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PubMed2004

The germinal center response.

The germinal center reaction is the foundation of T-cell-dependent humoral responses. Antigen-specific B cells recruited into germinal centers undergo a complex cellular program that allows for extensive expansion, isotype switching, somatic hypermutation, and differentiation into antibody-forming cells and memory cells. Importantly, the germinal center environment filters the repertoire of differentiating B cells such that high affinity variants are preferentially selected while low affinity or self-reactive clones are eliminated by apoptosis. The present article reviews the many processes that govern germinal center B-cell differentiation, as well as the cellular and molecular elements necessary to initiate and sustain a germinal center response. The major histologic features of the germinal center are also discussed, as well as the current dominant models of the germinal center reaction in humans and mice. Finally, a new model of murine B-cell differentiation is described on the basis of a multiparameter flow cytometric kinetic analysis of germinal center B cells.

Animals↗
PubMed1976

Blackouts: relationship with memory capacity and alcoholism history.

Male alcoholic inpatients with a high incidence of memory blackouts did not differ on several memory measures from subjects with a low incidence of blackouts. Alcoholism chronicity also did not differentiate between subjects on the Wechsler Memory Scale, tests of storage and decay of a memory trace, and maintenance of a concept along a temporal continuum. A history of blackouts was, however, related to drinking pattern. High-incidence subjects reported a significantly greater frequency of drinking to intoxication or until falling asleep, craving a drink, and increased tolerance to alcohol.

Adult↗
PubMed1994

Stimulation of GABAB receptors in the basal forebrain selectively impairs working memory of rats in the double Y-maze.

The present experiments were conducted to evaluate the possible contribution of GABAergic inputs to the basal forebrain in the region of the nucleus basalis magnocellularis (nbm) to memory. In two experiments, rats implanted with bilateral intra-nbm guide cannulae were trained in the double Y-maze task to perform working- and reference-memory components. Animals were placed in one of two start arms of the first "Y" and the reference-memory component required travelling to its central stem for food. Access to the second "Y" then was given and the working-memory component for Expt. 1 required travelling to the goal arm diagonally opposite the start arm in the first "Y" of that trial. In Expt. 2, the working-memory component required travelling to the goal arm opposite to the goal arm entered in the second "Y" on the preceding trial, with 0- and 15-s delays between trials. In Expt. 1, pretrained rats (n = 8) received the GABAA agonist, muscimol (0.1 microgram in 0.5 microliter), the GABAB agonist, R(+)-baclofen (0.01, 0.05 and 0.1 microgram), and its less active enantiomer, S(-)-baclofen (0.1 microgram), in a counterbalanced order with retraining to criterion between injections. In Expt. 2, pretrained rats (n = 9) received saline (0.5 microliter), R(+)-baclofen (0.1 microgram), the GABAB antagonist, phaclofen (1 microgram), and R(+)-baclofen+phaclofen. Results of Expt. 1 revealed that intra-nbm muscimol and, in a dose-dependent manner, R(+)-baclofen differentially affected working but not reference memory. In Expt. 2, the differential mnemonic impairment produced by R(+)-baclofen was replicated and co-injection with phaclofen reversed this effect. A 15-s delay between trials significantly impaired working but not reference memory. Results suggest that both GABAA and GABAB receptors may be involved in modulating the possible mnemonic functions of nbm cholinergic neurons.

Animals↗
PubMed2003

[Disorders of cognitive processes in simulation of Alzheimer's disease in monkeys].

Two groups of monkeys were learned to differentiate stimuli with different types of information and to make a spatial choice. Characteristics of the operative memory were revealed in the delayed differentiation tasks prior to and after administration of p75-saporin (I group) and saline (II group). For the first time the Alzheimer disease in monkeys was shown to entail a deficit of operative memory due to disorders in the sensory and cognitive components of the memory. The degree of reduction of the correct decision making was shown to depend on the delay duration and the type of visual information. Following the saline administration, no significant changes occurred in the monkeys (II group). The data obtained suggest that structural-functional organisation of the cholinergic and noradrenergic mechanisms predetermining the sensory processing, differs from those involved in decision-making.

Alzheimer Disease↗
PubMed2004

Chewing gum differentially affects aspects of attention in healthy subjects.

