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PubMed1997

Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes.

A successful T cell immune response has two major products: effector T cells which directly or indirectly remove the antigens, and memory T cells, which allow a faster and more efficient recall response when challenged by related antigens. An important issue is whether costimulatory molecules on the antigen-presenting cells are involved in determining whether T cells will differentiate into effector or memory cells after antigenic stimulation. To address this issue, we have produced mice with targeted mutations of either the heat-stable antigen (HSA), or both HSA and CD28. We show that CD28/B7 and HSA provide two alternative costimulatory pathways for induction of immunological memory to influenza virus. Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells. Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules. These results have important implications on lineage relationship between effector and memory T cells.

Animals↗

PubMed2006

Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshock.

Extensive evidence from contextual fear conditioning experiments suggests that the hippocampus is involved in processing memory for contextual information. Evidence also suggests that the rostral anterior cingulate cortex (rACC) may be selectively involved in memory for nociceptive stimulation. In contrast, many findings indicate that the basolateral amygdala (BLA) is more broadly involved in modulating the consolidation of different kinds of information. To investigate further the differential involvement of these brain regions in memory consolidation, the present experiments used a modified inhibitory avoidance training procedure that took place on 2 sequential days to separate context training from footshock training. Male Sprague-Dawley rats were implanted with unilateral cannulae aimed at the (i) hippocampus, (ii) rACC, or (iii) BLA, and given infusions of the muscarinic cholinergic agonist oxotremorine (OXO) immediately after either context training (day 1) or footshock training in that context (day 2). OXO enhanced retention when infused into the hippocampus after context, but not footshock, training. Conversely, OXO infusions enhanced memory when administered into the rACC immediately after footshock, but not context, training. Lastly, intra-BLA OXO infusions enhanced retention when administered after either context or footshock training. These findings are consistent with evidence that the hippocampus and rACC play selective roles in memory for specific components of training experiences. Additionally, they provide further evidence that the BLA is more liberally involved in modulating memory consolidation for various aspects of emotionally arousing experiences.

Amygdala↗

PubMed2003

Memory T cells and vaccines.

T lymphocytes play a central role in the generation of a protective immune response in many microbial infections. After immunization, dendritic cells take up microbial antigens and traffic to draining lymph nodes where they present processed antigens to naïve T cells. These naïve T cells are stimulated to proliferate and differentiate into effector and memory T cells. Activated, effector and memory T cells provide B cell help in the lymph nodes and traffic to sites of infection where they secrete anti-microbial cytokines and kill infected cells. At least two types of memory cells have been defined in humans based on their functional and migratory properties. T central-memory (T(CM)) cells are found predominantly in lymphoid organs and can not be immediately activated, whereas T effector-memory (T(EM)) cells are found predominantly in peripheral tissue and sites of inflammation and exhibit rapid effector function. Most currently licensed vaccines induce antibody responses capable of mediating long-term protection against lytic viruses such as influenza and small pox. In contrast, vaccines against chronic pathogens that require cell-mediated immune responses to control, such as malaria, Mycobacterium tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are currently not available or are ineffective. Understanding the mechanisms by which long-lived cellular immune responses are generated following vaccination should facilitate the development of safe and effective vaccines against these emerging diseases. Here, we review the current literature with respect to memory T cells and their implications to vaccine development.

Animals↗

PubMed1998

Errors associated with the use of adaptive differential pulse code modulation in the compression of isometric and dynamic myo-electric signals.

Muscle activity produces an electrical signal termed the myo-electric signal (MES). The MES is a useful clinical tool, used in diagnostics and rehabilitation. This signal is typically stored in 2 bytes as 12-bit data, sampled at 3 kHz, resulting in a 6 kbyte s-1 storage requirement. Processing MES data requires large bit manipulations and heavy memory storage requirements. Adaptive differential pulse code modulation (ADPCM) is a popular and successful compression technique for speech. Its application to MES would reduce 12-bit data to a 4-bit representation, providing a 3:1 compression. As, in most practical applications, memory is organised in bytes, the realisable compression is 4:1, as pairs of data can be stored in a single byte. The performance of the ADPCM compression technique, using a real-time system at 1 kHz, 2 kHz and 4 kHz sampling rates, is evaluated. The data used include MES from both isometric and dynamic contractions. The percent residual difference (PRD) between an unprocessed and processed MES is used as a performance measure. Errors in computed parameters, such as median frequency and variance, which are used in clinical diagnostics, and waveform features employed in prosthetic control are also used to evaluate the system. The results of the study demonstrate that the ADPCM compression technique is an excellent solution for relieving the data storage requirements of MES both in isometric and dynamic situations.

