around a lesion of the thoracic cord until PD26–30, there is a rough temporal correlation between the transition from radial glia to mature appearing astrocytes and the end of the critical period for plasticity. © 1993 Wiley‐Liss, Inc.
Hospital survival time in dementia: A controlled study of the effect of marital status on the interval between first admission and death
Authors: Ryan D. H.
Published: January 2005

The influence of marital status on ‘hospital survival time’ (the interval between first admission and death) was investigated in a controlled study of hospital dementia patients. There was no evidence of a significant relationship between marital status and hospital survival time after controlling for age and sex differences. The presence of a supporting spouse did not apparently shorten hospital survival time or postpone admission. Mortality following admission was analysed during the period of the study 1971–86. The probability of death during the six months following first admission was 45% for males and 32% for female patients (patients of all marital status combined), and the respective 12‐month figures were 59% and 44%. The median hospital survival time for married male and female patients was 0.6 years and 1.8 years, which suggests that first admission to hospital occurred as a late event. It follows that additional community support to families may not be effective in further reducing the demand for hospital care during the terminal stages of dementia.
A pilot study of interictal cognitive changes in elderly patients during ECT
Authors: Rosen Jules , Mulsant Benoit H. , Nebes Robert D.
Published: January 2005

Ten elderly patients were evaluated serially for interictal cognitive changes during the course of ECT using the Mini Mental State Exam (MMSE) and a modification of the Digit Symbol Substitution task (M‐DSS), an assessment of attention that measures the speed of mental processing. Performance decrease on the M‐DSS and MMSE correlated with both the number of seizures and cumulative seizure duration. The M‐DSS correlated with the MMSE items of ‘orientation’ and ‘attention’, but not with the ‘recall’ item, suggesting that the interictal memory and attentional changes induced by ECT may occur independently. For most patients, the serial performance on both the MMSE and M‐DSS decreased significantly during the course of ECT; however, the increase in the M‐DSS (indicating a performance decrement) was greater than 100%, compared to a decrease in MMSE score of less than 10%. These data are preliminary and replication with more patients and extension of the assessment for several weeks following cessation of treatment is needed.
Mapping of SPECT regional cerebral perfusion abnormalities in obsessive‐compulsive disorder
Authors: Harris Gordon J. , Hoehn‐Saric Rudolf , Lewis Robert , Pearlson Godfrey D. , Streeter Chris
Published: January 2005

Locations of cerebral perfusion abnormalities in obsessive‐compulsive disorder (OCD) were mapped with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). This report is a new, more thorough analysis of a previous study of these subjects that used region‐of‐interest methods. Ten obsessive‐compulsive patients and seven age‐ and sex‐matched control subjects were studied. Image sets were converted into stereotaxic space, normalized to each subject's mean cerebral value, then group averaged. Difference images were calculated and searched for regions with significant between‐group cerebral perfusion differences. Obsessive‐compulsive patients had significantly higher relative cerebral perfusion in medial‐frontal and right frontal cortex and in cerebellum, and significantly reduced perfusion in right visual association cortex. Increased frontal Perfusion agrees with several prior reports. The caudate nucleus, which has been controversial in neuroimaging studies of OCD, did not display a difference between groups. The results of this study provide information about the locations and extents of cerebral perfusion abnormalities in OCD. Regional abnormalities were compared with those reported in prior functional neuroimaging studies. Issues related to OCD hyperfrontality and frontal lateralization of psychopathology are discussed. Normal caudate nucleus findings are considered in relation to prior functional imaging studies and hypotheses of OCD pathology. © 1994 Wiley‐Liss, Inc.
Functional neuroanatomy of verbal free recall: A replication study
Authors: Becker James T. , Mintun Mark A. , Diehl David J. , Dobkin Jeffrey , Martidis Adam , Madoff David C. , Dekosky Steven T.
Published: January 2005

The functional neuroanatomy of verbal memory was investigated using verbal free recall during H215O positron emission tomography (PET). Twelve young (25–40 years old) normal control subjects participated in eight scans during a single scanning session during which they performed three memory tasks differing by word list length. Four subjects also had scans during a “rest” condition. Temporal lobe activation was observed during all tasks, including single‐word repetition. The frontal cortices, specifically Brodmann areas 9 and 10, were activated only when the recall word lists exceeded the memory spans (i. e., 12 and 15 words). Activation was also observed in the anterior cingulate cortex (BA24 and BA32). These data, obtained using a within‐subject design, extend previously reported findings that used mixed within‐and between‐subject designs and demonstrate important functional components of normal auditoryverbal short‐term memory. © 1994 Wiley‐Liss, Inc.
Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI
Authors: Cohen Jonathan D. , Forman Steven D. , Braver Todd S. , Casey B. J. , Servan‐Schreiber David , Noll Douglas C.
Published: January 2005

