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Hippocampal place cells, context, and episodic memory.

Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which, if combined with temporal information, could provide a means of differentiating memory episodes.

Action Potentials↗

Normative clinical relationships between orientation and memory: age as an important moderator variable.

The present study examined the relationship between memory and orientation to time, place, and personal and general information, as moderated by age, education, and simple attentional ability. A heterogeneous sample of 312 clinical referrals was divided into four groups, according to delayed memory functioning. Patients with globally good, globally poor, poor visual, and poor auditory memory were at differential risk of being disoriented, with the globally poor memory patients having the greatest risk. Overall, poorly oriented patients were older and less educated, with worse recall of digits backward. Discriminant Function Analysis selected visual and auditory memory and age as predictors of orientation. Normative tables stratified by age and memory performance are presented.

Adolescent↗

Differential CD4-dependent regulation of naive and memory CD4+ T cell adhesion is not related to differences in expression and function of CD4 and p56lck.

We have previously reported that antigen-independent adhesion of CD45RO+ memory CD4+ T cells to B cells is negatively regulated by CD4-MHC class II interaction, whereas that of CD45RA+ naive CD4+ T cells is not. We have now found that both cross-linking of CD4 ligands [anti-CD4 mAbs, HIV gp160 (env) protein and a 12mer peptide encompassing the 35-46 sequence of the HLA-DR beta 1 domain] on CD4+ naive T cells and activation-induced conversion of naive CD4+ T cells to memory T cells leads to CD4-dependent down-regulation of adhesion. To further elucidate CD4-dependent differential regulation of naive and memory T cell adhesion to B cells, we investigated the expression and function of CD4 and p56lck, a tyrosine kinase associated with the cytoplasmic domain of CD4. p56lck tyrosine kinase activity was equally enhanced by anti-CD4 mAbs and gp160 (120) in the two subsets. Furthermore, cell-surface CD4 down-modulation by phorbol myristate acetate or anti-CD4 mAbs was similar in the two subsets, which express the same amounts of both cell-surface CD4 and CD4-associated p56lck. Finally, the pattern of tyrosine phosphorylation of cellular proteins induced by gp120 (160) was similar in the two subsets. Taken together, these results indicate that the different sensitivity of naive and memory CD4+ T cells to CD4-dependent regulation of adhesion is not accounted for by differences in the tyrosine kinase activity of p56lck; it probably, therefore, involves a step downstream of p56lck or another pathway differentially used in naive and memory CD4+ T cells.

Amino Acid Sequence↗

An emotional mediation theory of differential age effects in episodic and semantic memories.

Although there is a large decrement in central episodic memory processes as adults age, there is no appreciable decrement in central semantic memory processes (Allen et al., Journal of Gerontology: Psychological Sciences, 57B, P173-P186, 2002; Allen et al., Experimental Aging Research, 28, 111-142, 2002; Mitchell, Journal of Experimental Psychology: Learning, Memory, and Cognition, 15, 31-49, 1989). The authors develop a theory of episodic memory's connections to cognitive, emotional, and motivational systems to explain these differential age effects. The theory is discussed within the context of the cognitive neuroscience research regarding limbic system connectivity in conjunction with Damasio's notion of somatic markers (Descartes' error: Emotion, reason, and the human brain, New York: Grosset/Putnam, 1994). The central hypothesis is that elements of limbic system circuitry, including portions of the medial temporal lobes and frontal cortex, are associated with both working and long-term episodic memory performance, and by extension, with the capacity to engage in emotion-guided, self-regulatory processes that depend heavily on episodic memory. In contrast, the semantic memory system may have less shared interface with episodic and affective networks (i.e., the limbic-related system), and therefore remain independent of neurocognitive changes impacting emotional states and episodic-type memory processes. Accordingly, this framework may account for the pattern of age-related declines in episodic relative to semantic memory, particularly if older adults experience less emotional activation, and therefore fewer somatic markers, than younger adults. An initial empirical examination of this emotional mediation theory is presented, using preexisting data that include indicators of age, chronic tendency to focus on negative emotional stimuli (neuroticism), and working memory performance.

Adolescent↗

Differential impairment of semantic and episodic memory in Alzheimer's and Huntington's diseases: a controlled prospective study.