Electromyography↗

PubMed1997

Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.

Telomerase activity and the regulation of telomere length are factors which have been implicated in the control of cellular replication. These variables have been examined during human lymphocyte development, differentiation, activation, and aging. It was found that telomere length of peripheral blood CD4+ T cells decreases with age as well as with differentiation from naive to memory cells in vivo, and decreases with cell division in vitro. These results provide evidence that telomere length correlates with lymphocyte replicative history and residual replicative potential. In contrast, telomere length appears to increase during tonsil B-cell differentiation and germinal center (GC) formation in vivo. It was also found that telomerase activity is highly regulated during T-cell development and B-cell differentiation in vivo, with high levels of telomerase activity expressed in thymocytes and GC B cells, and low levels of telomerase activity in resting mature peripheral blood lymphocytes. Finally, resting lymphocytes retain the ability to upregulate telomerase activity upon activation, and this capacity does not appear to decline with age. Although the precise role of telomerase in lymphocyte function remains to be elucidated, telomerase may contribute to protection from telomere shortening in T and B lymphocytes, and may thus play a critical role in lymphocyte development, differentiation and activation. The future study of telomerase and its regulation of telomere length may enhance our understanding of how the replicative lifespan is regulated in lymphocytes.

Animals↗

PubMed1979

B-cell influences on the induction of allotype suppressor T cells.

Allotype suppressor T-cell (Ts) populations that persist for the life of the animal arise in (BALB/c x SJL)F(1) hybrids exposed perinatally to antibody to the paternal (Ig-1b) allotype on IgG(2a)-isotype immunoglobulin H chains. These Ts suppress Ig-lb production by depleting the supply of allotype- specific helper T cells (Th) required, in addition to carrier-specific Th, for the latter stages of Ig-1b memory B-cell differentiation. In this publication, we show that specific Ig-1 allotype Ts are induced by perinatal exposure to antisera which interfere with normal B-cell maturation, i.e., by antibodies reactive with surface IgM on immature precursors of IgG(2a), memory cells. Antibodies to IgM (Ig-6) allotypes carried on precursors induce specific suppression for the IgG2, allotype produced by progeny of the target precursor. Anti-Ig-6a and anti-Ig-6b induce Ts that specifically suppress Ig-1a and Ig-1b, respectively. Heterologous (goat) anti-IgM induces suppression for both IgG(2a) immunoglobulins (Ig-1a and Ig-1b). Ts activity in these antiprecursor-Ig-suppressed mice is expressed in adoptive transfer assays and, as with anti-Ig-1b-induced Ts, is rendered ineffective by cotransfer of adequate numbers of T cells but not B cells from nonsuppressed mice. The Ts induction, in contrast with Ts expression, is reversed by the introduction of appropriate adult B-cell populations from nonsuppressed donors. Taken together, these data suggest that the development of mature B cells plays a central role in the early establishment of the balance between helper cells and suppressor cells that determines whether Ts or Th will dominate in regulating Ig-1b production in adult animals.

Age Factors↗

PubMed2004

Differential regulation of primary and secondary CD8+ T cells in the central nervous system.

T cell accumulation and effector function following CNS infection is limited by a paucity of Ag presentation and inhibitory factors characteristic of the CNS environment. Differential susceptibilities of primary and recall CD8+ T cell responses to the inhibitory CNS environment were monitored in naive and CD8+ T cell-immune mice challenged with a neurotropic coronavirus. Accelerated virus clearance and limited spread in immunized mice was associated with a rapid and increased CNS influx of virus-specific secondary CD8+ T cells. CNS-derived secondary CD8+ T cells exhibited increased cytolytic activity and IFN-gamma expression per cell compared with primary CD8+ T cells. However, both Ag-specific primary and secondary CD8+ T cells demonstrated similar contraction rates. Thus, CNS persistence of increased numbers of secondary CD8+ T cells reflected differences in the initial pool size during peak inflammation rather than enhanced survival. Unlike primary CD8+ T cells, persisting secondary CD8+ T cells retained ex vivo cytolytic activity and expressed high levels of IFN-gamma following Ag stimulation. However, both primary and secondary CD8+ T cells exhibited reduced capacity to produce TNF-alpha, differentiating them from effector memory T cells. Activation of primary and secondary CD8+ T cells in the same host using adoptive transfers confirmed similar survival, but enhanced and prolonged effector function of secondary CD8+ T cells in the CNS. These data suggest that an instructional program intrinsic to T cell differentiation, rather than Ag load or factors in the inflamed CNS, prominently regulate CD8+ T cell function.

