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Differential impairment of memory in Korsakoff's syndrome.

Groups of Korsakoff, alcoholic and non-alcoholic subjects were given picture-recognition memory (patterns and objects) and verbal learning tasks. Korsakoff subjects were impaired relative to the two control groups on verbal learning and object-picture memory; on pattern memory Korsakoff and alcoholic subjects were comparable but both were inferior to non-alcoholics. These findings gave some support to the idea (Butters and Cermak, 1976) that visuo-spatial functions (represented here by pattern memory) are impaired through chronic alcoholism whilst the development of Korsakoff's syndrome induces an additional impairment in semantic processing of information (represented here by verbal learning and object-picture memory).

Adult↗

Hippocampal cGMP and cAMP are differentially involved in memory processing of inhibitory avoidance learning.

Cyclic GMP (cGMP) and cyclic AMP (cAMP) have been proposed to participate in the early and late stages of long-term potentiation (LTP), respectively. Here we report on the effect of post-training intrahippocampal infusion of membrane-permeable analogues of these cyclic nucleotides on the consolidation of inhibitory avoidance learning in rats and on the effect of this task on hippocampal cGMP and cAMP levels. Bilateral intrahippocampal microinjection of 8 Br-cGMP (1.25 micrograms per side) enhanced retention test performance when given immediately (0 min), but not when given 180 min, after training. In marked contrast, intrahippocampal infusion of the same dose of 8 Br-cAMP facilitated memory consolidation when given 180 min, but not 0 min, after training. Rats submitted to an inhibitory avoidance task showed a significant increase in the amount of cGMP in the hippocampus at 0 and 30 min after training, and in the amount of cAMP 30 and 180 min after training. Taken together, these results indicate that cGMP-regulated processes in the hippocampus play an important role in the early stages of memory consolidation and that cAMP signalling pathways are involved in the late post-training memory processing of inhibitory avoidance learning.

8-Bromo Cyclic Adenosine Monophosphate↗

Alcohol and triazolam: differential effects on memory, psychomotor performance and subjective ratings of effects.

The effects of alcohol (0.80 g/kg) and the benzodiazepine hypnotic triazolam (0.25 mg/70 kg) were compared directly in a double-dummy, double-blind, placebo-controlled, repeated-measures design in 18 healthy volunteers. While alcohol (0.80 g/kg) and triazolam (0.25 mg/70 kg) produced comparable levels of psychomotor performance impairment, a dissociation was observed, such that the magnitude of memory impairment (measured by d', participants' sensitivity in discriminating between old and new words in the recognition memory paradigm) was greater with triazolam than with alcohol, whereas subjective ratings of the overall strength of drug effect were higher with alcohol than with triazolam. Participants also adopted a more conservative response bias in the recognition memory paradigm in the alcohol (0.80 g/kg) condition relative to both placebo and triazolam (0.25 mg/70 kg). In addition to characterizing the adverse effects of two widely used psychoactive substances, the present results may also contribute to the understanding of underlying neurochemical mechanisms.

Adult↗

The relevance of the nature of learned associations for the differentiation of human memory systems.

In a previous functional magnetic resonance imaging (fMRI) study we demonstrated an involvement of the medial temporal lobe (MTL) during an implicit learning task. We concluded that the MTL was engaged because of the complex contingencies that were implicitly learned. In addition, the basal ganglia demonstrated effects of a paralleled proceduralization of fixed stimulus-response associations. In the present study we directly tested the hypothesis that the MTL activation depends upon implementing the complex regularity in task material, whereas activation of basal ganglia does not. Therefore, we rearranged task material such that it did not contain any complex regularity. The statistical comparison of behavioral and fMRI data between the materials allowed for isolating effects that were directly related to the implicit learning process regarding the complex regularity. The results showed a reliable difference of fMRI signal limited to the MTL, indicating a specific functional role of the MTL in implicit learning of complex contingencies. Furthermore, no difference of BOLD (Blood-Oxygenation Level Dependent) signal in the basal ganglia and cerebellum were detected, supporting the assumption of a functional involvement of the structures in proceduralization of simple stimulus-response associations but not in implicitly learning complex relations. We therefore conclude that the nature of the learned associations is relevant for determining the neuronal focus of learning, rather than the accompanying awareness.

