bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneity in gap junction expression in astrocytes cultured from different brain regions
Authors: Batter David K. , Corpina Richard A. , Roy Christine , Spray David C. , Hertzberg Elliot L. , Kessler John A.
Published: January 2005

Heterogeneity among astrocytes suggests that their role in the central nervous system is more complex than is commonly recognized. This paper describes just such a functional difference, comparing gap junctions in astrocytes derived from two brain regions. Astrocytes, both in situ and in culture, employ gap junctions as a means of intercellular communication. Recent evidence utilizing cultured rat cortical and striatal astrocytes has shown that these channels consist of subunits of connexin 43, the same protein as that composing cardiac gap junctions. Here we report that astrocytes cultured from neonatal rat hypothalamus contain a greater number of functional channels than astrocytes from the striatum, a difference reflected in both connexin 43 protein and mRNA. Specifically, in hypothalamic astrocytes the level of connexin 43 protein was approximately four times that found in comparable cultures from the striatum, as determined by immunoblotting. Complementary results from immunocytochemical experiments using an antibody specific for connexin 43 reveal significantly greater fluorescence in astrocytes cultured from the hypothalamus as compared to those from the striatum. Northern blot analysis showed that connexin 43 mRNA levels were also approximately 4‐fold greater in the hypothalamic cultures, consistent with difference seen by immunoblotting. Finally, dye coupling studies using confluent cultures consistently showed that within 1 min Lucifer Yellow injected into striatal astrocytes spread to immediately surrounding cells while in hypothalamic astrocytes dye often spread to apparent third or fourth order neighbors within the same time period. Thus, the higher level of connexin 43 expression seen in hypothalamic astrocytes results in cells with greater numbers of functional channels. Interestingly, both the immunocytochemical and dye coupling experiments also revealed heterogeneity, among cells derived from each brain area, indicating that both region contain subpopulations of astrocytes. Taken together, our data show differences in gap junction expression, both within and between astrocytes derived from two brain regions. Further, this heterogeneity appears to derive from differences in either transcriptional regulation or in mRNA stability, and not from changes in the relative levels of phosphorylated forms of connexin 43. Thus, these data, which are consistent with light microscopic immunocytochemical studies in tissue sections of rat brain, predict that, in vivo, region‐specific coupling subserves functional specialization within the central nervous system. © 1992 Wiley‐Liss, Inc.
Purification and characterization of an astrocyte GABA‐carrier inducing protein (GABA‐CIP) released from cerebellar granule cells in culture
Authors: Nissen Jan , Schousboe Arne , Halkier Torben , Schousboe Inger
Published: January 2005

A glycoprotein that induces γ‐aminobutyric acid (GABA) carriers in cultured cerebellar astrocytes was isolated and purified from conditioned media from cultured cerebellar granule cells by anion exchange chromatography, affinity chromatography, and gel filtration. Following gel filtration three fractions corresponding to Mr 30,000, 60,000, and 240,000 exhibited GABA carrier inducing activity. SDS‐PAGE of the Mr 30,000 fraction revealed under non‐reducing conditions three bands corresponding to Mr 30,000, 60,000, and 120,000. Under reducing conditions only the band corresponding to an Mr of 30,000 was visible. An identical N‐terminal amino acid sequence and amino acid composition was found in the Mr 30,000 and the Mr 60,000 fraction from the gel filtration. These results suggest that the protein polymerizes into di‐ and tetramers. Computer base analysis of the N‐terminal amino acid sequence revealed no obvious homology with previously reported N‐terminal amino acid sequences.

Application of the glycoprotein to cerebellar astrocytes led time and dose dependently to an increased GABA uptake. The effect became maximal after 24h exposure of the cells. Kinetic analysis of the GABA uptake showed that exposure of the astrocytes to the glycoprotein led to an increase in Vmax for GABA uptake without affecting Km, suggesting an increase in the number of GABA carrier molecules. Addition of actinomycin D together with the glycoprotein abolished this effect suggesting that the glycoprotein acts by stimulating de novo synthesis of GABA carriers. Hence, the newly purified protein secreted from neurons is named GABA‐carrier inducing protein (GABA‐CIP). © 1992 Wiley‐Liss, Inc.
Microglial involvement in experimental autoimmune inflammation of the central and peripheral nervous system
Authors: Gehrmann Jochen , Gold Ralf , Linington Christopher , Lannes‐Vieira Joseli , Wekerle Hartmut , Kreutzberg Georg W.
Published: January 2005

