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PubMed1989

Animal studies of brain acetylcholine and memory.

Memory loss is a common feature of aging in the human but not all memories are equally lost. Usually the loss is more severe for the memory of recent events and information rather than the memory of remote events and information. Associated with memory losses of this type is a reduction in levels of cortical acetylcholine and a loss of cholinergic cells of the nucleus basalis magnocellularis. In the rat it is possible to assess two types of memory analogous to recent and remote memories in humans. Reference memory would refer to information concerning the task that is invariant from trial to trial. Working memory would refer to information that changes from trial to trial. In support of the hypothesis that decreases in cholinergic function lead to a differential impairment of working memory, rats trained in this task and given scopolamine showed a specific increase in working memory errors. In more recent studies rats have been trained in a task and then given unilateral neurotoxic lesions of the NBM. These results raise the intriguing possibility that degeneration of the NBM and associated memory impairment seen in aging and in Alzheimer's disease may be related to a change in the ratio of these or related endogenous tryptophan metabolites.

Acetylcholine↗
PubMed2004

In multiple myeloma clonotypic CD38- /CD19+ / CD27+ memory B cells recirculate through bone marrow, peripheral blood and lymph nodes.

It is believed that myeloma cells are derived from a germinal center (GC) or post GC B cell. The GC B cell can differentiate into both a memory B cell and a plasma cell (PC). In this study, we investigated the recirculating potential of memory B cells clonally related to the myeloma PC (termed clonotypic). The V(H)DJ(H) immunoglobulin gene rearrangement of the myeloma clone was identified for 10 myeloma patients and allele-specific oligonucleotides (ASO) IgH RT-PCR assays were designed for each patient. Memory B cells (CD38- /CD19+ /CD27+) and their subsets defined by the monoclonal antibodies CD62L, CCR6, CXCR4, CXCR5, CCR7 were flow-sorted as single cells and analyzed by ASO RT-PCR analysis. In addition, aspirated peripheral lymph nodes (PLN) of 7 myeloma patients in complete or partial remission were analyzed for the presence of clonotypic cells. Circulating clonotypic memory B cells were identified in PBMNC of 7/10 patients and both CD62L positive and negative clonotypic memory B cells were identified. Furthermore, comparable frequencies of clonotypic cells were found in the CCR6 +/- and CXCR4 +/- memory B cell subsets, whereas all clonotypic memory and later stage B cells were CXCR5 positive. In accordance with their immunophenotype, clonotypic memory B-cells were identified in peripheral blood, bone marrow and PLNs. Clonotypic memory B-cells were present in the majority of myeloma patients and seem to have the same diverse recirculating/homing capacity as normal memory B cells.

ADP-ribosyl Cyclase↗
PubMed2006

Preparation and characterization of HLA-A*0201 tetramer loaded with IE-1316-324 antigenic peptide of human cytomegalovirus.

Major histocompatibility complex (MHC) class I tetramer technology has become the central technique for analyzing antigen-specific CD8(+) T cell responses and it has been widely used to explore the differentiation and formation of memory CD8(+) T cells. Previously, a simplified and efficient procedure for preparing high quality HLA-A*0201 tetramers has been established in our lab and the tetramers loaded with HCMV peptide pp65(495-503) has been successfully applied to investigate HCMV-specific CD8(+) T cells in Chinese populations. Using similar procedure we reported here the construction of HLA-A*0201 tetramer loaded with another dominant epitope derived from immediate early (IE)-1(316-324) (VLEETSVML, VLE) of HCMV (A2-VLE) and characterization of this tetramer. After A2-VLE monomer was prepared and purified, its tetramer was then formed at a yield of 83%. The optimized amount of A2-VLE tetramer for staining 100 microl whole blood was 0.5 microg with incubation at 4 degrees C for 1 h. Furthermore, the dissociation constant of the tetramer binding to the specific CD8(+) T cells of one HLA-A2(+) donor was estimated to be 32.7 nmol/L, which is markedly higher than that of MHC monomer. The construction of A2-VLE tetramer provides an alternative choice for investigating HCMV-specific CD8(+) T cell responses and will deepen our understanding of the differentiation and formation of HCMV-specific memory CD8(+) T cells.

Biotin↗
PubMed2004

Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders.

Memory B cells are responsible for the rapidly emerging antibody response after antigen reexposure. The signals required for the restimulation of memory B cells have not been fully explained. We used a murine model of anti-factor VIII (FVIII) antibody responses in hemophilia A to study the requirements for the restimulation of FVIII-specific memory B cells and their differentiation into anti-FVIII antibody-producing cells. We were particularly interested in the significance of activated T cells and costimulatory interactions. Our results indicate that the restimulation of FVIII-specific memory B cells is strictly dependent on interactions with activated T cells. These activated T cells can be specific for either FVIII or third-party antigens. Restimulation by T cells specific for third-party antigens requires the presence of FVIII, indicating that signals induced by B-cell receptor (BCR) triggering and by interactions with activated T cells are important. The blockade of B7-1 or B7-2 as well as the blockade of CD40L inhibits the restimulation and differentiation of FVIII-specific memory B cells in vitro and in vivo. The interference with inducible costimulator-inducible costimulator ligand (ICOS-ICOSL) interactions, however, does not cause any modulation. As expected, the production of anti-FVIII antibodies by plasma cells is not dependent on any of the costimulatory interactions tested.