Adult↗

The 13th J. A. F. Stevenson memorial lecture. Sexual differentiation of the brain: possible mechanisms and implications.

The mammalian brain appears to be inherently feminine and the action of testicular hormones during development is necessary for the differentiation of the masculine brain both in terms of functional potential and actual structure. Experimental evidence for this statement is reviewed in this discussion. Recent discoveries of marked structural sex differences in the central nervous system, such as the sexually dimorphic nucleus of the preoptic area in the rat, offer model systems to investigate potential mechanisms by which gonadal hormones permanently modify neuronal differentiation. Although effects of these steroids on neurogenesis and neuronal migration and specification have not been conclusively eliminated, it is currently believed, but not proven, that the principle mechanism of steroid action is to maintain neuronal survival during a period of neuronal death. The structural models of the sexual differentiation of the central nervous system also provide the opportunity to identify sex differences in neurochemical distribution. Two examples in the rat brain are presented: the distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus and of tyrosine hydroxylase-immunoreactive fibers and cells in the anteroventral periventricular nucleus. It is likely that sexual dimorphisms will be found to be characteristic of many neural and neurochemical systems. The final section of this review raises the possibility that the brain of the adult may, in response to steroid action, be morphologically plastic, and considers briefly the likelihood that the brain of the human species is also influenced during development by the hormonal environment.

Animals↗

Differential patterns of memory loss in patients with Alzheimer's disease and Korsakoff's disease.

Patients with Korsakoff's disease or the likely diagnosis of Alzheimer's dementia were tested on various mnemonic tasks and the results compared to the performance of alcoholic or normal controls. The experimental outcome indicates similar perceptual learning processes of Alzheimer and Korsakoff subjects. On the other hand, both groups of patients showed a somewhat different pattern of episodic memory loss, and a different proportion of intrusion and omission errors in the learning of semantically related words. The results are discussed with respect to some neuropathological and neuropsychological sequelae.

Alcohol Amnestic Disorder↗

A double-blind crossover comparison of antiparkinson drug therapy: amantadine versus anticholinergics in 90 normal volunteers, with an emphasis on differential effects on memory function.

Anticholinergic antiparkinson drugs administered orally at standard clinically prescribed doses impaired new memory acquisition and mood in normal volunteer subjects, based on tests of free recall, recognition memory, and time production, self-rating of memory function, and an evaluation of mood states. Elderly subjects were more severely impaired than were young adults. Amantadine did not impair new memory acquisition, and on self-report measures, it was significantly better tolerated than were anticholinergics. Among patients being treated for psychotic illness, there are two groups in which an effort to avoid anticholinergic therapy is especially worthwhile because of the severe consequences of memory dysfunction. These individuals are young neuroleptic-responsive patients who are in an early stage of their disease and elderly patients. For these two groups, amantadine should be considered as the initial mode of treatment, with low-dose anticholinergics being used for those patients who do not achieve adequate relief from extrapyramidal side effects with amantadine.

Adult↗

Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory.

Functional dissociations between the medial septal area (MSA) and the nucleus basalis magnocellularis (NBM) were examined using the concepts and experimental procedures developed by scalar timing theory. Rats were tested in variations of a signalled discrete-trial peak-interval schedule of reinforcement in which the response rate functions identified the time when the rats expected reinforcement. The variations assessed aspects of both reference and working memory for information obtained from prior trials and from the current trial. A double dissociation was found in reference memory. Rats with NBM lesions, like those with frontal cortex (FC) lesions, remembered the time of reinforcement as having occurred later than it actually did; rats with MSA lesions, like those with fimbria-fornix (FF) lesions, remembered the time of reinforcement as having occurred earlier than it did. A single dissociation was found in working memory. MSA lesions and FF lesions impaired working memory, while NBM and FC lesions had no effect on it. These data begin to identify the brain mechanisms underlying temporal memory; they indicate that the frontal and hippocampal systems are both involved, but in complementary ways; and they provide information that helps specify more clearly the functions of the frontal and hippocampal systems.