A controlled prospective study compared the performance of 14 patients with dementia of Alzheimer type (DAT) and 14 patients with Huntington's Disease (HD), who were matched for overall level of dementia, on a battery of semantic and episodic memory tests. The DAT patients were significantly more impaired on measures of delayed verbal and figural episodic memory, and in addition showed a more rapid rate of decline on tests which depend upon the integrity of semantic knowledge (naming, number information, similarities and category fluency). In contrast, the HD patients were significantly worse, and showed a more rapid decline on the letter fluency test, a task especially sensitive to deficiencies in retrieval. The HD patients were also more impaired than DAT patients on a vocabulary test and on copying geometric figures. The observed double dissociations offer compelling evidence that aetiologically distinct forms of dementing illness result in different patterns of cognitive impairment.

Aged↗

Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes.

The lineage relationship between short-lived effector T cells and long-lived memory cells is not fully understood. We have described T-GFP mice previously, in which naive and early activated T cells express GFP uniformly, whereas cells that have differentiated into effector cytotoxic T cells selectively lose GFP expression. Here we studied antigen-specific CD8 T cell differentiation using T-GFP mice crossed to the TCR transgenic (Tg) mice P14 (specific for the lymphocytic choriomeningitis virus glycoprotein peptide, gp33-41). After activation with antigenic peptide, P14XT-GFP CD8(+) T cells cultured in high-dose IL-2 developed into cells with effector phenotype and function: they were blastoid, lost GFP expression, expressed high levels of activation and effector markers, and were capable of immediate cytotoxic function. In contrast, cells cultured in IL-15 or low-dose IL-2 never developed into full-fledged effector cells. Rather, they resembled memory cells: they were smaller, were GFP(+), did not express effector markers, and were incapable of immediate cytotoxicity. However, they mediated rapid-recall responses in vitro. After adoptive transfer, they survived in vivo for at least 10 weeks and mounted a secondary immune response after antigen rechallenge that was as potent as endogenously generated memory cells. In addition to providing a simple means to generate memory cells in virtually unlimited numbers, our results suggest that effector differentiation is not a prerequisite for memory cell generation.

Animals↗

Differential age effects in semantic and episodic memory, Part II: Slope and intercept analyses.

This study tested for dissociations between age-related slowing in peripheral and central processes across semantic and episodic memory tasks. We report the mixed-model analysis of variance (ANOVA) results using reaction time (RT), error, and data from four different experimental tasks and eight data sets (the four tasks involved either multiple sessions or different stimuli) conducted on the same 80 participants (40 younger and 40 older adults). An earlier paper (Allen, Sliwinski, Bowie, & Madden, in press) reported the factor analysis and structural equation modeling results of this study. We employed two semantic memory tasks (lexical decision and multiplication verification) using data from two different sessions (for a total of four semantic data sets), and two episodic memory tasks (hybrid visual search and memory search with digits and with words as stimuli). For RT analyses, we found Age x Task interactions for all four episodic memory data sets, but no Age x Task interactions for the four semantic memory data sets. Also, the intercept (assumed to index peripheral processes) and slope (assumed to index central processes) analyses demonstrated that older adults (relative to younger adults) showed both intercept and slope decrements for episodic memory tasks, but only intercept decrements for semantic memory tasks. These data are consistent with a theoretical framework in which there are age-related dissociations between peripheral and central processes across semantic and episodic memory.

Adolescent↗

CD4 memory T cells survive and proliferate but fail to differentiate in the absence of CD40.

Secondary T cell responses are enhanced because of an expansion in numbers of antigen-specific (memory) cells. Using major histocompatibility complex class II tetramers we have tracked peptide-specific endogenous (non-T cell receptor transgenic) CD4 memory T cells in normal and in costimulation-deficient mice. CD4 memory T cells were detectable after immunization for more than 200 days, although decay was apparent. Memory cells generated in CD40 knockout mice by immunization with peptide-pulsed wild-type dendritic cells survived in the absence of CD40 and proliferated when boosted with peptide (plus adjuvant) in a CD40-independent fashion. However, differentiation of the memory cells into cytokine-producing effector cells did not occur in the absence of CD40. The data indicate that memory cells can be generated without passing through the effector cell stage.

Amino Acid Sequence↗

Differential effects of everyday stress on the episodic memory test performances of young, mid-life, and older adults.