Microglial cells form a network of potential antigen presenting cells throughout the nervous system. Much progress has recently been made towards a better understanding of their immunological properties. This study examines their activation in 2 models of T cell‐mediated autoimmune inflammation of the nervous system, experimental autoimmune encephalomyelitis (EAE) and its peripheral counterpart, experimental autoimmune neuritis (EAN), induced by the transfer of antigen‐specific T cell lines. In both models microglial activation occurs at early stages of the disease. Activated microglial cells show an increased expression of MHC class I and II antigens. In EAE ultrastructural analysis revealed that MHC antigen expression is pronounced on perivascular microglial cells, suggesting this cell population may be important for antigen presentation at a site close to the blood‐brain barrier. In contrast to EAE, the microglial reaction in EAN occurs at sites remote from the inflammatory response in the peripheral nerve, not only in the spinal cord but also in the terminal projection fields of primary sensory neurons in the lower brainstem. This early microglial activation in EAN suggests that a rapid and remote signaling mechanism can operate following peripheral inflammation. Immuno‐electron microscopy revealed that activated microglial cells are also involved in the synaptic deafferentation of spinal cord motoneurons during autoimmune reactions. The rapid involvement of microglial cells in experimental autoimmune inflammation of the nervous system further points to their role as the main intrinsic immuneffector cell population of the central nervous system.
Cytotoxicity of microglia
Authors: Banati Richard B. , Gehrmann Jochen , Schubert Peter , Kreutzberg Georg W.
Published: January 2005

The most characteristic property of microglia is their swift activation in response to neuronal stress and their capacity for site‐directed phagocytosis. The transformation of microglia into intrinsic brain macrophages appears to be under strict control and takes place if neuronal and/or terminal degeneration occurs in response to nerve lesion. The differentiation of microglia into brain macrophages is accompanied by the release of several secretory products, e.g., proteinases, cytokines, reactive oxygen intermediates, and reactive nitrogen intermediates. Interference with the microglial activation or the productions of cytotoxic metabolites by microglia may thus offer new therapeutic opportunities for the prevention of neuronal cell death in CNS disease.
Pregnenolone metabolism in rodent embryonic neurons and astrocytes
Authors: Kabbadj Khadija , El‐Etr Martine , Baulieu Etienne‐Emile , Robel Paul
Published: January 2005

The rat CNS has been previously shown to synthesize pregnenolone (PREG) and to convert it into progesterone (PROG) and some of its 5α‐reduced metabolites. However, the brain cell types involved in the metabolic conversions of PREG are poorly known. Selective conditions were used to obtain purified cultures of neurons and astrocytes from mouse or rat fetal striatum and cerebral cortex. Neurons converted PREG to only one identified metabolite, 20α‐dihydro PREG, whereas astrocytes converted PREG also to PROG, 5α‐dihydro PROG, and 3α (3β)‐5α‐tetrahydro PROG. Therefore, astrocytes can convert the neurosteroid PREG into the steroid hormone PROG and the neuromodulatory steroid 3α, 5α‐tetrahydro PROG, whereas neurons lack the Δ5‐3β‐hydroxysteroid dehydrogenase isomerase activity (and cholesterol side‐chain cleavage activity), necessary for the biosynthesis of PROG. Provision of steroid substrates is another example of cross‐talk between glial cells and neurons.
Induction of astrocyte glutamine synthetase activity by the lathyrus toxin β‐N‐oxalyl‐L‐α,β‐diaminopropionic acid (β‐L‐ODAP)
Authors: Miller Stephan , Nunn Peter B. , Bridges Richard J.
Published: January 2005

β‐N‐Oxalyl‐L‐α,β‐diaminopropionic acid (β‐L‐ODAP) is thought to be the causative agent in lathyrism due to its neuroexcitatory and neurotoxic properties. We have recently reported that β‐L‐ODAP is also gliotoxic at high concentrations (Bridges et al.: Brain Res 561:262, 1991). Evidence is now presented that low, subgliotoxic concentrations of β‐L‐ODAP may alter the ability of astrocytes to regulate glutamate concentrations in the CNS by increasing astrocyte glutamine synthetase activity. When astrocytes cultured from rat cortex were exposed to 100 μM β‐L‐ODAP for 24 h, the resulting glutamine synthetase activity was 155% of control levels. This effect was enantiomer and isomer‐specific, dose‐dependent, and required protein translation as the induction was blocked with cycloheximide. The effect of β‐L‐ODAP on glutamine synthetase was not mimicked by α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionate (AMPA) or kainate, suggesting that the induction was not transduced solely through activation of cell surface non‐N‐methyl‐D‐aspartate (NMDA) glutamate receptors. An intracellular site of action of β‐L‐ODAP is proposed because its effect on glutamine synthetase activity could be blocked by the amino acid uptake blocker dihydrokainate.
Characterization of stretch‐activated ion channels in cultured astrocytes
Authors: Islas Leon , Pasantes‐Morales Herminia , Sanchez Jorge A.
Published: January 2005