Animals↗

PubMed1982

Spatial mapping, working memory, and the fimbria-fornix system.

Rats with lesions severing either the subcallosal fornix (Fo) or the medial half of the fimbria (Fi) were used. They were compared with control (Co) animals in a working memory task (serial alternation) and a reference memory task (cue-guided alternation). Neither task required spatial mapping strategy. Damaging the Fi, but not the Fo, caused a severe deficit in the serial alternation task. Analysis of individual performance revealed that Fi rats either adopted a "side strategy, " resulting in worse than chance performance. This active perseveration required intact working memory mechanism. In the cue-guided alternation task, Fo animals proved superior to Co and Fi rats. These findings are inconsistent with notions that the exclusive role of the hippocampus is spatial mapping or storing of recent memories. They indicate also differential involvement of the fimbria and fornix fibers in behavior.

Animals↗

PubMed2007

On keeping (intrusive) thoughts to one's self: testing a cognitive model of auditory hallucinations.

BACKGROUND: Previous studies have linked intrusive cognitions (hallucinations and obsessions) with inhibitory dysregulation. Combined deficits in intentional inhibition and context memory have been proposed to explain the intrusive nature and perceived nonself origin of auditory hallucinations (Waters et al., 2006). This study tested the prediction, from this model, that individuals with obsessive-compulsive disorder (OCD), who do not mistake the origin of their intrusive thoughts, will show a deficit of intentional inhibition but intact contextual memory. METHOD: The performance of 14 individuals with OCD and 24 healthy controls was compared on two measures of intentional cognitive inhibition and on a context memory task.Results. Participants with OCD were significantly impaired on both measures of inhibition but were not significantly different from controls in any condition of the context memory task. CONCLUSIONS: The predictions were confirmed. Individuals with OCD, like schizophrenia patients with auditory hallucinations, showed impaired intentional inhibition. This impairment might be responsible for the intrusive thoughts reported in both disorders, and might also partially account for the high rates of comorbidity of OCD and schizophrenia. Finally, intact context memory abilities in OCD may contribute to an efficient memory system, and may differentiate this group from those with hallucinations.

Adult↗

PubMed1995

Isolated retrograde amnesia for autobiographical material associated with acute left temporal lobe encephalitis.

Retrograde amnesia for autobiographical material in the absence of anterograde amnesia or other memory disturbances was found in a patient with acute viral encephalitis. Memory loss showed a temporal gradient, but new learning was spared. Both brain perfusion imaging with 99mTc-HMPAO SPECT, and EEG localized the lesion in the left temporal lobe while CT and MRI were normal. This observation supports the anatomical differentiation between the different memory functions. The uncommon combination of isolated retrograde amnesia without other neuropsychological findings may raise the doubt of psychogenic aetiology, which in this case was refuted.

Adult↗

PubMed1989

[Early diagnosis of Alzheimer's disease].

An early diagnosis of Alzheimer's disease is nowadays required for a better assistance of the patient and his family, and also to carry out therapeutic trials at that stage. This early diagnosis rests on a systematic study of disorders of memory and behaviour in an elderly subject, on the demonstration of a deficient cognition and on the use of accurate diagnostic criteria.

Alzheimer Disease↗

PubMedDate not supplied

[Reproduction of a memory trace in amnesia and forgetting following alteration in the activity of pre- and postsynaptic dopamine receptors].

