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Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells.

The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naïve CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naïve CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation.

Adoptive Transfer↗

Replicative senescence: the final stage of memory T cell differentiation?

One of the major obstacles to effective prolonged CD8 T cell control over HIV and other latent infections may be the intrinsic, genetically programmed barrier to unlimited proliferation that is characteristic of all normal human somatic cells. Replicative senescence, characterized extensively in cell culture for a variety of cell types, comprises both irreversible cell cycle arrest and striking changes in function. CD8 T cells with features similar to senescent CD8 T cell cultures (i.e., absence of CD28, inability to proliferate, telomeres in the 5-7 kb range, resistance to apoptosis) increase progressively during aging and in chronic HIV infection, suggesting that replicative senescence may be occurring in vivo, and, in fact, may constitute the final stage in the normal differentiation of human T cells. CD8 T cells with characteristics suggestive of senescence have also been implicated in modulating immune function and altering bone homeostasis. Further characterization of the underlying mechanism leading to the generation of senescent memory CD8 T cells and analysis of their functional attributes will help elucidate their role in HIV disease pathogenesis.

CD8-Positive T-Lymphocytes↗

Organizational effects of early gonadal secretions on sexual differentiation in spatial memory.

Neonatally castrated (MNC) and control male rats (MC) and female rats treated neonatally with estradiol benzoate (FNE) and female controls (FC) were studied. In Exp. 1 spatial memory was assessed using a 12-arm radial maze. During acquisition, MC and FNE groups were more accurate in choice behavior than FC and MNC groups. In Exp. 2 the discriminative control exerted by different types of cues was evaluated. Alteration of the geometry of the room but not movable landmarks disrupted performance of MC and FNE groups. For the FC and MNC groups, alteration of either geometry or landmarks did not disrupt performance. In Exp. 3 the effect of a 15-min delay was determined. MC and FNE groups were more disrupted by a delay than MNC and FC groups. Together, these data suggest that early exposure to gonadal steroids (probably estradiol) improves acquisition of spatial tasks by reorganizing and simplifying associational-perceptual processes that guide spatial ability.

Animals↗

Differential lateralization of memory discrimination and response bias in temporal lobe epilepsy patients.

Recognition memory for words and designs was assessed in epilepsy patients who underwent unilateral anterior temporal lobectomy. Memory was assessed during the intracarotid amobarbital test (IAT) performed prior to surgery and also following surgery. Memory discrimination and response bias lateralized differently. Memory discrimination, or memory accuracy, lateralized as a function of the type of material used in memory testing. Left temporal lobe lesions resulted in more impaired discrimination of verbal materials; right temporal lobe lesions resulted in more impaired discrimination of visuospatial materials. Response bias, the decision rule adopted in situations of uncertainty, was more liberal following left temporal lobe lesions for both verbal and visuospatial materials. Findings suggest that the two cerebral hemispheres are differentially specialized for encoding different types of information in long term memory, and that this impacts on decision strategies in situations of memory uncertainty.

Adult↗

Characteristics of basolateral amygdala neuronal firing on a spatial memory task involving differential reward.

Previous research has shown that spatial, movement, and reward information is integrated within the ventral striatum (VS). The present study examined the possible contribution of the basolateral nuclei of the amygdala (BLA) to this interaction by examining behavioral correlates of BLA neurons while rats performed multiple memory trials on an 8-arm radial maze. Alternate arms consistently held 1 of 2 different amounts of reward. Recorded cells were correlated with motion, auditory input, space, and reward acquisition. Reward-related units were found that anticipated reward encounter, that responded during reward consumption, and that differentiated between high and low reward magnitude. This is consistent with the hypothesis that BLA neurons may provide the VS with reward-related information that could then be integrated with spatial information to ultimately affect goal-directed behavior.

Amygdala↗

Stress-induced changes in spatial memory are sexually differentiated and vary across the lifespan.

Stress exposure, depending on intensity and duration, elicits adaptive or maladaptive physiological changes. The same general pattern of advantageous versus deleterious stress effects appears to exist for some cognitive functions, particularly spatial learning and memory performance. This article reviews sex differences in response to stress on a variety of spatial tasks. In general, females are more resistant than males to stress-induced impairments on spatial tasks, including the radial arm maze and object placement. In young adulthood, chronic stress (restraint, 6 h per day for 21 days) impairs male performance on both tasks but leads to behavioural enhancements in females. Furthermore, these sex-dependent stress effects are influenced by both organisational and activational oestrogenic effects. Additionally, sex-specific stress responses vary depending on developmental age at the time of stress exposure. Male behavioural stress responses appear fixed across the lifespan (i.e. stress-induced cognitive impairments) whereas female stress responses appear more variable (i.e. stress-induced enhancements observed in young adulthood are different in response to prenatal stress and diminished following stress exposure at old age). These findings underscore the point that many effects obtained in males cannot be generalised to females and highlight the need to investigate the stress response at different ages and in both sexes.