The presence of a stretch‐activated channel in rat cerebellar astrocytes in culture is described. This stretch‐sensitive channel is K+ ‐selective and its open probability increases with suction following a Boltzmann‐like distribution with half activation at 45 mm Hg. Kinetic analysis of the single‐channel data indicated that there are two open and two closed states and that the shortest time constants of both open and closed states are the most sensitive to suction. A symmetrical two‐barrier‐one‐site permeation model can quantitatively describe the inward rectification of the single‐channel current to voltage relations. It is suggested that this stretch‐activated channel plays a role in the regulatory volume response of astrocytes to hyposmotic conditions. © 1993 Wiley‐Liss, Inc.
Changes in ultrastructure and voltage‐dependent currents at the glia limitans of the frog optic nerve following retinal ablation
Authors: Blanco Rosa E. , Marrero Hector , Orkand Paula M. , Orkand Richard K.
Published: January 2005

The surface of the frog optic nerve consists of astrocytic processes separated by narrow extracellular clefts underlying a pial sheath of loose connective tissue. Macroscopic voltage dependent currents can be recorded from this surface using the loose patch‐clamp technique. In this study the changes in ultrastructure and voltage dependent Na currents have been studied for up to 1 year following removal of the retina. During the first 1–4 weeks, many of the myelinated and unmyelinated axons of the retinal ganglion cells degenerate, and the debris is phagocytosed by macrophages and glial cells. However, some morphologically intact axons remain even 12 weeks after surgery. Finally, after 16 weeks all the axons have disappeared, leaving a nerve consisting only of glial cells, some of which contain phagosomes. At 40–52 weeks after enucleation, the nerve persists, at 20–40% of the normal diameter, consisting mostly of normal looking astrocytes. The amplitude of the voltage dependent Na currents recorded from nerves during the first 1–4 weeks after enucleation, with the pial sheath intact, decreases by about 50%. After 8 weeks, the Na current recorded from the surface is about 30% of control. At 16–52 weeks after removal of the retina, when there are no intact axons, the Na current is reduced by 90%. If, however, the pial sheath is stripped away, the Na currents recorded from the glial surface are 40–50% of control during this same 16‐ to 52‐week period, suggesting that in the all‐glia nerve, the currents are shunted by the relatively thicker pial sheath. In contrast to their normal TTX sensitivity, the voltage dependent Na currents recorded from these all glial nerves are insensitive to TTX (5 μM) but disappear when the external Na is replaced by TMA. The results suggest that in situ glial voltage dependent membrane properties depend on interactions between the glial cells and the neighboring axons. © 1993 Wiley‐Liss, Inc.
Glial plasmalemmal vesicles: A subcellular fraction from rat hippocampal homogenate distinct from synaptosomes
Authors: Nakamura Yoichi , Iga Kozo , Shibata Taiho , Shudo Masachika , Kataoka Kiyoshi
Published: January 2005

By a Percoll density‐gradient centrifugation of rat hippocampal ho‐mogenate, We found a novel subcellular fraction (specific gravity ≈ 1.046 g/ml), besides synaptosomes (≈1.060 g/ml), which showed a high activity of Na+‐dependent glutamate uptake. The initial rate of the glutamate uptake in this fraction was as high as twice that in synaptosomes. Activities of choline acetyltransferase and high affinity choline uptake were, on the other hand, much lower. γ‐Aminobutyric acid uptake activity was nearly equivalent in both fractions. Electron microscopic observations revealed that the fraction was morphologically different from synaptosomal or myelin fractions, but mainly consisted of two different types of empty membrane vesicles; irregular (0.3−0.8 μm in diameter) and spheroid type (0.2 μm). The immunoreactivity to glial fibrillary acidic protein was appreciably high in this fraction. The marker enzyme analysis showed the fraction was rich in plasma membranes. On the basis of these results, the fraction is termed glial plasmalemmal vesicles(GPV).

We analyzed kinetically the reaction of Na+ ‐dependent glutamate uptake by GPV comparing with that by synaptosomes. Km values for glutamate in GPV was 4.7 μM and Vmax was 33 nmol/mg/min, while in synaptosomes 11 μM and 17 nmol/mg/min, respectively. Hill coefficients of Na+ activation in GPV and synaptosome were 1.1 and 2.0, respectively. Thus, the mechanism or transporter molecule in glial cells for Na+‐dependent glutamate transport is likely to be different from that in neurons. © 1993 Wiley‐Liss, Inc.
Glutamate blocks astroglial stellation: Effect of glutamate uptake and volume changes
Authors: Shao Yanping , Enkvist M. O. Kristian , McCarthy Ken D.
Published: January 2005