Animals↗

CD27 and CD57 expression reveals atypical differentiation of human immunodeficiency virus type 1-specific memory CD8+ T cells.

The failure of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells to control chronic HIV-1 infection could be due to the progressive loss of their capacities to undergo normal memory effector differentiation. We characterized and compared the expressions of CD27, CD28, CD57, and CD62L by Epstein-Barr virus (EBV)-, cytomegalovirus (CMV)-, and HIV-1-specific CD8+ T cells by six-color, eight-parameter flow cytometry. In contrast to the maturation of EBV- and CMV-specific memory CD8+ T cells, we found that HIV-1-specific CD8+ T cells did not display coordinated down-regulation of CD27 and up-regulation of CD57 and accumulated in an atypical CD27(high) CD57(low) subset. Moreover, the accumulation of CD27(high) CD57(low) HIV-1-specific CD8+ T cells was positively correlated with HIV-1 plasma viremia. The differentiation of HIV-1-specific CD8+ T cells to an effector subset is therefore impaired during chronic HIV-1 infection. This lack of normal CD8+ T-cell differentiation could contribute to the failure of cellular immune control of HIV-1 infection.

Adult↗

Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs.

Memory is a hallmark of immunity. Memory carried by antibodies is largely responsible for protection against reinfection with most known acutely lethal infectious agents and is the basis for most clinically successful vaccines. However, the nature of long-term B cell and antibody memory is still unclear. B cell memory was studied here after infection of mice with the rabies-like cytopathic vesicular stomatitis virus, the noncytopathic lymphocytic choriomeningitis virus (Armstrong and WE), and after immunization with various inert viral antigens inducing naive B cells to differentiate either to plasma cells or memory B cells in germinal centers of secondary lymphoid organs. The results show that in contrast to very low background levels against internal viral antigens, no significant neutralizing antibody memory was observed in the absence of antigen and suggest that memory B cells (i) are long-lived in the absence of antigen, nondividing, and relatively resistant to irradiation, and (ii) must be stimulated by antigen to differentiate to short-lived antibody-secreting plasma cells, a process that is also efficient in the bone marrow and always depends on radiosensitive, specific T help. Therefore, for vaccines to induce long-term protective antibody titers, they need to repeatedly provide, or continuously maintain, antigen in minimal quantities over a prolonged time period in secondary lymphoid organs or the bone marrow for sufficient numbers of long-lived memory B cells to mature to short-lived plasma cells.

Animals↗

Stable telomere length and telomerase expression from naïve to memory B-lymphocyte differentiation.

Telomere length and telomerase activity play important roles in regulating replicative lifespan of cells. The length of telomeres also serves as a marker for the replicative history and for the remaining replicative potential of cells. Differential telomere length has been reported in human naïve and memory T cells but not in naïve versus memory B-lymphocytes. We report here an analysis of telomere length and induced telomerase expression in naïve (CD27(-)) and memory (CD27(+)) B cells from normal adults. Although both naïve and memory B cells lose telomere repeats with age, there is no consistent difference in telomere length between these two B cell subsets. Furthermore, both naïve and memory B cells are capable of inducing telomerase activity at similar levels after in vitro stimulation independent of donor's age. Finally, there is a slow increase of memory B cells in peripheral blood with age. Together, these findings suggest that B cells are capable of maintaining telomere length during differentiation from naïve to memory B cells and this ability is maintained through age.

Adolescent↗

Stability of a diverse immunological memory is determined by T cell population dynamics.