The paper deals with analysis of the action of enantiomers 3-PPP on memory trace reproduction disturbed by amnestic effects and spontaneous forgetting in mice. A considerable antiamnestic effect is shown of (+)3-PPP and (-)3-PPP in 10 mg/kg doze changing the activity of postsynaptic dopamine receptors. The influence of drugs in 2 mg/kg doze changing the activity of presynaptic receptors consisted in recovery of conditioned habit only in situation of a weak amnestic effect and at forgetting, when the level of reproduction was like a weak amnesia. The range of enantiomers 3-PPP action on reproduction processes disturbed by amnesia or forgetting is determined by the possibility of specific activation of pre- and postsynaptic receptors at different depth of disturbances of memory trace reproduction causing differentiation of 3-PPP effects.

Amnesia↗

PubMed1996

Memory disorders in Alzheimer's disease and the organization of human memory.

The Squire and Zola-Morgan parallel organization model of the memory and the Tulving hierarchical model were developed mainly through the study of amnesic patients. The predictions of these two models are different, the first being more open to double dissociations and less restrictive than the second. Alzheimer's Disease is characterized by a differential impairment of the memory systems and by an interindividual variability which may take the form of dissociations between preserved and disturbed abilities in some patients. The objective of this study was to use the memory dysfunctions of patients with AD to test the validity of the two models. Analysis of the group data provided an average profile of memory disturbance consistent both with much of the data given in AD literature and with the two models. Using a multiple single-case strategy, we demonstrated several simple dissociations which are for the greater part compatible with the two models. Two of the dissociations underline the limits of the Tulving model, which otherwise accounts for a lot of results. The study supports the relevance of AD for the understanding of the cognitive architecture of the human memory.

Aged↗

PubMed2004

Retrovirus silencing, variegation, extinction, and memory are controlled by a dynamic interplay of multiple epigenetic modifications.

Retrovirus silencing in stem cells produces silent or variegated provirus. Additional memory and extinction mechanisms act during differentiation. Here we show that retrovirus is silent or variegated in mouse embryonic stem (ES) cells that are de novo methyltransferase (dnmt3a and dnmt3b) null. Memory is maintained during differentiation, and extinction occurs on variegated retrovirus, indicating that DNA methylation is dispensable for all forms of retrovirus silencing. Silent and variegated provirus are marked by hypoacetylated histone H3 and bound H1. In wild-type ES cells, silent and variegated proviruses are methylated and bound by hypoacetylated H3, MeCP2, and less H1. Silencing, variegation, and extinction are partially reactivated by 5-AzaC in this context. Lentivirus vectors are also silent or variegated, marked by silent chromatin, and exhibit memory and extinction. We conclude that the universal epigenetic mark of retrovirus silencing is silent chromatin established via the dynamic interplay of multiple epigenetic modifications that include but do not require DNA methylation. A molecular mechanism of competitive H1 and MeCP2 binding may account for this epigenetic interplay, and a model for variegation is discussed.

Animals↗

PubMed2003

Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes.

In contrast to item memory, which refers to recognition or recall of previously presented information, source memory refers to memory for the context of previously presented information. The relatively few functional MRI (fMRI) source memory studies conducted to date have provided evidence that item memory and source memory are associated with differential activity in right and left prefrontal cortex, respectively. To both confirm this distinction in prefrontal cortex and to determine whether other differences in the neural substrates associated with these cognitive functions exist, an event-related fMRI study was conducted. In this study, item memory and source memory encoding phases were identical; participants viewed a series of abstract visual shapes presented on the left or right side of the screen and were instructed to remember each shape and its spatial location. During the item memory retrieval phase, shapes from the encoding phase were intermixed with new shapes and participants made an old-new judgment. During the source memory retrieval phase, all shapes were from the encoding phase and participants made a left-right judgment. An event-related analysis of item memory and source memory revealed a right and left prefrontal cortex distinction. Moreover, only item memory was associated with activity in the medial temporal lobes. These results confirm and extend previous findings that item memory and source memory are associated with distinct neural substrates.

Adult↗

PubMed2003

[What is dementia? 6. From physiological aging to dementia].