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of the prefrontal cortex during performance of subjects in a nonspatial working memory task. Subjects observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Functional scanning was performed using a newly developed spiral scan image acquisition technique that provides high‐resolution, multislice scanning at approximately five times the rate usually possible on conventional equipment (an average of one image per second). Using these methods, activation of the middle and inferior frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Effect sizes (2–4%) closely approximated those that have been observed within primary sensory and motor cortices using similar fMRI techniques. Furthermore, activation increased and decreased with a time course that was highly consistent with the task manipulations. These findings corroborate the results of positron emission tomography studies, which suggest that the prefrontal cortex is engaged by tasks that rely on working memory. Furthermore, they demonstrate the applicability of newly developed fMRI techniques using conventional scanners to study the associative cortex in individual subjects. © 1994 Wiley‐Liss, Inc.
Structural equation modeling and its application to network analysis in functional brain imaging
Authors: McLntosh A. R. , Gonzalez‐Lima F.
Published: January 2005

The analysis of brain imaging data has recently focused on the examination of the covariances of activity among neural regions during different behaviors. We present some of the theoretical and technical issues surrounding one of these covariance‐based methods: structural equation modeling. In structural equation modeling, connections between brain areas are based on known neuroanatomy, and the interregional covariances of activity are used to calculate path coefficients representing the magnitude of the influence of each directional path. The logic behind the use of structural equation modeling stems from the suggestion that brain function is the result of changes in the covariances of activity among neural elements. The technical foundations for neural structural equation models are presented, emphasizing the ability to make inferential comparisons to evaluate the experimental changes in path coefficients. Simulated data sets were used to test the effects of omitted regions and omitted connections. The results suggested that structural modeling algorithms can give hints as to possible external influences and missing paths, but that the final decision as to model modifications requires the guidance of the researcher. The utility of anatomically based models to distinguish between the direct effect of one region on another, and indirect effects of darkness or patterned light on the metabolic activity in the rat visual system. The anatomical framework for the structural equation models revealed that the total impact of ascending thalamocortical influences was modified by corticocortical interactions. Extensions of structural equation modeling to human brain imaging experiments are presented. We conclude by suggesting that neural covariances may be a more accurate way to examine the dynamic functional organization of the central nervous system. ©1994 Wiley‐Liss, Inc.
Emergence and propagation of interictal spikes in the subcortically denervated hippocampus
Authors: Buzsáki György , Hsu Melissa , Slamka Craig , Gage Fred H. , Horváth Zsolt
Published: January 2005

Spontaneous and evoked field potentials and cellular discharges of the subcortically denervated dorsal hippocampus were studied by multisite recordings in the freely behaving rat. Characteristic short‐duration (<100 ms), large‐amplitude (up to 10 mV) transients, termed interictal spikes (IIS), were seen after fimbria–fornix (FF) lesion. Both pyramidal cells and putative interneurons fired maximally during IIS, with some interneurons sustaining long bursts (up to 400 ms) of highfrequency discharges (400–600 Hz) after the IIS. The speed of propagation of IIS along the longitudinal axis of the hippocampus varied from 0.2 m/s to >3 m/s. The majority of IIS (type 1) could be accounted for by an enhanced activity of the intrahippocampal associational systems; a second class of IIS (type 2) had positive polarities in the stratum radiatum of CA1 and CA3 and propagated very rapidly (>1.5 m/s). The authors propose that type 2 IIS reflect somatic depolarization and discharge of pyramidal neurons due to nonsynaptic (probably ephaptic) effects. Ephaptic interactions may also explain the longitudinal propagation of IIS at speeds higher than the conduction velocities (0.5 m/s) of hippocampal fiber systems.

IIS emerged during the first 3 weeks after fimbria–fornix lesion, their incidence reaching a plateau of 2/min thereafter. During the same time period, paired‐pulse suppression increased in the dentate gyrus. The amplitude of test responses to angular bundle stimulation was potentiated by small‐amplitude IIS but suppressed by large‐amplitude IIS. The incidence of IIS was significantly suppressed during walking relative to standing still. Tetanic stimulation of the angular bundle or handling‐induced stress resulted in a 10‐ to 20‐fold increase in the incidence of IIS that lasted for about 30 minutes. There was a negative correlation between evoked field PSP slope and population spike amplitude in the dentate gyrus of FF‐lesioned rats; this correlation was positive in intact rats.