Neurotransmitters which increase intracellular cAMP levels can cause cultured astroglia to change from a flat, polygonal shape to a stellate morphology. Little is known about how glial stellation can be regulated by other transmitters. In the present study, we demonstrated that L‐glutamate blocked isoproterenol (ISO) or dibutyryl‐cAMP induced stellation in astroglia. The glutamate inhibition was concentration dependent, with its maximal effect on >90% of cells at 500 μM. Glutamate also reversed glial stellation within a short period (<30 min). Glutamate uptake analogues, D‐glutamate and D‐aspartate, rather than receptor agonists, kainate and quisqualate, mimicked the glutamate effect. Likewise, the glutamate uptake blocker, D‐thero‐ß‐hydroxyaspartate, blocked the glutamate effect. The glutamate inhibition was not a result of inhibition of cAMP formation, since norepinephrine, which inhibited 80% of ISO‐stimulated cAMP, also caused glial stellation. Increases in extracellular K+ to 50 mM also reduced glial stellation, whereas 25 mM K+ had little effect. Since 25 mM K+ caused much greater depolarization than 400 μM glutamate, it was unlikely that the effects of both glutamate and high [K+] on glial stellation were due to membrane depolarization. Hypotonic treatment (120 mOsm) enhanced, whereas hypertonic treatment (520 mOsm) prevented, the glutamate reversal of glial stellation. Thus, glial swelling appeared to be a primary mechanism for the inhibitory effect of glutamate and high [K+] on glial stellation. This mechanism could also explain the observation that glutamate inhibited stellation induced by PMA, a PKC activator. Our data suggest that glutamate released from neurons during neuronal activity or pathology can be taken up by astrocytes and alter their morphology. Changes in glial morphology may in turn affect the volume and composition of the extracellular space and, as a result, neuronal activity. © 1994 Wiley‐Liss, Inc.
Development of microglia in mouse neopallial cell cultures
Authors: Neuhaus Jochen , Fedoroff Sergey
Published: January 2005

Microglia develop in cultures initiated from disaggregated neopallial cells of newborn C3H/HeJ mice when the cultures are subjected to nutritional deprivation for 10 or more days (Hao et al: Int J Dev Neurosci 9:1‐14, 1991). In the present experiments, the cultures were pulsed with BrdU for 3 hours at different times during incubation and then the cells were immunoreacted with antibodies against BrdU, GFAP, and CR3 receptor. The dividing cells (BrdU+) were found to be either GFAP+ or GFAP−, but not Mac‐1+/BrdU+. Infection of proliferating cells after 2 or more days of incubation with replication‐deficient retroviral vector containing E. coli lacZ reporter gene resulted in many labeled astroglia cell clones but no labeled microglia. However, when cells were infected right after disaggregation of neopallium, labeled Mac‐1+ microglia were found. When Mac‐1+ cells in a suspension of disaggregated neopallial cells were killed using complement mediated lysis before setting up the cultures, Mac‐1+ microglia developed, in spite of the treatment. We conclude that in cultures initiated from mouse neopallium there are MAC‐1−/GFAP− microglia progenitor cells which do not divide in nutritionally deprived cultures but can transform into Mac‐1+ microglia under the influence of astroglia‐derived trophic factors. Microglia, which become Mac‐1+ (i.e., express CR3 receptor), proliferate extensively in the presence of CSF‐1 (which is produced by astroglia). © 1994 Wiley‐Liss, Inc.
Divergent lineages for oligodendrocytes and astrocytes originating in the neonatal forebrain subventricular zone
Authors: Luskin Marla B. , McDermott Kieran
Published: January 2005

Although previous studies have revealed that the prenatal rat ventricular zone contains separate progenitor cells for neurons, astrocytes, and oligodendrocytes during the development of the cerebral cortex as early as the beginning of neurogenesis (Luskin et at., 1993; Grove et al., 1993), it is still unclear whether there are bipotential progenitor cells in the neonatal telencephalic subventricular zone which give rise to both astrocytes and oligodendrocytes during the peak of gliogenesis. To investigate this possibility, discrete groups of clonally related cells, generated by infecting progenitor cells of the neonatal subventricular zone with a retroviral lineage tracer, were analyzed ultrastructurally.

An intracerebral injection of retrovirus encoding the reporter gene E. coli ß‐galactosidase (lacZ) was made into the subventricular zone of newborn rats. Two weeks later their brains were perfused, sectioned, and histochemically reacted with X‐Gal to identify at the light microscopic level clones of lacZ‐positive cells. The sections were processed for electron microscopy to enable the identity of clonally related cells to be assessed at the ultrastructural level.

All of the clones analyzed contained cells of the same phenotype and could be divided into four distinct types: immature cell clones situated in the subependymal zone surrounding the lateral ventricle, oligodendrocytes clones, and white or gray matter astrocyte clones. Not all of the cells in every clone displayed ultrastructural features of a mature cell. Rather, in some glial clones the lacZ‐positive cells appeared to be at different stages of differentiation. However, we never encountered clones which contained both macroglial subtypes or clones containing neurons. Although the existence of bipotential progenitor cells cannot be completely dismissed, our results indicate the absence of progenitor cells in vivo in the neonatal subventricular zone which divide and generate astrocytes and oligodendrocytes. © 1994 Wiley‐Liss, Inc.
Transport of L‐arginine in cultured glial cells
Authors: Schmidlin Andreas , Wiesinger Heinrich
Published: January 2005