In a study published previously in this journal (Wilkinson et al., 2002), the effect of chewing gum on cognitive functioning was examined. The results of this study indicated that chewing a piece of gum results in an improvement of working memory and of both immediate and delayed recall of words but not of attention. In the present study, memory and a variety of attentional functions of healthy adult participants were examined under four different conditions: no chewing, mimicking chewing movements, chewing a piece of tasteless chewing gum and chewing a piece of spearmint flavoured chewing gum. The sequence of conditions was randomised across participants. The results showed that the chewing of gum did not improve participants' memory functions. Furthermore, chewing may differentially affect specific aspects of attention. While sustained attention was improved by the chewing of gum, alertness and flexibility were adversely affected by chewing. In conclusion, claims that the chewing a gum improves cognition should be viewed with caution.

Adult↗
PubMed1986

Methylphenidate and memory: dissociated effects in hyperactive children.

Fourteen children with Attention Deficit Disorder with Hyperactivity (ADD + H) were administered the psychostimulant methylphenidate in a double-blind, placebo-controlled, crossover study. Subjects were evaluated on a well-validated measure of verbal memory and learning with an experimental design comprised of four conditions: placebo and active drug at three doses. Positive memory effects were found in the drug conditions. Significant dose-response relationships were found, indicating enhanced learning from placebo to low to medium to high dose. However, there was a differential drug effect on the memory task; methylphenidate selectively enhanced storage and retrieval mechanisms without affecting immediate acquisition.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system.

In the interest of better understanding the role of human memory B cells in protection against disease, we developed an assay to quantitate antigen-specific memory B cells in human blood. This assay utilizes a 6-day polyclonal stimulation of PBMC followed by an antigen-specific ELISPOT for the detection of memory B cells that have differentiated into antibody secreting cells (ASC) in vitro. We have used this assay to demonstrate that the anthrax vaccine (AVA; BioThrax) elicits a substantial population of protective-antigen (PA) specific memory B cells, and these B cells satisfy the canonical surface phenotype of human memory B cells: CD19(+)CD20(+)Ig(+)CD27(+). These anti-PA antigen-specific memory B cells are IgG(+) and represent up to 2% of circulating IgG(+) B cells. Furthermore, these results confirm that vaccine-elicited memory B cells reside in the CD27(+) B cell population. This ELISPOT-based system has been designed in a generalized manner, such that the assay can be rapidly adapted to detect human antigen-specific memory B cells of any given specificity. This method should be useful for quantitatively assessing the potency of vaccines and the longevity of B cell immunological memory to various vaccines or infectious diseases.

Anthrax Vaccines↗
PubMed2005

Gender and adolescent alcohol use disorders on BOLD (blood oxygen level dependent) response to spatial working memory.

AIMS: To determine how alcohol use differentially affects brain functioning in male and female adolescents. METHODS: Adolescents with alcohol use disorders (AUDs; 7 female, 11 male) and control adolescents without AUDs (9 female, 12 male), aged 14-17 years, performed spatial working memory and vigilance tasks during functional magnetic resonance imaging. RESULTS: Gender, AUD and their interaction were significantly associated with brain activation patterns to the tasks. There were interactions in the superior frontal, superior temporal, cingulate and fusiform regions, in which female and male adolescents with AUDs showed a different brain response from each other and control subjects. Overall, female adolescents with AUDs showed a greater departure from normal activation patterns than male adolescents with AUD. CONCLUSIONS: Adolescent alcohol involvement may affect male and female brains differently, and adolescent females may be somewhat more vulnerable to adverse alcohol effects. With continued drinking, these adolescents may be at an increased risk for behavioural deficits.

Adolescent↗
PubMed1997

Level of consciousness and memory during the intracarotid sodium amobarbital procedure.

Controversy exists regarding differential effects on consciousness of left/right cerebral inactivation via intracarotid amobarbital. Further, the effects of level of consciousness (LOC) on memory during the intracarotid sodium amobarbital procedure (IAP) are unclear. A modified version of the Glasgow Coma Scale altered to avoid the confounding effects of aphasia was employed to assess LOC in 97 patients during the IAP. A greater impairment in LOC occurred with left cerebral inactivation. Memory was more impaired following left hemisphere injections as well as from injections contralateral to seizure focus. Memory was correlated with LOC, and this effect was more prominent for right hemisphere injections and for injections ipsilateral to seizure focus. These findings support differential cerebral roles in consciousness and demonstrate that IAP memory performance may be affected by the patient's LOC.