The authors attribute the above pathophysiological changes to sprouting of both excitatory and inhibitory GABAergic pathways as a result of denervation of the intrahippocampal circuitry. They hypothesize that the majority of the observed physiological alterations can be traced to a weakening of feedforward inhibition coupled with an enhancement of feedback inhibition and excitation.
Origins of the variations in long‐term potentiation between synapses in the basal versus apical dendrites of hippocampal neurons
Authors: Arai Amy , Black Joel , Lynch Gary
Published: January 2005

Responses to theta pattern stimulation, and the long‐term potentiation (LTP) they induce, were compared in the basal versus apical dendrites of neurons in field CA1 of hippocampus. A series of 10 theta bursts produced more than twice as much LTP in basal synapses as in their apical counterparts as measured with field EPSPs. This confirms earlier field potential studies showing that the maximum degree of potentiation (the LTP ceiling) is considerably greater in stratum oriens than stratum radiatum. Experiments with whole‐cell clamp recording obtained similar results, indicating that synapses at different loci on the same neuron reach different LTP ceilings following prolonged theta burst stimulation. The basal synapses also required fewer theta bursts to reach their LTP ceiling than did the apical synapses. Tests with paired‐pulse facilitation and an antagonist of the NMDA receptor gave no indication that the greater LTP in basal synapses was qualitatively different from the lesser effect obtained in apical contacts. Intracellular recording revealed significant differences between basal versus apical responses to single theta bursts and trains of bursts: the within‐burst depolarization was greater and the between‐burst hyperpolarization was smaller for the basal dendritic responses. These two variables have previously been proposed to influence the magnitude of LTP and the observed differences between basal versus apical synapses are in accord with this hypothesis. Together with recently described immunocytochemical results, the findings reported here suggest that variations in LTP across dendritic subfields of hippocampus reflect a differential distribution of a subclass of GABAergic interneurons.
Properties of GABA and glutamate responses in identified glial cells of the mouse hippocampal slice
Authors: Steinhäser Christian , Jabs Ronald , Kettenmann Helmut
Published: January 2005

In this study, the patch‐clamp technique was applied to brain slices to test for the presence of GABAA and glutamate receptors in glial cells of an intact tissue preparation, the hippocampus from 9–12 day old mice. Two types of glial cells were studied in the CA1 stratum pyramidale, termed passive and complex cells, which were distinct by their characteristic pattern of voltage‐dependent currents. Both cell types were previously identified as glial by combining electrophysiology with ultrastructural inspection (Steinhäuser et al., 1992, Eur J Neurosci 4:472–484). A subpopulation of passive cells was positive, all complex cells were negative for immunocytochemical staining against glial fibrillary acidic protein, a marker of mature astrocytes. In both cell types, GABA activated currents compatible with GABAA‐receptor mediated responses. The glutamate response in complex and in most of the passive cells was mediated by a ligand‐gated ion channel and closely matched the pharmacology of the kainate receptor. Activation of glutamate receptors led to a transient decrease of the resting K+ conductance in complex cells and to an irreversible decrease in the passive cells. In three passive cells, glutamate‐activated currents were most likely dominated by an electrogenic uptake. In a small group of passive cells NMDA‐activated currents were observed. This study provides evidence that glial cells from an intact tissue express receptors for the most abundant transmitters in the central nervous system, glutamate, and GABA.
Relational features of acetylcholine, noradrenaline, serotonin and GABA axon terminals in the stratum radiatum of adult rat hippocampus (CA1)
Authors: Umbriaco Denis , Garcia Sylvia , Beaulieu Clermont , Descarries Laurent
Published: January 2005

In a well‐defined sector of adult rat hippocampus (CA1, stratum radiatum), the ultrastructural features of acetylcholine (ACh), noradrenaline (NA), serotonin (5‐HT) and GABA axon terminals (varicosities) were compared by electron microscopy after immunostaining with antibodies against choline acetyltransferase, NA, 5‐HT and glutamic acid decarboxylase. Approximately 100 sectional profiles of each type were analyzed for size, presence of a synaptic membrane specialization (synaptic incidence) and composition of the microenvironment. An equivalent number of immunonegative varicosity profiles selected at random from the same micrographs were similarly examined. ACh, NA and 5‐HT varicosity profiles were of comparable size, and significantly smaller than GABA profiles. They exhibited a low frequency of junctional specialization, amounting to 7%, 15% and 21%, respectively, when extrapolated to the whole volume of these terminals. In contrast, GABA varicosities appeared entirely synaptic. The ACh, NA and 5‐HT varicosities also differed from their GABA counterparts in being juxtaposed to a greater number of unlabeled axonal varicosities and a lower number of dendritic branches. In addition, the microenvironment of immunostained terminals showed a much lower number of dendritic spines than that of immunonegative varicosities. This latter finding was viewed as another indication that predominantly asynaptic varicosities do not maintain particular relationships with their immediate surround. It was also concluded that volume transmission represents a major mode of transmission for ACh, NA and 5‐HT in adult rat hippocampus, thus contributing to the properties and functions assigned to these transmitters in this part of brain. © 1995 Wiley‐Liss, Inc.
Interaction between diazepam and noradrenergic function in man
Authors: Nutt David J.
Published: January 2005