Uptake of radiolabelled L‐arginine was studied in four different kinds of glial cultures, in astroglia‐rich primary cultures derived from neonatal rat and mouse brains, in pure murine astrocyte cultures, and in rat glioma cells C6‐BU‐1. A saturable component of uptake was found in all cases with KM values between 15 and 35 μM and Vmax values between 0.8 and 2.5 nmol · min−1 · (mg protein)−1. In addition, in all cell types a non‐saturable component dominated total uptake at high concentrations of extracellular arginine. Rates of uptake of arginine were not affected when Na+ or Cl− were absent from the incubation buffer. Carrier‐mediated uptake of arginine was reduced by depolarizing concentrations of K+ and strongly inhibited by an excess of lysine or ornithine. Histidine, asparagine, glutamine, citrulline, creatine, NG‐nitro‐L‐arginine, NG‐monomethyl‐L‐arginine, or L‐canavanine inhibited L‐arginine transport to various degrees. Uptake of arginine was not reduced in the presence of serine or alanine, cysteic acid, N‐methyl‐α‐aminoisobutyric acid, or 2‐aminobicyclo‐(2.2.1)‐heptane‐2‐carboxylic acid. Rates of uptake of arginine were increased when cells had been preloaded with lysine. Preincubation of primary cultures, but not glioma cells, with bacterial lipopolysaccharide stimulated transport of arginine by increasing the Vmax value of uptake. This stimulation was dependent on protein synthesis. The results suggest that, at physiological concentrations, arginine is taken up into the glial cells with the help of the transport system “y+” for basic amino acids. In glial primary cultures, uptake of arginine appears to be regulated by compounds which also exert influence on nitric oxide synthesis. © 1994 Wiley‐Liss, Inc.
Stability over one year in patients admitted to a nursing home dementia unit
Authors: Rovner Barry W. , Lucas‐Blaustein Jane , Folstein Marshal F. , Smith Shannon W.
Published: January 2005

The majority of nursing home patients in the United States have dementia or behavioral problems yet the outcome of care they receive for those disorders is unknown. We compared the outcomes of Alzheimer's disease patients residing on a dementia unit with other Alzheimer's patients in the same nursing home over a one‐year period. We found that the functional capacity of dementia unit patients remained stable over the study period while that of non‐unit patients declined. This study suggests the usefulness of dementia units in nursing homes and raises issues relevant to their future study.
Single photon emission tomography in dementia
Authors: Beats Barbara , Burns Alistair , Levy Raymond
Published: January 2005

Single photon emission tomography (SPET) is a technique which allows simple non‐invasive measures of cerebral blood flow and indirectlymetabolism. It has considerablepotential as a tool for the differential diagnosis ofdementia. A review is presented tracing the development and current applications of the technique and the practical implications of its use.
The kingston standardized cognitive assessment
Authors: Rodenburg Martin , Hopkins Robert W. , Hamilton Pamela F. , Ginsburg Lynne , Nashed Yousery , Minde Nina
Published: January 2005

In spite of the fact that demographic trends show an increase in the number of elderly persons, and hence more diagnosed as suffering from senile dementia, the cognitive assessment of the organically brain damaged elderly person still too often depends on the use of brief and incomplete rating scales, and is thus often poorly performed. The simple dementia rating scales in current use may fail to provide the range or depth needed for an adequate evaluation of the individual patient. The Kingston Standardized Cognitive Assessment is offered as an improved method of assessment. This instrument is described here in terms of its structure, function, statistical properties and normative data. We also provide examples of its clinical use.
Clinical assessment of psychopathology among elderly residents (CAPER): Development and pilot testing of a screening instrument to detect the presence of psychiatric disorders among residents of long‐term instituions
Authors: Reichenfeld H. F. , Bazile E. , Khan B. B. , Raman S.
Published: January 2005

Although psychiatric illnesses are common occurrences in institutions taking care of the elderly, admission is seldom preceded by a mental health evaluation and only rarely are there provisions for ongoing psychiatric care. Screening a population for specific psychiatric disorders is traditionally carried out by lay interviewers. In field studies organized under the Epidemiological Catchment Area Program of the National Institute of Mental Health they were specially trained to complete the Diagnostic Interview Schedule (DIS) (Munson et al., 1985; Robins et al., 1985). An initial examination carried out by a trained psychiatrist can, however, also be regarded as a screen for the detection of the presence or absence of a psychiatric disorder, and defining a ‘case’ (Leighton et al., 1966). It represents the first step in the evaluation. The establishment of a specific diagnostic label, though at times possible as a result of one examination, is more usually determined at the second, third or fourth step after obtaining additional information from relatives or caregivers, and assessing the results of neuropsychological and biological tests. CAPER (Clinical Assessment of Psychopathology among Elderly Residents) was developed to provide in a semistructured format such a typical initial examination of elderly residents of long‐term institutions. It is designed to represent the first step in a comprehensive evaluation, can be completed in 15–20 minutes and generates clinically useful information. CAPER allows the examiner to draw conclusions commonly encountered in everyday practice and gives a choice between (1) no psychopathology, (2) definite psychopathology and (3) suspected psychopathology. A great deal of demographic data are also accumulated and entered into a specifically designed multi purpose computer program. The program can be used for epidemiological studies to determine the prevalence of specific disorders in different populations, but also has applications in correlating the findings of an initial clinical examination with the results of neuropsychological tests.
Does visuospatial memory in senile dementia of the Alzheimer type depend on the severity of the disorder?
Authors: Sahgal Arjun , Lloyd Stephen , Wray Catherine J. , Galloway Peter H. , Robbins Trevor W. , Sahakian Barbara J. , McKeith Ian G. , Cook Julia H. , Disley Jennifer C. A. , Edwardson James A.
Published: January 2005

