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During humoral immune responses, B-lymphocyte activation is followed by differentiation along either the plasma cell pathway or the memory B-cell pathway. Recent studies suggest that CD40-CD40 ligand, OX-OX40 ligand, a group of cytokines and intracellular transcriptional factors may all contribute to B-lymphocyte differentiation control.
Appropriately activated CD8+ T cells differentiate into cytotoxic effectors capable of eliminating cancer cells and virally infected cells. Successful generation and maintenance of effective CD8+ T-cell memory, through either natural infection or through vaccination, establishes long-term protection against various pathogenic agents and, therefore, contributes significantly to our health. This report is a review of recent advances in CD8+ T-cell memory research. The pool of memory CD8+ T cells is maintained through a mechanism of rapid turnover that is antigen-independent, class I major histocompatibility complex (MHC I) antigen-dependent, and, potentially, IL-15-dependent. Memory CD8+ T cells, in marked contrast to naive CD8+ T cells, constitutively express cytotoxic effector function in the absence of antigen stimulation. Furthermore, the vast majority of activated CD8+ T cells in mice infected with lymphocytic choriomeningitis virus are antigen-specific, prompting revision of the commonly held view that many antigen-nonspecific CD8+ T cells are activated in response to viral infection. These newly published results not only provide exciting insights into the inner workings of CD8+ memory maintenance, but they also establish a sound foundation for future investigation. As more detailed molecular and cellular mechanisms of the regulation of memory CD8+ T-cell survival emerge, the most exciting challenge will be to apply this understanding toward the rational design of vaccines and immunotherapies. These potentials are even more relevant in view of the critical nature of CD8+ T cells in combating viral infection and cancer, and the relative paucity of effective drugs against these diseases.
In this paper we address the question: How do replicating mammalian cells remember with high fidelity their proper state of differentiation? Several possible mechanisms for cell memory are discussed, and it is concluded that only mechanisms involving DNA methylation are supported by strong experimental evidence. This evidence is reviewed. The establishment and modulation of methylation patterns are discussed and a hemimethylation model for stem cells is presented. The overall conclusion is that, although little is yet known about the details, there should be little doubt about the existence of a methylation system functioning at least to aid cell memory.
In this review we address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation. Epigenetic mechanisms typically involve alterations in chromatin structure, which in turn regulate gene expression. An emerging idea is that the regulation of chromatin structure through histone acetylation and DNA methylation may mediate long-lasting behavioral change in the context of learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term 'memory' at the cellular level, for example when cells differentiate. An additional intriguing aspect of the hypothesis of a role for epigenetic mechanisms in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.
Better knowledge of the preclinical phase of Alzheimer's disease and of the symptomatic pre-dementia stage designated "mild cognitive impairment" will require considerable progress in our understanding of neuropsychological processes. The results of studies suggest that impaired performance in memory tests may serve as a marker for Alzheimer's disease. The best current predictors include stringent tests of episodic memory and recognition tests. The early stages of Alzheimer's disease also seem to involve subtle deficits in semantic memory and attentional processes. Face recognition and denomination seem to be useful tools. Greater accuracy and precision in the transitional zone between healthy aging and the first manifestations of Alzheimer's disease will require work combining data on neuropsychological profiles and neuroimaging.
There is extensive plasticity in the T-cell response to antigen. Helper CD4(+) T cells, cytotoxic CD8(+) T cells, the progression from naïve to effector and memory T cells, and differentiation into Th1, Tc1, Th2 and Tc2 subsets have long been recognized. More recently it has become apparent that T-cell populations display additional diversity in terms of phenotype, anatomical distribution and effector function.
BACKGROUND: AD causes visuospatial disorientation that is associated with posterior cortical atrophy and impaired visual motion processing. OBJECTIVE: The authors characterized memory capacity and visual motion processing in young normal (YN) and older normal (ON) adult subjects and in patients with mild cognitive impairment (MCI) and AD to see if deficits in these realms occur as isolated impairments. METHODS: Each participant underwent neuropsychological testing and gave push-button responses to indicate perception of panoramic visual motion stimuli. RESULTS: One fifth of the ON subjects, one third of the patients with MCI, and half of the patients with AD showed increasingly pervasive impairments of visual motion perception. These impairments were associated with poorer performance on the Money Road Map test of spatial navigation but not with verbal or visual memory deficits. CONCLUSION: Impaired visual motion processing may accompany memory deficits in MCI or AD, or may occur alone in otherwise intact ON subjects. This suggests that visuospatial impairment may develop as an independent sign of neurodegenerative disease, possibly preceding the clinical onset of AD.