Animals↗
PubMedDate not supplied

Adult age, presentation time, and memory performance.

The present investigation involved an examination of the influence of the task variable of presentation time on the free recall performance of young and elderly adults. The two age groups of participants were initially asked to predict the number of words (out of 16) they would be able to recall if given a particular presentation duration. These predictions were subsequently compared to actual recall performance of the two groups when lists were displayed for the durations employed during the prediction phase. Results indicated that young adults more accurately predicted their recall performance than did older adults. Both age groups, however, were found to vary their recall predictions in a similar fashion as a function of changes in hypothetical presentation time of the word lists. The findings of the present study, therefore, supported those of previous investigations which concluded that age differences in memory knowledge do not accurately reflect age differences in memory task performance. No support, however, was provided for the hypothesis that age differences exist with respect to knowledge about the relationship between the task variable of presentation time and memory performance. Thus, these findings suggest that different dimensions of memory knowledge may be differentially influenced by the aging process.

Adolescent↗
PubMed1989

Differentiating Alzheimer's disease from Huntington's disease with the Wechsler Memory Scale-Revised.

The WMS-R represents a significant improvement over the original version of the WMS. Patterns of performance on the five WMS-R indices successfully differentiated patients with a "cortical" (that is, DAT) from patients with a "subcortical" (that is, HD) dementia. The differences between ACI and GMI also indicated that DAT patients' attention and concentration were better preserved than those of equally demented HD patients. Analyses of the differences between GMI and DMI indicated that rapid forgetting was more apparent for DAT than for HD patients in the early stages of these disorders. When savings scores for the Logical Memory and Visual Reproduction tests were used to examine retention over a 30-minute period, both mildly and moderately demented DAT patients demonstrated more rapid forgetting than did HD patients with similar levels of cognitive decline. Discriminant analyses performed with these indices of forgetting showed 95 per cent accurate classification of DAT and elderly controls, and 79 per cent correct classification of DAT and HD patients. Assessment of the patients' tendencies to make prior-item intrusion errors on the Visual Reproduction tests of the WMS and WMS-R yielded significant differences between patient groups and the two versions of the test. Patients with DAT made significantly more prior-figure intrusion errors than did HD patients on both versions of the VRT, but the original WMS form of this figural memory test was more likely to elicit such errors than was the revised version. Despite many improvements in the revised scale, a number of limitations still exist including standardization and a lack of norms for elderly individuals, as well as failures to include tests of verbal recognition and adequate measures of nonverbal memory.

Alzheimer Disease↗
PubMed2005

The implications of memory profiles in schizophrenia on vocational and neuropsychological functioning.

Studies in schizophrenia suggest that verbal learning and memory may distinguish three subgroups of patients: an unimpaired memory profile group and two groups that have memory profiles similar to those seen in cortical and subcortical dementias. Using the Hopkins Verbal Learning Test, Revised edition (HVLT-R), this study attempted to differentiate patients into three memory profile groups and to examine the validity of these groups with respect to vocational outcomes and neuropsychological functioning. Results from this study replicated previous findings and extended them by demonstrating a link to vocational outcome. In addition, the proportion of patients in each group closely resembled that obtained in previous studies. Specifically, the relatively unimpaired memory group (42%) showed overall better memory and neuropsychological performance than the two impaired groups, the subcortical group (38%) showed impaired recall but intact recognition and deficits in visuospatial functioning, and the cortical group (20%) showed deficits in recall, recognition, and sustained attention/executive functioning. There were no clinical differences between the three groups, but both the unimpaired and subcortical groups increased the number of hours worked following a vocational rehabilitation program. Given these differences, more research is warranted to explore the effect of memory impairment subtypes on vocational outcome measures.

Adult↗
PubMed2006

GABA(B(1)) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories.