Many studies have been devoted to the cognitive changes associated with age, and several attempts have been made for their classification in order to distinguish normal from pathologic changes. In the last few years, a consensus has been reached to classify elderly people in three groups: a) cognitively normal subjects whose cognitive functions score in the range of those of healthy subjects paired according to age and educational level, presenting or not memory complaints; b) subjects with dementia; c) an intermediate group of subjects presenting a cognitive impairment not severe enough to meet the criteria for dementia. The term mild cognitive impairment (MCI) has been proposed to describe these subjects who are at high risk to progress to dementia in the years following the diagnosis. For the first time, MCI construct allows the recognition of the prementia phase of degenerative or vascular cerebral diseases progressing to dementia. However, the lack of clear operational diagnostic criteria and ambiguities about the signification of MCI make the interpretation of the results of studies devoted to this concept hazardous. From a practical point of view, the physician, when faced with a patient complaining of his\her memory, should answer two main questions. "How to recognize memory disorders resulting from incipient AD?" and "What is the signification of memory complaints not related to AD?" The semioloy of memory complaints and the qualitative aspects of the memory deficit allow the diagnosis of incipient AD with pretty good accuracy. Due to the location of the first lesions of AD in hippocampal regions, memory disturbances in AD are related to a deficit in memorization of new information in episodic memory. Conversely, memory disorders related to normal aging, depression, and degenerative or vascular brain lesions not involving hippocampus, are related to deficits in the processes of recall of previously memorized informations. Benign memory complaints have been considered to be linked to the decrease of memory performance, and defining a special group of normal elderly subjects. However, no direct relationship has been demonstrated between memory complaints and performance. In our opinion, all memory complaints are essentially related to psychoaffective disturbances, mainly anxiety, changes in identity and decrease of self-esteem associated with aging.

Aged↗

PubMed1986

Effects of scopolamine and unilateral lesions of the basal forebrain on T-maze spatial discrimination and alternation in rats.

Cholinergic systems are thought to play a role in memory. It has been suggested that cholinergic neurons, possibly the cortically projecting cells of the nucleus basalis magnocellularis, are differentially involved in working and reference memory. To evaluate this hypothesis the effects on memory of scopolamine (0, 0.3, 0.6 mg/kg) or unilateral kainic acid (4.7 nmoles in 1 microliter) lesions of the basal forebrain of rats were tested. Working memory, the recall of recent events of transient importance that is vulnerable to interference, was tested using a T-maze alternation task; reference memory, information stored over the long term that is relatively resistant to interference, was evaluated using a spatial discrimination task in the T-maze. The differential sensitivity of the two tasks to interference effects was confirmed by the finding that the insertion of a 30-sec delay between trials significantly reduced performance in the alternation but not the spatial discrimination task. Furthermore, scopolamine or the lesions significantly impaired alternation but not spatial discrimination performance. Biochemical assays of the kainate-injected brains confirmed that the cortical cholinergic marker, choline acetyltransferase, was significantly reduced. These results support the hypothesis that working and reference memory may be differentially controlled by cholinergic systems.

Animals↗

PubMed1994

Biology of germinal centers in lymphoid tissue.

Germinal centers in lymphoid tissue are the sites of generation of memory B cells undergoing isotype switching and somatic mutation in their Ig genes. Their formation cannot be induced by stimuli other than immunogenic ones. It seems likely that in the function and possibly also in the formation of germinal centers, one important factor is the localization of immune complexes with fixed complement on the surface of follicular dendritic cells. CD4+ T cells, located primarily in the "apical light zones" of the centers, are necessary for germinal center formation. However, their exact role in the process needs clarification, as both cell to cell contact and cytokine production could be involved at different stages of the germinal center generation. These T cells are usually specific for the antigen inducing the germinal center, but they may sometimes respond to other surface components on the B cell surface. In view of the possible stimulatory role of CD4+ T cells in follicular center-derived lymphomas, the functional significance of these T cells in germinal center proliferation is important to unravel. The B cells in germinal centers proliferate extremely rapidly, especially those located in the "dark zones." Many of them undergo apoptosis, particularly in the "basal light zones." The microenvironment of these centers is well suited to the task of expanding and selecting memory B cells of high affinity for the inducing antigen. The interactions of the proliferating B cells with dendritic cells and T cells, unevenly distributed in the various zones of the germinal center, are thought to determine which cells deserve rescue from apoptosis and induction to differentiation into small resting memory B cells. The memory B cells that emerge from the germinal center bear sIg, usually of "switched" isotype, and exhibit somatic mutations in the variable regions of their rearranged Ig genes.

Aging↗