Visuospatial memory was studied in patients suffering from senile dementia of the Alzheimer type (SDAT). They had been allocated into one of two groups depending on the severity of their disorder (mild or moderate), and a control group of healthy elderly subjects was included. Three different microcomputer‐controlled tasks were used. The spatial span task was able to distinguish between the two SDAT groups. Both groups were impaired, relative to control, on spatial recognition. The deficit in spatial working memory was also equivalent in the mild and moderate groups and was accompanied by evidence of an intact strategic approach to the task. The normal positive relationship between spatial memory performance and strategy was in fact reversed in the SDAT groups, suggesting a pure spatial memory deficit. These results show that spatial memory processes are impaired in the early stages of SDAT and get worse as the disease progresses. They also suggest that the neuroanatomical foci of the deficits may be predominantly in posterior cortical regions (including hippocampus), rather than the frontal cortex.
Dementia of frontal lobe type in monozygotic twins
Authors: Hodgson R. E. , Barrett K. , Crook R.
Published: January 2005

A pair of monozygotic twins who are concordant for dementia of frontal lobe type are discussed. This is believed to be the first case report of twins with this type of dementia. The salient features of dementia of frontal lobe type are also discussed.
Neural modeling and functional neuroimaging
Authors: Horwitz Barry , Sporns Olaf
Published: January 2005

Two research areas that so far have had little interaction with one another are functional neuroimaging and computational neuroscience. The application of computational models and techniques to the inherently rich data sets generated by “standard” neurophysiological methods has proven useful for interpreting these data sets and for providing predictions and hypotheses for further experiments. We suggest that both theory‐ and data‐driven computational modeling of neuronal systems can help to interpret data generated by functional neuroimaging methods, especially those used with human subjects. In this article, we point out four sets of questions, addressable by computational neuroscientists whose answere would be of value and interest to those who perform functional neuroimaging. The first set consist of determining the neurobiological substrate of the signals measured by functional neuroimaging. The second set concerns developing systems‐level models of functional neuroimaging data. The third set of questions involves integrating functional neuroimaging data across modalities, with a particular emphasis on relating electromagnetic with hemodynamic data. The last set asks how one can relate systems‐level models to those at the neuronal and neural ensemble levels. We feel that there are ample reasons to link functional neuroimaging and neural modeling, and that combining the results from the two disciplines will result in furthering our understanding of the central nervous system. © 1994 Wiley‐Liss, Inc.

This Article is a US Goverment work and, as such, is in the public domain in the United State of America.
Neural network interactions related to auditory learning analyzed with structural equation modeling
Authors: Gonzalez‐Lima F. , McLntosh A. R.
Published: January 2005

If learning is an emergent property of interacting brain regions, understanding it requires a network analysis of the patterns of interaction between brain regions. Brain mapping techniques have the potential of providing information about functional interactions within entire neural systems, but computational methods are needed to make sense of the complex interactions that take place in the brain. This review paper illustrates, with examples from auditory learning studies, the application of a computational method that quantifies the interactions among neural regions in terms of networks, and what is gained from this approach. The method is Structural Equation Modeling, and it computes network interactions by combining anatomical circuitry with the covariation in the activity between auditory structures. Activity was assessed by fluorodeoxyglucose uptake, and the functional strengths of auditory pathways were quantified by computing path coefficients representing the strength of the functional influence through each anatomical path. Changes in these values were used as indices of how learned information was processed and modified within the auditory system. Structural models of the auditory system revealed the patterns of network interactions related to habituation to a sound, as well as the patterns related to the opposite learned associative properties of the same sound. They illustrated how the functional interactions among parallel auditory neural pathways were modified as a result of auditory learning. This analysis supports the hypothesis that auditory learning is an emergent network property, distributed among connected brain regions showing specific patterns of interaction. ©1994 Wiley‐Liss, Inc.
Cluster analysis in individual functional brain images: Some new techniques to enhance the sensitivity of activation detection methods
Authors: Poline Jean‐Baptiste , Mazoyer Bernard
Published: January 2005