This research explored the differential association of everyday stress with the episodic memory test performances of young, mid-life, and older adults. Participants included 98 community-dwelling adults ranging in age from 19-89 years. Everyday stress was assessed via the Perceived Stress Scale and the Elder Life Stress Inventory. A brief battery of episodic memory tasks was administered which included tests of Logical Memory, Verbal Paired Associates, Digit Symbol Substitution, and Digit Symbol Incidental Learning. Results suggest that everyday hassles and irritations as well as the accumulation of challenging life events may exacerbate age-related decline on episodic memory tests that require greater executive resources and more integrated and elaborative processing. The functional relationship between affective status and risk for dementia is discussed, and consideration of individual differences in everyday stress is suggested so as to allow more sensitive interpretation of episodic memory tests commonly used to discern mild cognitive impairment.

Adult↗

Cyclic AMP differentially modulates CD40L expression on human nai;ve and memory CD4(+) T cells.

Although differences in nai;ve and memory T cell signaling have been recognized, how these differences relate to cell regulation and function is not well understood. In this study, we investigated CD40 ligand (CD40L) regulation by cyclic AMP (cAMP) and prostaglandin E(2) (PGE(2)) and observed differential effects depending upon the cell subset and mode of activation. cAMP inhibited CD3-induced CD40L in both nai;ve and memory subsets, although greater inhibition was observed in memory cells. With CD3/CD28 costimulation, cAMP inhibited CD40L in memory cells but had a minimal effect on nai;ve cells. In primed T cells, cAMP increased CD40L on nai;ve cells but inhibited expression on memory cells. Differential cAMP effects appear interrelated to calcium signaling since the level of CD40L induced by calcium ionophore was increased by cAMP in both cell subsets, although nai;ve cells were more calcium responsive. Calcium-dependent calcineurin activity appeared necessary for CD40L expression, although no interaction of calcineurin and cAMP regulation was demonstrable. In contrast, inhibitors of Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) blocked cAMP effects to increase CD40L and resulted in marked CD40L inhibition. The importance of CaMKIV in cAMP regulation was confirmed by transfection studies using a dominant negative CaMKIV construct. We conclude that cAMP differentially regulates CD40L expression in a manner that appears dependent upon CaMKIV activation. In view of the central role of CD40L expression in immunity as well as the pathophysiology of common diseases, it is of interest that cAMP can either increase or decrease CD40L expression depending upon the T cell subtype and mechanism of cell activation.

CD4-Positive T-Lymphocytes↗

Following the development of a CD4 T cell response in vivo: from activation to memory formation.

The in vivo differentiation of CD4 T cells from naive to memory cells was followed after their adoptive transfer together with syngeneic dendritic cells into MHC mismatched adoptive hosts lacking lymphocytes and NK cells. Functional and molecular changes were measured as the antigenic stimulus, provided by the cotransferred dendritic cells, disappeared. Memory cells as opposed to effector cells show an inversion in the relative expression of Bcl-2 family members in favor of antiapoptotic molecules, and compared with naive cells they have an increased ratio of bcl-xL to bcl-2. They differ qualitatively from naive T cells, suggesting that accelerated CD4 memory responses can occur without the need for increased frequencies of specific T cells.

Adoptive Transfer↗

Similarities and differences in CD4+ and CD8+ effector and memory T cell generation.

Naive CD4+ and CD8+ T cells undergo unique developmental programs after activation, resulting in the generation of effector and long-lived memory T cells. Recent evidence indicates that both cell-intrinsic and cell-extrinsic factors regulate memory T cell differentiation. This review compares and contrasts how naive CD4+ and CD8+ T cells make the transition to effector and/or memory cells and discusses the implications of these findings for vaccine development.

Animals↗

Verbal and abstract designs paired associate learning after unilateral temporal lobectomy.

The combined use of a new abstract designs Paired Associates test with the Verbal Paired Associates test of Form 1 of the Wechsler Memory Scale was investigated with respect to eliciting material specific memory deficits after unilateral temporal lobectomy. Although the verbal test differentiated between the memory ability of these two groups more clearly than the abstract designs test, the effectiveness of looking at the difference between total scores on the two tests was demonstrated. The two tests produced similar levels of performance in control subjects.

Analysis of Variance↗

Memorizing and copying visual patterns: a Piagetian interpretation.