Adolescent↗
PubMed2000

Antigen-specific B cell memory: expression and replenishment of a novel b220(-) memory b cell compartment.

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220(-)CD138(-)) that are distinct from antibody-secreting B cells (B220(+/)-CD138(+)) and B220(+)CD138(-) memory B cells. These nonsecreting somatically mutated B220(-) memory responders rapidly dominate the splenic response and comprise >95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75-85%) and the bone marrow (>95%) expresses the B220(-) phenotype. Upon adoptive transfer, B220(-) memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220(+) counterparts. The pattern of cellular differentiation after transfer indicates that B220(-) memory B cells act as stable self-replenishing intermediates that arise from B220(+) memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220(-) compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.

Animals↗
PubMed2006

Divergent generation of heterogeneous memory CD4 T cells.

Mechanisms for the generation of memory CD4 T cells and their delineation into diverse subsets remain largely unknown. In this study, we demonstrate in two Ag systems, divergent generation of heterogeneous memory CD4 T cells from activated precursors in distinct differentiation stages. Specifically, we show that influenza hemagglutinin- and OVA-specific CD4 T cells activated for 1, 2, and 3 days, respectively, exhibit gradations of differentiation by cell surface phenotype, IFN-gamma production, and proliferation, yet all serve as direct precursors for functional memory CD4 T cells when transferred in vivo into Ag-free mouse hosts. Using a conversion assay to track the immediate fate of activated precursors in vivo, we show that day 1- to 3-activated cells all rapidly convert from an activated phenotype (CD25(high)IL-7R(low)CD44(high)) to a resting memory phenotype (IL-7R(high)CD25(low)CD44(high)) 1 day after antigenic withdrawal. Paradoxically, stable memory subset delineation from undifferentiated (day 1- to 2-activated) precursors was predominantly an effector memory (CD62L(low)) profile, with an increased proportion of central memory (CD62L(high)) T cells arising from more differentiated (day 3-activated) precursors. Our findings support a divergent model for generation of memory CD4 T cells directly from activated precursors in multiple differentiation states, with subset heterogeneity maximized by increased activation and differentiation during priming.

Amino Acid Sequence↗
PubMed1990

Modulation of memory retention by neuropeptide K.

Neuropeptide K (NPK) is one of the structures in beta-preprotachykinin which also includes substance P. NPK, a 36 amino acid peptide, contains the sequence of neurokinin A as amino acids 27-36 of its C-terminus. Neurokinin A is also contained separately in the gamma-preprotachykinin precursor. Both NPK (2.5-10 micrograms) and neurokinin A administered intracerebroventricularly after footshock avoidance training in the T-maze enhanced memory retention in CD-1 male mice. Local microinjections of NPK enhanced memory retention when injected into the rostral and caudal portions of the hippocampus (0.25 and 0.50 microgram) and the amygdala (1.0 microgram), but were without effect when injected into the septum and the caudate. The differential effects of NPK on memory retention across brain regions differed from those previously reported for substance P and neuropeptide Y. These studies suggest that NPK, acting through discrete anatomical areas, modulates memory processing. The functional significance of co-localization of neuropeptides with classical neurotransmitters and other transmitter peptides in the same neurons is not well understood, but recent studies have indicated that the neuropeptides modulate the release of the primary transmitter. Since NPK occurs in the same precursor molecule as substance P, NPK may be co-released with the putative neurotransmitter substance P and act with it, in a synergistic manner, to enhance memory processing. These studies provide further evidence that the hippocampus is an anatomical structure involved in memory processing that occurs shortly after training.

Amino Acid Sequence↗
PubMed2001

Chromatin remodeling in development and differentiation.

During development and differentiation, early inductive processes that influence cell fate at a later stage leave marks at distinct gene loci that are maintained through several rounds of mitosis. The structure of chromatin is part of this epigenetic memory that restricts or permits differential expression of genes in descendant cells. Establishing a cell-type-specific chromatin pattern thus predestines future cell differentiation and deters cell-lineage infidelity, as it often occurs during neoplastic transformation. As such, understanding the dynamics and mechanisms underlying chromatin remodeling has been a major focus of recent molecular genetic research that holds great promise for biomedical discoveries.