The correlation between properties of the T cell memory pool and the two regulatory mechanisms of cell death (apoptosis) and memory entry (differentiation) is investigated mathematically. Apoptosis of T cells occurs at the end of an immune response, removing unwanted activated T cells. T cells escaping apoptosis enter the memory pool composed of T cells specific for previously encountered antigens. We find that the relative efficiencies of these two pathways determine the clonal distribution and the long-term stability of the memory pool by regulating the number of new entries. The main result presented in this paper is that immunological memory of previously encountered pathogens cannot be erased by either severe or repeat infections with a particular pathogen (the diversity of the memory pool is ensured) only if apoptosis and/or memory differentiation are regulated by population dependent processes. Furthermore, vaccination properties are improved significantly by population dependent mechanisms and our mathematical analysis reveals that the T cell population must communicate with other parts of the immune system to ensure optimal performance of immunological memory.

Apoptosis↗

Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells.

Because the chemokine receptor CCR5 is expressed on Th1 CD4(+) cells, it is important to investigate the expression and function of this receptor on other T cells involved in Th1 immune responses, such as Ag-specific CD8(+) T cells, which to date have been only partially characterized. Therefore, we analyzed the expression and function of CCR5 on virus-specific CD8+ T cells identified by HLA class I tetramers. Multicolor flow cytometry analysis demonstrated that CCR5 is expressed on memory (CD28+CD45RA-) and effector (CD28-CD45RA- and CD28-CD45RA+) CD8+ T cells but not on naive (CD28+CD45RA+) CD8+ T cells. CCR5 expression was much lower on two effector CD8+ T cells than on memory CD8+ T cells. Analysis of CCR7 and CCR5 expression on the different types of CD8+ T cells showed that memory CD8+ T cells have three phenotypic subsets, CCR5+CCR7-, CCR5+CCR7+, and CCR5-CCR7+, while naive and effector CD8+ T cells have CCR5-CCR7+ and CCR5+CCR7- phenotypes, respectively. These results suggest the following sequence for differentiation of memory CD8+ T cells: CCR5-CCR7+-->CCR5+CCR7+-->CCR5+CCR7-. CCR5+CD8+ T cells effectively migrated in response to RANTES, suggesting that CCR5 plays a critical role in the migration of Ag-specific effector and differentiated memory CD8+ T cells to inflammatory tissues and secondary lymphoid tissues. This is in contrast to CCR7, which functions as a homing receptor in migration of naive and memory CD8+ T cells to secondary lymphoid tissues.

CD28 Antigens↗

A novel subpopulation of CD45RA+ CD4+ T cells expressing IL-2 receptor alpha-chain (CD25) and having a functionally transitional nature into memory cells.

Differential expression of various isoforms of leukocyte common antigen (CD45), which arises from alternate mRNA splicing, identifies naive and memory populations of human T cells. Some memory (CD45RO+ CD45RA-) populations of CD4+ T cells from adult individuals express IL-2 receptor (IL-2R) alpha-chain (CD25), but naive (CD45RO- CD45RA+) CD4+ T cells only do so to a small degree. We found that a small but significant fraction of CD4+ T cells in neonatal blood expressed CD25, although most generally exhibited the phenotype of naive cells. It was demonstrated that purified neonatal CD25+ CD4+ T cells expressed mRNA for the IL-2R alpha-chain. Two-color immunofluorescence analysis disclosed that a CD25+ population of neonatal CD4+ T cells had the naive (CD45RA+ CD45RO-) phenotypes. These CD25+ CD4+ T cells from newborns could express mRNA for some specified lymphokines such as IL-4, IL-5, and interferon-gamma on activation in a similar manner to CD45RO+ (memory) CD4+ T cells from adults. Notably, polymerase chain reaction analysis demonstrated that neonatal CD45RA+ CD4+ T cells expressing CD25 contained spliced mRNA transcripts possibly encoding CD45RO in addition to CD45RA-associated transcripts, seemingly indicating that this population might be in the recently antigen-primed states. Such a small population of CD45RA+ CD4+ T cells expressing CD25 appeared to be present in the blood throughout human life. The results suggest that CD4+ T cells with the naive (CD45RA+) phenotype expressing IL-2R alpha-chain (CD25) represent the novel transitional population in the maturation process of naive into memory CD4+ T cells.

Adult↗

Effector and memory T-cell differentiation: implications for vaccine development.

Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a programme of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this programme of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies.

Animals↗