Six-, 8-, 10-, and 12-year-old children (10 boys and 10 girls) reconstructed two visual patterns from immediate memory, while other 5- and 6-year-old children (10 boys and 10 girls) reconstructed the identical patterns by direct copying. Patterns were simple and composed entirely of circles or squares as component items. Four results were emphasized: (a) Numerous errors mady by the copying groups led to the conclusion that memory loss is often overestimated in young children. Since an independent estimate of perceptual encoding errors is rarely carried out, encoding mistakes are often included among forgetting errors. (b) One pattern was both copied and remembered more poorly than the other in accord with a Piagetian interpretation of a conceptual conflict inherent in the pattern design between spatial and numerical correspondence of component pattern items. (c) A memory strategy emphasizing configuration preservation was suggested for the 6-year-olds who made slightly fewer memory than copying errors for two configural scoring categories. (d) Performance in an unrelated planning-for-memory task significantly differentiated between better and worse performers on the visual pattern memory task.

Age Factors↗

Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning.

The hippocampus is an essential neural structure in developing contextual memory in a situation in which rapid development of associative learning should occur. We tested a subregion-specific contribution in the hippocampus to memory acquisition and retrieval, using the contextual fear-conditioning paradigm. The current results suggest that all three subregions (i.e., CA3, CA1, and dentate gyrus) of the hippocampus contribute to rapid acquisition of contextual memory in the initial phase of acquisition. The involvement of CA3 seems to be important at the earliest stage of acquisition, presumably for developing instant representation of a context. The role of CA3, however, was minimal in retrieving contextual memory after a long time period (i.e., 24 h), whereas the other subregions (i.e., CA1 and dentate gyrus) were critically involved. The results indicate time-dependent differential contributions of the hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning.

Animals↗

Nature of discriminating and categorizing functions of verbal labels on recognition memory for shape.

The purpose of this experiment was to investigate the hypothesis that the discriminating and categorizing functions of a label associated with an ambiguous shape can differentially influence delayed recognition memory for the shape. The temporal course of shape recognition was measured after the subjects were trained to associate the shapes with relevant verbal labels, irrelevant verbal labels, or no verbal labels. Either immediately or after delays of 15 min or 1 wk, subjects were given a shape recognition test and both free- and aided-recall tests for retention of the associated verbal labels. Results indicated that relevant verbal labels differentially affect memory for shape and that the discriminating function of the label operates effectively at the time of stimulus encoding. The categorizing function of the label affects the changes occurring during the storage stage of memory. These results are interpreted as supporting the view that the courses of shape recognition and relevant label recall are not independent.

Adult↗

Immunophenotype of HIV+ patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system.

OBJECTIVE: To investigate immunological changes during CD4-guided therapy interruption in HIV(+) patients who suspended HAART. PATIENTS: Seventeen patients aged > 18 years, who had received HAART for at least 12 months, and had a pre-interruption CD4+ cell count > 500 cells/microl, interrupted treatment. Median nadir CD4(+) cell count was 288 cells/microl. HIV plasma viral load at discontinuation was < 50 or > 50 copies/ml. Criteria for restarting treatment were: a CD4(+) T-lymphocyte count < 350 cells/microl on two separate occasions, a clinical manifestation of AIDS, and the patient's desire to resume HAART. Eleven patients were still off therapy after 12 months (group A); according to the first criterion, six patients restarted therapy within 12 months (group B). METHODS: Haematological, viro-immunological, cytofluorimetic and molecular assays were performed at baseline and every 2 months following standard methods. Statistical analysis was performed under Stata 7.0. RESULTS: In the first 2 months of treatment interruption, a significant increase in viral load and CD8(+) lymphocyte activation occurred. Then such parameters decreased and remained stable. In all patients, a decrease in CD4(+) lymphocytes took place as well, that affected in a similar manner naive, central memory, effector memory and terminally differentiated cells. Group B always presented lower amounts of CD4(+) effector memory lymphocytes. The expression of CD127 was always higher in group A. CONCLUSIONS: The loss of CD4(+) lymphocytes upon viral rebound is equal among naive and memory subsets. Patients with higher expression of CD127, who are likely to exert a better capacity to utilize endogenous interleukin-7 by T cells, could remain off therapy for longer periods.

Adult↗