Animals↗
PubMed2005

Retrieval-time properties of the Little-Hopfield model and their physiological relevance.

We perform an extensive numerical investigation on the retrieval dynamics of the synchronous Hopfield model, also known as Little-Hopfield model, up to sizes of 2(18) neurons. Our results correct and extend much of the early simulations on the model. We find that the average convergence time has a power law behavior for a wide range of system sizes, whose exponent depends both on the network loading and the initial overlap with the memory to be retrieved. Surprisingly, we also find that the variance of the convergence time grows as fast as its average, making it a non-self-averaging quantity. Based on the simulation data we differentiate between two definitions for memory retrieval time, one that is mathematically strict, tau(c), the number of updates needed to reach the attractor whose properties we just described, and a second definition correspondent to the time tau(eta) when the network stabilizes within a tolerance threshold eta such that the difference of two consecutive overlaps with a stored memory is smaller that eta. We show that the scaling relationships between tau(c) and tau(eta) and the typical network parameters as the memory load alpha or the size of the network N vary greatly, being tau(eta) relatively insensitive to system sizes and loading. We propose tau(eta) as the physiological realistic measure for the typical attractor network response.

Action Potentials↗
PubMed1984

[Mechanism of the suppression of the formation of immunologic memory].

An extract from splenocytes of mice immunized with sheep red blood cells contains suppressor factor (SF) that specifically inhibits the primary immune response. The system of adoptive transfer was studied for the action of the SF on the formation of immunologic memory for sheep and rat blood cells. It was established that the SF carrying a receptor for specific antigen causes nonspecific suppression of the generation of immunologic memory cells. Within the system in question radioresistant T helper cells act as suppression targets. It is suggested that the final effect of the SF lies in the inhibition of the release of transmitters promoting differentiation or proliferation of T memory cells.

Animals↗
PubMed2005

Differential activity profile of cAMP-dependent protein kinase isoforms during long-term memory consolidation in the crab Chasmagnathus.

The isoforms of cAMP-dependent protein kinase (PKA) show distinct biochemical properties and subcellular localization, suggesting different physiological functions, and conferring the fine-tuning between the activation of cAMP-PKA cascade and the cellular response. The critical role of PKA in memory and synaptic plasticity has been extensively demonstrated both in vertebrates and invertebrates, but the role of PKA isoforms is a matter of debate. Here we present experimental data showing differential PKA activation profiles after two different experiences: an instance of associative contextual learning (context-signal learning) and a single exposure to a novel context, both in the learning and memory model of the crab Chasmagnathus. Differences were found in the temporal course of activation and in the involvement of PKA isoforms. We found increased PKA activity immediately and 6 h after context-signal training correlating with the critical periods during which pharmacological inhibition of PKA disrupts memory formation. In contrast, PKA activity increased immediately but not 6 h after single exposure to a novel context. The amounts of PKA I and PKA II holoenzymes were analyzed to determine changes in holoenzyme levels and/or differential activation induced by both experiences. Results indicate that context-induced PKA activation is at least in part due to PKA II, and that PKA activation 6 h after context-signal learning coincides with an increase in the total level of PKA I. Considering the higher sensitivity of PKA I to cAMP, its increment can account for the PKA activation found 6 h after training and is proposed as a novel mechanism providing the prolonged PKA activation during memory consolidation.

Animals↗
PubMed2003

Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study.

Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.

Adolescent↗
PubMed2003

Differentiation of effector/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites.

Vdelta2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and mount both immediate effector functions and memory responses after microbial infection. However, how Vdelta2 T cells mediate different facets of a memory response remains unknown. Here, we show that the expression of CD45RA and CD27 antigens defines four subsets of human Vdelta2 T cells with distinctive compartmentalization routes. Naive CD45RA+CD27+ and memory CD45RA-CD27+ cells express lymph node homing receptors, abound in lymph nodes, and lack immediate effector functions. Conversely, memory CD45RA-CD27- and terminally differentiated CD45RA+CD27- cells, which express receptors for homing to inflamed tissues, are poorly represented in the lymph nodes while abounding at sites of inflammation, and display immediate effector functions. These observations and additional in vitro experiments indicate a lineage differentiation pattern for human Vdelta2 T cells that generates naive cells circulating in lymph nodes, effector/memory cells patrolling the blood, and terminally differentiated effector cells residing in inflamed tissues.

Animals↗