Chronic infections in mice can result in defects in memory CD8 T cell properties including low expression of the IL-7Ralpha (CD127). To determine whether defects in memory CD8 T cell formation exist during human chronic infections and to what extent these defects may be allele- or epitope-specific, we compared influenza (Flu), vaccinia (VV) and EBV-specific CD8 T cells to HIV-specific CD8 T cells, using a panel of 13 HIV tetramers. Compared to Flu, VV or EBV, HIV tetramer+ CD8 T cells expressed significantly lower levels of CD127, and this reduction was pervasive across all epitopes and alleles tested and over a wide range of viral loads and CD4 counts. These results indicate impaired HIV-specific memory CD8 T cell differentiation, regardless of level of control of viremia, epitopes targeted or restricting HLA alleles.
A simple in vitro experimental system was devised to reflect the in vivo generation of a T cell anamnestic response so that T cell differentiation could be examined at the level of lymphokine gene expression. Comparison of neonatal and adult T cells revealed that both populations expressed the genes for interleukin 2 (IL-2) and its receptor, but only adult T cells were capable of transcribing mRNAs for IL-3, IL-4, IL-5, IL-6, interferon gamma, and granulocyte/macrophage colony-stimulating factor. However, neonatal T cells could be induced to undergo functional differentiation in vitro, thereby acquiring the capacity to express the lymphokine gene repertoire characteristic for adult T cells. These data suggest that the T cells generated from neonatal blood by a primary stimulation in vitro are functionally indistinguishable from the T cells in adult blood that presumably have undergone primary stimulation in vivo. Therefore, we propose that the term "memory cell" be applied to those T cells that can be identified by their differentiated state of inducible effector-lymphokine gene expression.
The first part of this research assessed the longitudinal relationships between alcohol-related associative strength and alcohol use measured at two time-points, 6 months apart. Cross-lagged results support the utility of alcohol-related associative strength to predict drinking behaviours prospectively and vice versa. These results remained after competing explanations of previous use, autocorrelations between memory measures, sensation seeking and background variables of age and gender were accounted for. Findings offer further evidence for an implicit cognitions approach to drinking processes. In the second part of our study, cross-sectional analysis investigated potential mediating mechanisms in the relation of associative strength to quantity and frequency dimensions of drinking. Mediational models provide preliminary evidence that implicit memory processes may have differential effects on quantity and frequency dimensions of drinking behaviours. The results point to the possibility that increasing awareness of implicit alcohol-related associations may have utility in interventions for young adults.
In 2002, dementia is more prevalent in the elderly population than a few years ago. However, drugs are now available that can delay the onset of the symptoms of Alzheimer's disease, with or without vascular components. But to be effective, they require a rapid diagnosis and the management of the patient's problem by the primary care physician. This paper wants to be practical. The author describes how and why the patient and the family seek medical help. The concept of depressive pseudo-dementia is explained. Diagnostic criteria and most common causes of dementia are reviewed. Clinical pointers are discussed to help differentiate between mild cognitive impairment and memory loss indicative of dementia. User-friendly screening tests with their interpretation are suggested for the clinical investigation of the problem. The natural history of Alzheimer's disease and the differential diagnosis are discussed, using frequency and possibilities of intervention as guidelines.
We reported previously that the glycosaminoglycan heparin (HP) has the facility to improve learning in adult rodents when administered into the nucleus basalis of the ventral pallidum. Here we gauged the effects of chronic intraventricular infusion of HP (20 ng per day over 28 days) in 26-month-old rats in terms of Morris water maze performance, habituation to a novel open field, retention of a step-through inhibitory avoidance task and changes in forebrain acetylcholine (ACh) levels. Control groups included vehicle-infused old and adult (3-month-old) rats. The chronic infusion of HP did not significantly influence the performance of the old animals in any of the learning and memory tasks employed. HP only slightly facilitated the retention of the inhibitory avoidance task and the rate of habituation in the open-field paradigm. In the water maze, the glycosaminoglycan did not counteract the navigation deficits observed for aged controls and even impaired performance during the initial place-learning trials. After behavioural testing, tissue levels of ACh were determined in frontal cortex, ventral striatum, neostriatum and hippocampus without detecting any obvious neurochemical differences between groups. The current results, together with our previous work, indicate that HP differentially affects learning and memory parameters in adult and aged rats. Thus, whereas the glycosaminoglycan proved effective in facilitating mnemonic functions in normal adult animals, no such a clear-cut beneficial effect was observed in behaviourally impaired old rats.