A challenge test of clonidine (1·5 ug kg−1 i.v.) was given to 8 male volunteers, before, after a single acute dose of diazepam (15 mg the previous night), after 3 weeks chronic treatment with diazepam (25 mg/d) and in the withdrawal phase, 4–5 days after stopping diazepam. The effect of clonidine was measured on the clonidine‐induced growth hormone release, hypotension, bradycardia and sedation. Baseline (pre‐clonidine) measures of these, with the exception of increased sedation during the acute treatment, were unaltered during treatment. Clonidine‐induced growth hormone and sedation responses were not different between tests however enhanced hypotension was observed in the chronic phase. These results are discussed in the light of the mechanisms of tolerance development to diazepam.
Combined serotonin‐5‐HT2 and dopamine‐D2 antagonism in schizophrenia: Clinical, extrapyramidal and neuroendocrine response in a preliminary study with risperidone (R 64 766)
Authors: Bersani G. , Bressa G. M. , Meco G. , Marini S. , Pozzi F.
Published: January 2005

Previous studies suggested a therapeutic action of the selective serotonin 5‐HT2‐antagonist ritanserin on negative symptoms of schizophrenia and on neuroleptic‐induced parkinsonism. In this open trial the effect of risperidone, a combined serotonin‐5‐HT2‐and dopamine‐D2‐antagonist, was studied on a sample of 31 schizophrenic outpatients with an unsatisfactory response to conventional neuroleptic treatment, predominance of negative symptoms, together with troublesome extrapyramidal side‐effects. After 28 days of oral treatment (2–6 mg daily) the patients showed a significant improvement as measured by means of the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms. It is possible that the 5‐HT2 receptor antagonist properties of risperidone may improve negative symptoms. In addition, confirming previous studies, extrapyramidal symptoms showed a reduced incidence compared to previous neuroleptic treatment, suggesting a serotonin‐‐dopamine interaction in the basal ganglia. No electrocardiographic, cardiovascular or laboratory abnormalities were observed.
Performance tests in human psychopharmacology (3): Construct validity and test interpretation
Authors: Parrott A. C.
Published: January 2005

The content, criterion and face validity of human performance tests in psychopharmacology research were examined in an earlier paper. Most evidence on test meaning and interpretation, however, comprises construct validity. This is critically scrutinized here, through a brief analysis of human performance theory (Broadbent, Sanders, Sternberg), and taxonomies of human performance function (Fleishman, Holding). While much construct evidence is rather nebulous and untestable (non‐disprovable), it is probably the most accurate representation of current views on performance assessment. Tests gradually fall out of favour (or) into favour, rather than being shown to be clearly invalid (or) valid. Factor analysis, and task discrimination, are, however, two procedures for placing test interpretation/meaning on a sounder empirical basis. Returning to the overall problem of how best to investigate test validity, several proposals are made. Further criterion information should be sought, in large‐scale studies, designed specifically to compare the practical utility of different tests and test batteries. There needs to be greater atmosphere of critical debate on test meaning, in order to clarify the performance functions being assessed. Factor analysis and task discrimination procedures also need to be more widely employed. Lastly, although many tests can be seen as measures of ‘information processing’, the inference that they provide indices of ‘real‐life performance’, can rarely be made on current evidence.
The effect of acute MDMA administration on body temperature, serum corticosterone and neurotransmitter concentrations in male and female rats
Authors: McNamara Mairead G. , Kelly John P. , Leonard Brian E.
Published: January 2005