Low signal‐to‐noise ratio is the fundamental limit of current voxel‐based strategies for detecting activations in functional brain maps. We propose some new techniques to enhance detection sensitivity in the analysis of brain activation maps. These new techniques are: (1) a multi‐filtering strategy; and (2) the use of a hierarchical decomposition. Multi‐filtering is used to optimize detection sensitivity when multiple signals of various sizes are present, while hierarchical decomposition allows selection of activation foci on the basis of their spatial extent and magnitude. Both techniques are combined within a single testing procedure that contrals the overall type I error. This approach shows significantly higher detectioin sensitivity on both simulated and experimental single‐subject datasets. ©1994 Wiley‐Liss, Inc.
Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin
Authors: Liguori Michael J. , Anderson Mark G. , Bukofzer Stanley , McKim James , Pregenzer Jeffrey F. , Retief Jacques , Spear Brian B. , Waring Jeffrey F.
Published: January 2005

Idiosyncratic drug toxicity, defined as toxicity that is dose independent, host dependent, and usually cannot be predicted during preclinical or early phases of clinical trials, is a particularly confounding complication of drug development. An understanding of the mechanisms that lead to idiosyncratic liver toxicity would be extremely beneficial for the development of new compounds. We used microarray analysis on isolated human hepatocytes to understand the mechanisms underlying the idiosyncratic toxicity induced by trovafloxacin. Our results clearly distinguish trovafloxacin from other marketed quinolone agents and identify unique gene changes induced by trovafloxacin that are involved in mitochondrial damage, RNA processing, transcription, and inflammation that may suggest a mechanism for the hepatotoxicity induced by this agent.
In conclusion,

this work establishes the basis for future microarray analysis of new compounds to determine the presence of these expression changes and their usefulness in predicting idiosyncratic hepatotoxicity.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;41:177–186.)
Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C
Authors: Radkowski Marek , Gallegos-Orozco Juan F. , Jablonska Joanna , Colby Thomas V. , Walewska-Zielecka Bozena , Kubicka Joanna , Wilkinson Jeffrey , Adair Debra , Rakela Jorge , Laskus Tomasz
Published: January 2005

It is unclear whether the current antiviral treatment for chronic hepatitis C virus (HCV) infection results in complete elimination of the virus, or whether small quantities of virus persist. Our study group comprised 17 patients with chronic HCV who had sustained virological response (SVR) after interferon/ribavirin treatment. Serum and peripheral blood mononuclear cells were collected 2 to 3 times at 3- to 6-month intervals starting 40 to 109 months (mean, 64.2 ± 18.5 months) after the end of therapy. In addition, lymphocyte and macrophage cultures were established at each point. In 11 patients, frozen liver tissue samples were available from follow-up biopsies performed 41 to 98 months (mean, 63.6 ± 16.7 months) after therapy. Presence of HCV RNA was determined by sensitive reverse-transcriptase polymerase chain reaction, and concentration of positive and negative strands was determined by a novel quantitative real-time reverse transcriptase polymerase chain reaction. Only 2 of 17 patients remained consistently HCV RNA negative in all analyzed compartments. HCV RNA was detected in macrophages from 11 patients (65%) and in lymphocytes from 7 patients (41%). Viral sequences were also detected in 3 of 11 livers and in sera from 4 patients. Viral replicative forms were found in lymphocytes from 2 and in macrophages from 4 patients.
In conclusion,

our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation. (Hepatology 2005;41:106–114.)
Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice
Authors: Su Grace L. , Gong Ke Qin , Fan Ming Hui , Kelley William M. , Hsieh Jason , Sun Jian Min , Hemmila Mark R. , Arbabi Saman , Remick Daniel G. , Wang Stewart C.
Published: January 2005

Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP–adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct.
In conclusion,

LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;41:187–195.)
Diosgenin-induced biliary cholesterol secretion in mice requires Abcg8
Authors: Kosters Astrid , Frijters Raoul J. J. M. , Kunne Cindy , Vink Edwin , Schneiders Marit S. , Schaap Frank G. , Nibbering Catherina P. , Patel Shailendra B. , Groen Albert K.
Published: January 2005

The plant sterol diosgenin has been shown to stimulate biliary cholesterol secretion in mice without affecting the expression of the adenosine triphosphate-binding cassette transporter heterodimer Abcg5/g8. The aim of this study was to investigate the mechanism of diosgenin-induced cholesterol hypersecretion and to identify the genes involved. Surprisingly, despite its lack of effect on Abcg5/g8 expression in wild-type mice, diosgenin did not stimulate biliary cholesterol secretion in mice deficient for

Abcg8
. Analysis of the kinetics of cholesterol secretion suggested that diosgenin probably activates a step before Abcg5/g8. To identify potential diosgenin targets, gene expression profiling was performed in mice fed a diosgenin-supplemented diet. Diosgenin feeding increased hepatic expression of genes involved in cholesterol synthesis as well as genes encoding for several cytochrome P450s. No significant change in expression of known cholesterol transporters was found. Comparison with published expression-profiling data for