Adaptation, Physiological↗

Memory and schizophrenia: differential link of processing speed and selective attention with two levels of encoding.

The purpose of this study was to investigate how underlying cognitive deficits such as a defect in processing speed or in selective attention contributed to different types of memory impairment observed in schizophrenia (superficial vs deep encoding). 49 schizophrenic patients and 40 normal controls were administered a verbal memory task. Superficial encoding was assessed by the ability to recall items in their serial order. Deep encoding was assessed by the ability to organise words into semantic categories. Two measures of processing speed (Digit Symbol Substitution Test and Stroop colour time) and one measure of selective attention (Stroop test) were used. Regression analyses were carried out. In the patient group, processing speed contributed to both superficial and deep encoding, and to a global verbal memory score. Selective attention only contributed to the superficial encoding processes. Thus, slowing of processing speed in schizophrenia seems to be more crucial for memory performance, since it affects memory in a pervasive way.

Adult↗

Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination.

B cells producing high-affinity antibodies are destined to differentiate into memory B cells and plasma cells, but the mechanisms leading to those differentiation pathways are mostly unknown. Here we report that the transcription factor IRF4 is required for the generation of plasma cells. Transgenic mice with conditional deletion of Irf4 in germinal center B cells lacked post-germinal center plasma cells and were unable to differentiate memory B cells into plasma cells. Plasma cell differentiation required IRF4 as well as the transcriptional repressor Blimp-1, which both acted 'upstream' of the transcription factor XBP-1. In addition, IRF4-deficient B cells had impaired expression of activation-induced deaminase and lacked class-switch recombination, suggesting an independent function for IRF4 in this process. These results identify IRF4 as a crucial transcriptional 'switch' in the generation of functionally competent plasma cells.

Animals↗

Differential representations of memory T cell subsets are characteristic of polarized immunity in leprosy and atopic diseases.

We identified functionally polarized subsets of CD4 memory T cells on the basis of the expression of CD11a, CD45RA and CD62L. Within the several phenotypically distinct subsets of CD4 memory cells are two that, upon stimulation, produce primarily IL-4 (MT(2), CD45RA(-)CD62L(+)CD11a(dim)) or primarily IFN-gamma (MT(1), CD45RA(-)CD62L(-)CD11a(bright)). In addition, four other phenotypically distinct subsets of CD4 cells have unique cytokine profiles. To determine the clinical relevance of the representation of these cell types, we analyzed blood from patients with the chronic diseases leprosy and atopy. These diseases are characterized as immunologically polarized, since T cell responses in affected individuals are often strongly biased towards T(h)1 (dominated by IFN-gamma production) or T(h)2 (IL-4 production). We show here that this polarization reflects homeostatic or differentiation mechanisms affecting the representation of the functionally distinct subsets of memory CD4 T cells, MT(1) and MT(2). Significantly, the representation of the MT(1) and MT(2) subsets differs dramatically between subjects with tuberculoid leprosy (a T(h)1 disease), or lepromatous leprosy or atopic disease (T(h)2 diseases). However, there was no difference in the cytokine profiles of these or any of the other finely resolved CD4 subsets, when compared between individuals across all disease states. Thus, it is the representation of these subsets in peripheral blood that is diagnostic of the polarized state of the immune system.

CD4-Positive T-Lymphocytes↗

Differential patterns of memory loss among patients with Alzheimer's disease, Huntington's disease, and alcoholic Korsakoff's syndrome.

Patients with Huntington's disease (HD), alcoholic Korsakoff's syndrome (KS), and Alzheimer's disease (AD) were compared with normal control subjects on a task designed to assess recognition memory for different classes of stimuli: spatial, verbal, color, pattern, and facial. In addition, recall of verbal stimuli was assessed at two delay intervals. On recognition testing, AD and KS patients were impaired on each of the five stimulus conditions. However, HD patients, though impaired on four of the recognition conditions, were unimpaired when verbal stimuli were used. On recall testing, the AD, HD, and KS groups were equally impaired at the shorter delay (15 s). However, at the longer delay (two minutes), the KS and HD patients, though still impaired relative to the normal control group, performed significantly better than the AD group.