The aim of this study was to examine the effect of acute administration of (±)3,4‐methylenedioxymethamphetamine (MDMA) (20 mg/kg, i.p.) on colonic temperature, serum corticosterone and brain biogenic amine concentrations in group‐housed male and female rats and to determine if there are any gender differences in susceptibility to MDMA‐induced changes. Prior to treatment, basal colonic temperatures were higher in female than in male rats (p <0·05). Temperatures were significantly increased 30 min following MDMA (20 mg/kg, i.p.) in male rats (p <0·05), and 120 min following MDMA in female rats (p <0·05), and were still elevated 240 min following MDMA administration in both sexes. Basal corticosterone concentrations were also higher in female than in male rats (p <0·05), prior to treatment. Serum corticosterone concentrations were significantly elevated in both male and female rates 15 min after MDMA administration (p <0·001), and remained elevated for up to 4 h following MDMA (p <0·001 and p <0·05 respectively). 5‐Hydroxytryptamine (5‐HT) and 5‐hydroxy‐indole‐3‐acetic acid (5‐HIAA) concentrations were significantly depleted in the frontal cortex, hypothalamus and striatum of both male and female rats. However, pineal 5‐HT was resistant to depletion by MDMA in both male and female rats. The 5‐HIAA concentration was significantly reduced in the pineal gland of female rats, probably due to decreased catabolism of pineal 5‐HT. There was a profound decrease in the ratio 5‐HT/5‐HIAA in the frontal cortex but no changes occurred in these ratios in the striatum. hypothalamus or pineal gland in either male or female rats. Dopamine (DA) concentrations were increased and 3,4‐dihydroxyphenyl‐acetic acid (DOPAC) levels decreased in the striatum in both male and female rats 4 h after MDMA administration. The noradrenaline (NA) content of the hypothalamus was increased in male rats 30, 60 and 120 min post MDMA (p <0·05) but no changes were noted in the hypothalamus of female rats. This study indicates that there are slight gender differences in susceptibility to MDMA induced changes in rats.
A controlled comparison of sertraline and fluoxetine in acute and continuation treatment of major depression
Authors: Van Moffaert M. , Bartholome F. , Cosyns P. , De Nayer A. R. , Mertens C.
Published: January 2005

In a double‐blind multicentre trial in patients with major depression, the efficacy and the tolerability of sertraline were compared with those of fluoxetine, during an eight‐week acute treatment phase followed by a 24‐week continuation treatment phase in treatment responders.

A total of 165 patients who met DSM III‐R criteria for moderate to severe major depression were randomized to receive either sertraline or fluoxetine for short‐term and continuation treatment with initial daily dosages of either 50 mg of sertraline or 20 mg of fluoxetine. In the event of an inadequate response after 4 weeks of double‐blind therapy these doses could be doubled.

Both treatment groups demonstrated similar improvements on both the Hamilton Rating Scale for Depression (HAM‐D) and the Montgomery and Asberg Depression Rating Scale (MADRS), during the acute phase as well as during the continuation phase. Both sertraline and fluoxetine were well tolerated, the most common side‐effects being gastrointestinal symptoms. Significantly more patients in the fluoxetine‐treatment group experienced activationg adverse events.

The study demonstrates similar antidepressant efficacy and tolerability for sertraline and fluoxetine in acute and continuation treatment and equivalence of sertraline 50 mg daily with fluoxetine 20 mg daily in the treatment of depression.
Transduction of satellite cells after prenatal intramuscular administration of lentiviral vectors
Authors: MacKenzie Tippi C. , Kobinger Gary P. , Louboutin Jean‐Pierre , Radu Antoneta , Javazon Elizabeth H. , Sena‐Esteves Miguel , Wilson James M. , Flake Alan W.
Published: January 2005

Background

We have previously reported long‐term expression of lacZ in myocytes after in utero intramuscular injection of Mokola and Ebola pseudotyped lentiviral vectors. In further experiments, we have noted that these vectors also transduce small cells at the periphery of the muscle fibers that have the morphology of satellite cells, or muscle stem cells. In this study we performed experiments to further define the morphology and function of these cells.

Methods

Balb/c mice at 14–15 days gestation were injected intramuscularly with Ebola or Mokola pseudotyped lentiviral vectors carrying CMV‐lacZ. Animals were harvested at various time points, muscles were stained with X‐gal, and processed for electron microscopy (EM) and immunofluorescence. To determine whether transduced satellite cells were functionally capable of regenerating injured muscles, animals were injected with notexin in the same area 8 weeks after the in utero injection of viral vector.

Results

Transmission EM of transduced cells confirmed the ultrastructural appearance of satellite cells. Double immunofluorescence for β‐galactosidase and satellite cell markers demonstrated co‐localization of these markers in transduced cells. In the notexin‐injured animals, small blue cells were seen at the areas of regeneration that co‐localized β‐galactosidase with markers of regenerating satellite cells. Central nucleated blue fibers were seen at late time points, indicating regenerated muscle fibers arising from a transduced satellite cell.

Conclusions

This study demonstrates transduction of muscle satellite cells following prenatal viral vector mediated gene transfer. These findings may have important implications for gene therapy strategies directed toward muscular dystrophy. Copyright © 2004 John Wiley & Sons, Ltd.