Conditioned taste aversion (CTA) is a form of aversive memory in which an association is made between a consumed substance and a subsequent malaise. CTA is a critical mechanism for the successful survival, and hence evolution, of most animal species. The role of excitatory neurotransmitters in the neurochemical mechanisms of CTA is well recognized; however, less is known about the involvement of inhibitory receptor systems. In particular, the potential functions of metabotropic GABA(B) receptors in CTA have not yet been fully explored. GABA(B) receptors are metabotropic GABA receptors that are comprised of two subunits, GABA(B(1)) and GABA(B(2)), which form heterodimers. The Gabbr1 gene is transcribed into two predominant isoforms, GABA(B(1a)) and GABA(B(1b)), which differ in sequence primarily by the inclusion of a pair of sushi domains (also known as short consensus repeats) in the GABA(B(1a)) N terminus. The behavioral function of mammalian GABA(B(1)) receptor isoforms is currently unknown. Here, using a point mutation strategy in mice, we demonstrate that these two GABA(B(1)) receptor isoforms are differentially involved in critical components of CTA. In contrast to GABA(B(1b))-/- and wild-type mice, GABA(B(1a))-/- mice failed to acquire CTA. In contrast, GABA(B(1b))-/- mice robustly acquired CTA but failed to show any extinction of this aversion. The data demonstrate that GABA(B) receptors are involved in both the acquisition and extinction of CTA; however, receptors containing the GABA(B(1a)) or the GABA(B(1b)) isoform differentially contribute to the mechanisms used to learn and remember the salience of aversive stimuli.

Animals↗
PubMed2006

Differential influences of negative emotion on spatial and verbal working memory: Evidence from event-related potential and source current density analysis.

We used the event-related potential technique to assess the influences of negative emotion on spatial and verbal working memory with a modified n-back task. In both spatial and verbal tasks, the anterior late positive component and the posterior P300 were affected by negative emotion. These effects were, however, greater in spatial tasks than in verbal ones. Especially, the parietal P300 was reduced by negative emotion in spatial tasks, but not in verbal tasks. Current density analysis revealed high current density in the frontal-parietal cortex, but only in the spatial tasks. The results suggest differential effects of negative emotion on spatial and verbal working memory and that the frontal-parietal cortex may be the area where negative emotion and spatial working memory interact.

Adult↗
PubMedDate not supplied

The presence of circulating clonal CD19+ cells in multiple myeloma.

Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of mature plasma cells (PC) localized in the bone marrow (BM). Several studies have identified circulating clonotypic CD19+ cells at a differentiation stage preceding the PC. The level of circulating clonotypic CD19+ cells is highly variable but generally low. Circulating clonotypic cells respond well to induction therapy, although a small subset within the CD19 compartment is resistant even to high-dose chemotherapy. The clonal CD19+ cells represent an ongoing differentiating population ranging from memory B-cells to plasmablasts. However, a clonal relationship gives no proof of malignant potential, and whether or not clonotypic precursor cells are involved in the disease process is a subject of intense debate. Translocations involving the immunoglobulin locus (14q32) are an early non-transforming event common to both monoclonal gammopathy of undetermined significance (MGUS) and MM introduced at the memory B-cell level. At the plasmablast stage, a phenotypic transformation occurs with downregulation of CD19 and upregulation of myeloma specific markers such as CD56, CD117 and CD28. Translocations involving the isotype-switch machinery and the introduction of tumor-specific markers at the plasmablast stage suggest that the clonal CD19+ memory B-cells and CD19+ plasmablasts are non-malignant, but immortalized relatives that gave rise to myeloma. A final proof of the malignant potential of CD19+ clonotypic cells might await the identification of the molecular events causing the transformation in myeloma.

Antigens, CD19↗
PubMed2001

Differential effects of delta 9-THC on spatial reference and working memory in mice.

RATIONALE: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of marijuana and cannabinoid derivatives. Thus, developing a better understanding of delta9-THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. OBJECTIVES: These experiments were conducted to determine whether delta9-THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds--scopolamine and phencyclidine--known to produce mnemonic deficits. In addition, the potency of delta9-THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. METHODS: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of delta9-THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. RESULTS: delta9-THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of delta9-THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. CONCLUSIONS: These data indicate that delta9-THC selectively impairs performance of a working memory task through a CB, receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of delta9-THC.

Animals↗
PubMed2001

Autoreactivity, dynamic tuning and selectivity.

The immune system adjusts its response to the context in which antigens, including self-antigens, are recognized. Recent observations support a conceptual framework for understanding how this may be achieved at the cellular and cell-population levels. At both levels, 'perturbations' elicit competition between excitation and de-excitation, resulting either in adaptation or in various responses. The responsiveness of individual cells is dynamically tuned, reflecting their recent experience. The tuning of T-cell activation thresholds by self-ligands facilitates positive selection and continuously regulates the level of autoreactivity in the periphery. Autoreactivity appears to be involved in regulation of the immune response, homeostasis, maintaining of the functional integrity of naïve and memory cells, and in other physiological functions.

Adaptation, Physiological↗
PubMed1998

EBV persistence in memory B cells in vivo.