Some people recall more positive memories in negative moods than in neutral moods, which is called mood-incongruent effect. Although previous research suggested that structure of self-knowledge influences mood-incongruent effect (Sakaki, 2004), it is possible that motivation for mood-regulation mediates relation between structure of self-knowledge and mood-incongruent effect. The present study aimed at exploring this possibility by using self-complexity. In Study 1, participants with higher self-complexity, whose self-knowledge has more self-aspects with a higher level of differentiation, recalled more positive memories in negative moods (compared to neutral moods) than participants with lower self-complexity, whose self-knowledge has a fewer self-aspects with larger overlap. Study 1 also revealed that these effects hold even when the motivation for mood-regulation was partialed out. Study 2 examined mood-incongruent effect under positive moods, in which participants are unlikely motivated to alter their moods, and it was found that participants with higher self-complexity recalled more negative memories in positive moods (compared to neutral moods) than participants with lower self-complexity.
This study had two goals. One was to assess whether the WMS-III Spatial Span subtest operates as a visual analogue of Digit Span while the second was to determine whether backward span is a more sensitive measure of working memory than the forward span condition. Analyses based on the WAIS-III-WMS-III standardization and clinical group data revealed some important distinctions between Digit and Spatial Span. The two tasks exhibited differences in patterns of performance on the forward versus backward conditions, in their relationships with age, and in their methodology. Moreover, the backward conditions of both Digit and Spatial Span did not appear more affected by risk factors such as aging or pathology than the forward scores. This runs contrary to the widespread notion that backward span provides differential sensitivity regarding working memory processing.
This paper reviews the literature concerning executive control impairments in degenerative dementias. The construct of executive control functioning is examined, as is the neuroanatomy of frontal-subcortical networks, believed to underlie executive function (EF) impairments. The pattern of EF impairments in Alzheimer's disease (AD) which affects temporal and parietal brain regions most severely is contrasted with observed executive dysfunctions in patients with dementias involving degeneration of primarily frontal and frontal-subcortical brain areas. EF impairments are present in each of these types of dementing illnesses. Although EF impairments are present in AD, they are less prominent than the memory disorder in the neuropsychological profile of the disease and tend to become more pronounced later in the course of the illness. In contrast, patients with frontal or frontal-subcortical dementia may demonstrate executive dysfunction, which occurs earlier in the disease progression and may be initially more severe.
An immune response cascade that is T cell independent begins with the stimulation of virgin lymphocytes by antigen to differentiate into large lymphocytes. These immune cells can either replicate themselves or differentiate into plasma cells or memory cells. Plasma cells produce antibody at a specific rate up to two orders of magnitude greater than large lymphocytes. However, plasma cells have short life-spans and cannot replicate. Memory cells produce only surface antibody, but in the event of a subsequent infection by the same antigen, memory cells revert rapidly to large lymphocytes. Immunologic memory is maintained throughout the organism's lifetime. Many immunologists believe that the optimal response strategy calls for large lymphocytes to replicate first, then differentiate into plasma cells and when the antigen has been nearly eliminated, they form memory cells. A mathematical model incorporating the concept of cybernetics has been developed to study the optimality of the immune response. Derived from the matching law of microeconomics, cybernetic variables control the allocation of large lymphocytes to maximize the instantaneous antibody production rate at any time during the response in order to most efficiently inactivate the antigen. A mouse is selected as the model organism and bacteria as the replicating antigen. In addition to verifying the optimal switching strategy, results showing how the immune response is affected by antigen growth rate, initial antigen concentration, and the number of antibodies required to eliminate an antigen are included.
Effects on adhesion molecules of immune cells might contribute to the mode of action of interferon-beta (IFN-beta) in multiple sclerosis (MS). We have serially monitored the cell surface expression of integrins CD49d (VLA-4) and CD11a (LFA-1) on fresh T lymphocyte subpopulations from 5 MS patients monthly for 2 months prior to treatment and for 3 months on treatment with IFN-beta1b. In parallel, we assessed inflammatory disease activity by monthly contrast-enhanced magnetic resonance imaging (MRI). IFN-beta treatment specifically downregulated CD49d expression on CD8+ and CD4+/CD45RO+ 'memory' T lymphocytes and differentially modulated the proportion of CD4+, CD8+ and CD27+ T cells. These effects may play an important role in the reduction of central nervous system cell trafficking and inflammation in MS.
The present experiment evaluated the ability of rats with lesions in the thalamic mediodorsal nucleus (MD) to perform a task which differentiates between "reference" and "working" memory. In this task, only four of the arms of an 8-arm radial maze were baited, and animals were to restrict their entries to arms which were baited and to avoid never-baited arms. Despite several postoperative acquisition trials, rats with MD lesions did not acquire the task to a degree comparable to control subjects. Subjects with lesions continued to enter never-baited arms (reference memory errors) and to reenter baited arms (working memory errors). Given the lack of specificity in the behavioural impairment, the reference-working memory distinction seems to be an inappropriate one for characterizing the MD lesion deficit in rats. This deficit may involve an inability to use environmental stimuli to distinguish among arms of the maze, or an alteration in motor mechanisms.