Adult↗

The differential pattern of memory deficit in normal aging and dementias of different etiology.

The study explored encoding, storage, and retrieval components of memory functioning in four groups of subjects: (1) normal elderly; (2) elderly subjects in the early prestages of DAT; (3) elderly subjects with a more advanced DAT; (4) younger subjects in the early prestages of AIDS dementia. Each group consisted of 26 subjects, who were administered the Rey Auditory-Verbal Learning Test. The results suggest impaired encoding and retrieval in the DAT groups. The AIDS group demonstrated deficient storage and retrieval. Their pattern of memory deficits was similar to that seen in normal aging. The results speak in favor of the hypothesis of subcortical nature of neurological changes in normal aging.

AIDS Dementia Complex↗

Role of membrane receptors in the induction of an in vitro secondary anti-hapten response. I. differentiation of B memory cells to plasma cells is independent of antigen-immunoglobulin receptor interaction.

In these experiments, we show that the interaction of antigen and B cell surface immunoglobulin is not essential for the generation of an IgG in vitro response to the hapten p-azophenyl-lactoside (lac). In our experimental system, keyhole limpet hemocyanin (KLH) was first selectively attached either to H-2, Ia or Ig receptors of lac-primed B cells by a hapten sandwich technique or to Fc receptors by complexes of azophenyl arsonate (ars)-coupled KLH and anti-ars. The labeled cells were then cultured with KLH-specific T cells for 5 days in the absence of antigen. Under all conditions of attachment we observed a significant anti-lac IgG response. We have demonstrated an absolute requirement for KLH-specific helper T cells. The results thus indicate that T helper cells are by themselves, regardless of the B cell antigen that serves to effect bridging, sufficient to activate B memory cells. We could find no evidence to support either a matrix theory or a two-signal hypothesis as currently proposed.

Animals↗

Differential sensitivity of memory cell subpopulations to anti-immunoglobulin and complement.

Evidence is presented for the unique sensitivity of memory cells bearing surface immunoglobulin G1 (IgG1) to functional elimination with anti-immunoglobulin (anti-Ig) sera and complement (C). Treatment of cells for adoptive transfer with C and anti-gamma1, anti-kappa, or anti-Ig significantly reduces the number of plaque-forming cells (PFC) of only the IgG1 isotype found in adoptive recipients. An increase in PFC of other isotypes accompanies the decrease in IgG1 PFC; there is no net change in the total PFC response. The depletion of IgG1 PFC requires treatment of transferred cells with both specific antisera and C; antisera directed against other isotypes show no significant effects. The maintenance of the magnitude of PFC response, compensation, is discussed.

Animals↗

Differential access to memory traces in the production of mental experience.

Two experiments were performed to determine the nature of the memory traces used in the production of mental experiences (dreams, daydreams). Free associations with dreams, collected upon experimental awakenings in Sleep Onset and rapid eye movement (REM) sleep, were classified as strict episodes, abstract self-references, or semantic traces, adapting Tulving's model (Experiment 1). Results showed that associations with Sleep Onset dreams were mainly strict episodes while REM associations were evenly distributed: that represents a psychophysiological state-dependency of the access to memory traces. A comparison of free associations with dream, daydreams, and films (Experiment 2) showed a similarity between access to memory traces in daydreaming and Sleep Onset dreaming. Physiological condition was not a discriminating factor. This homogeneity suggests that cognitive processes involved in the creation of original narrative sequences may be similar in sleep and waking. These findings and their interpretation tend to support a unitary theory of the mind rather than dichotomous models which, in dream research, have often been misleading.

Adult↗

Prefrontal cortex activity differentiates processes affecting memory in depression.

Deficits in the initiation and utilization of strategies contribute importantly to memory impairments in depression. Other research on depression has documented memory biases toward negative and away from positive material. This study investigated brain mechanisms accompanying the initiative deficit and negative bias processes affecting memory in depressed individuals. Electroencephalography was recorded prior to and during emotional narratives and correlated with subsequent memory recognition of narrative material. Hypothesized to reflect strategy initiation, bilateral activity of the prefrontal cortex (PFC) preceding a sad narrative was associated with memory performance for that narrative in nondepressed controls only. Negative memory bias in depressed participants was inferred from their association between right prefrontal activity during the sad narrative and memory performance, consistent with research implicating that region in withdrawal-related unpleasant emotions. These results highlight the importance of distinguishing processes that influence memory performance when investigating the neural mechanisms of cognitive deficit and bias in depression.

Adult↗

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory.

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.

Analysis of Variance↗