Epstein-Barr virus establishes latency in vitro by activating human B cells to become proliferating blasts, but in vivo it is benign. In the peripheral blood, the virus resides latently in resting B cells that we now show are restricted to the sIgD memory subset. However, in tonsils the virus shows no such restriction. We propose that EBV indiscriminately infects B cells in mucosal lymphoid tissue and that these cells differentiate to become resting memory B cells that then enter the circulation. Activation to the blastoid stage of latency is an essential intermediate step in this process. Thus, EBV may persist by exploiting the mechanisms that produce and maintain long-term B cell memory.

B-Lymphocyte Subsets↗
PubMed1998

Critical role of IL-12 in dendritic cell-induced differentiation of naive B lymphocytes.

Dendritic cells (DC) are potent APCs initiating immune responses. In a previous report, we demonstrated that DC directly enhance both proliferation and differentiation of CD40-activated naive and memory B cells. The present study deciphers the molecular mechanisms involved in DC-dependent regulation of B cell responses. Herein, we have identified IL-12 as the mandatory molecule secreted by CD40-activated DC that promote the differentiation of naive B cells into plasma cells secreting high levels of IgM. In fact, IL-12 synergizes with soluble IL-6R alpha-chain (sgp80), produced by DC, to drive naive B cell differentiation. IL-12 is critical for the differentiation of naive B cells into IgM plasma cells, whereas IL-6R signaling mainly promotes Ig secretion by already differentiated B cells. The differentiation of naive B cells in cocultures of B cells, T cells, and DC is IL-12 dependent, definitely demonstrating that the role of DC in humoral responses is not confined to the activation of T cells and further extending the physiologic relevance of DC/B cell interaction. Finally, this study also identifies differential requirements for DC-dependent naive and memory B cell differentiation, the latter being IL-12 independent. Altogether these results indicate that, in addition to prime T cells toward Thl development, DC, through the production of IL-12, may also directly signal naive B cell during the initiation of the immune response.

Antibodies, Blocking↗
PubMed2004

A chromosomal memory triggered by Xist regulates histone methylation in X inactivation.

We have elucidated the kinetics of histone methylation during X inactivation using an inducible Xist expression system in mouse embryonic stem (ES) cells. Previous reports showed that the ability of Xist to trigger silencing is restricted to an early window in ES cell differentiation. Here we show that this window is also important for establishing methylation patterns on the potential inactive X chromosome. By immunofluorescence and chromatin immunoprecipitation experiments we show that histone H3 lysine 27 trimethylation (H3K27m3) and H4 lysine 20 monomethylation (H4K20m1) are associated with Xist expression in undifferentiated ES cells and mark the initiation of X inactivation. Both marks depend on Xist RNA localisation but are independent of silencing. Induction of Xist expression after the initiation window leads to a markedly reduced ability to induce H3K27m3, whereas expression before the restrictive time point allows efficient H3K27m3 establishment. Our data show that Xist expression early in ES cell differentiation establishes a chromosomal memory, which is maintained in the absence of silencing. One consequence of this memory is the ability to introduce H3K27m3 efficiently after the restrictive time point on the chromosome that has expressed Xist early. Our results suggest that this silencing-independent chromosomal memory has important implications for the maintenance of X inactivation, where previously self-perpetuating heterochromatin structures were viewed as the principal form of memory.

Animals↗
PubMed1995

Interleukin-2 down-modulates memory T helper lymphocyte development during antigenic stimulation in vitro.

Using an in vitro antigenic stimulation model of murine spleen cells in the presence of the immunosuppressor cyclosporin A (CSA) we have previously reported that not only does this drug not interfere with the differentiation of T lymphocytes into memory cells it appears to favor this differentiation (Motta, I. et al., Eur. J. Immunol. 1991. 21:551). Because CSA blocks interleukin-2 (IL-2) gene expression, we have analyzed the effect of this cytokine on memory T helper cell development. Murine splenic cells were primed for 6 days with sheep red blood cells (SRBC) in protocols in which either IL-2 was not produced or its biological activity was neutralized by anti-IL-2 receptor (R) antibodies. The helper function of the recovered T cells was revealed by their capacity to help virgin B splenocytes produce anti-SRBC antibodies upon challenge in vitro. We found that CD4+ cells primed in the absence of IL-2, provoked either by IL-2 gene transcription blockade by CSA or by treatment with anti-IL-2R antibodies, afford the best helper functions. These cells exhibit a memory-type phenotype characterized by the low expression of the MEL-14 marker and the high expression of the CD44 marker. Evidence is also presented that memory T helper cells originate in part from naive subset displaying the MEL-14hi phenotype. The pattern of expression of the genes encoding different cytokines (IL-2, IL-4, IL-5 and interferon-gamma) following a secondary antigenic stimulation shows that the helper function of the cells primed in the absence of IL-2 correlates with the up-regulation of the IL-2 and the IL-5 genes. From these data, we conclude that IL-2 plays a major role in the control of memory T helper cell induction.

Animals↗