Srebp2

-overexpressing mice, another mouse model in which biliary cholesterol secretion is elevated, revealed a number of genes with unknown function that were upregulated in both diosgenin-fed mice and mice overexpressing

Srebp2
.
In conclusion,

we found that although Abcg8 is essential for most diosgenin-induced biliary cholesterol hypersecretion, diosgenin probably does not interact directly with Abcg5/Abcg8, but rather increases cholesterol delivery to the heterodimer.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;41:141–150.)
Experience‐dependent modifications of hippocampal place cell firing
Authors: Bostock Elizabeth , Muller Robert U. , Kubie John L.
Published: January 2005

Understanding the empirical rules that regulate alterations of hippocampal firing fields will enhance our understanding of hippocampal function. The current study sought to extend previous research in this area by examining the effect of substituting a new stimulus for a familiar stimulus in a familiar environment. Hippocampal place cells were recorded while rats chased food pellets scattered onto the floor of a cylindrical apparatus with a white cue card affixed to the apparatus wall. Once a place cell had been recorded in the presence of the white card, the white card was replaced by a black card of the same size and shape. The place cell was then recorded in the presence of the black card. Thirty‐six cells were recorded using this procedure. All cells had stable firing fields in the presence of the white card. Both the white and black cards had stimulus control over place cell firing; generally, rotation of either card caused an equal rotation of the firing fields present. When the black card was substituted for the white card, place cells showed time‐variant changes in their spatial firing patterns. The change was such that the spatial firing patterns of the majority of place cells were similar in the presence of the white and black cards during initial black card exposures. During subsequent presentations of the black card, the spatial firing patterns associated with the 2 cards became distinct from each other. Once the differentiation of firing patterns had occurred in a given rat, all place cells subsequently recorded from that rat had different firing patterns in the presence of the white and black cards. The findings are discussed relative to sensory‐, motor‐, attentional‐, and learning‐related interpretations of hippocampal function. It is argued that the time‐variant alteration of place cell firing fields observed following exposure to a novel stimulus in this study reflects an experience‐dependent modification of place cell firing patterns.
Independence of memory functions and emotional behavior: Separate contributions of the hippocampal formation and the amygdala
Authors: Zola‐Morgan Stuart , Squire Larry R. , Clower Robert P. , Alvarez‐Royo Pablo
Published: January 2005

Structures and connections in the medial temporal lobe of humans and nonhuman primates have long been recognized as important for normal memory and emotional behavior. The present study investigated memory and emotional behavior in normal monkeys and six groups of monkeys with lesions of the medial temporal lobe. Two groups had damage to the hippocampal formation (or adjacent perirhinal and parahippocampal cortex) but not the amygdaloid complex; two groups had either partial or complete damage to the amygdaloid complex but not the hippocampal formation; and two groups had damage to both the hippocampal formation and the amygdaloid complex. Memory was evaluated with three tasks sensitive to human amnesia: (1) delayed nonmatching to sample; (2) retention of object discriminations; and (3) concurrent discrimination learning. Emotional behavior was assessed by measuring the responsiveness of monkeys to 12 different stimulus situations. Damage to the hippocampal formation or anatomically related cortex impaired memory but did not affect emotional behavior. Partial or complete damage to the amygdaloid complex affected emotional behavior but not memory. These findings show that memory impairment and abnormal emotional behavior are anatomically dissociable and independent effects of damage to the medial temporal lobe.
Protein kinase C activity in the hippocampus following spatial learning tasks in mice
Authors: Noguès Xavier , Micheau Jacques , Jaffard Robert
Published: January 2005

Protein kinase C (PKC) is highly concentrated in the hippocampus and is thus a possible neural substrate of learning and memory. This study was designed to determine whether partial acquisition (i.e., the minimal amount of training leading to above‐chance performance) of a spatial discrimination in an eight‐arm radial maze alters hippocampal PKC activity. Mice were sacrificed at different times (5 minutes, 1 hour, 24 hours) after the second learning session, and PKC activity was measured in both cytosolic and membrane fractions of the hippocampus. In order to determine which component of the task was involved in the alterations in enzymatic activity, hippocampal PKC activity was also measured in a group of mice that was allowed to explore the maze freely. Significantly less PKC activity was found in the cytosolic fraction from the trained animals than from the quiet or active control groups. No differences were observed between the quiet and active controls. In contrast, there were no significant between‐groups differences in membrane‐bound PKC activity, although a negative correlation between the membrane‐bound PKC activity and learning scores (accuracy) was noted. These results suggest that hippocampal PKC activity is involved essentially in the associative component of the task. The lack of learning‐induced alterations in membrane‐bound PKC activity and the negative correlation between this enzymatic activity and learning accuracy are discussed.