Impact of video games on plasticity of the hippocampus.

The hippocampus is critical to healthy cognition, yet results in the current study show that action video game players have reduced grey matter within the hippocampus. A subsequent randomised longitudinal training experiment demonstrated that first-person shooting games reduce grey matter within the hippocampus in participants using non-spatial memory strategies. Conversely, participants who use hippocampus-dependent spatial strategies showed increased grey matter in the hippocampus after training. A control group that trained on 3D-platform games displayed growth in either the hippocampus or the functionally connected entorhinal cortex. A third study replicated the effect of action video game training on grey matter in the hippocampus. These results show that video games can be beneficial or detrimental to the hippocampal system depending on the navigation strategy that a person employs and the genre of the game.

Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise.

In a previous work, we reported that young transgenic (Tg) mice expressing the intracellular domain of Notch1 (N1(IC)) showed expansion of lin(-) CD24(+) CD29(high) mammary cells enriched for stem cells and later developed mammary tumors. Mammary tumor formation was abolished or greatly reduced in cyclin D1(-/-) or cyclin D1(+/-) N1(IC) Tg mice, respectively. Here, we studied the epithelial cell subsets present in N1(IC)-induced tumors. CD24(-) CD29(int) and CD24(+) CD29(high) cells were found to be present at low numbers in tumors. The latter had the same properties as those expanded in young Tg females, and neither cell population showed tumor-initiating potential nor were they required for maintenance of tumors after transplantation. CD24(int) CD29(int) cells were identified as tumor-initiating and mammosphere-forming cells and represent a large percentage tumor cells in this model. Their number was significantly lower in tumors from cyclin D1(+/-) N1(IC) Tg mice. Using cyclin D1 shRNA knockdown, we also show that N1(IC)-induced tumor cells remain addicted to cyclin D1 for growth and survival. Interestingly, at lower levels of cyclin D1 or after transplantation in the presence of normal mammary cells, these N1(IC)-expressing tumor cells reverted to a state of low malignancy and differentiate into duct-like structures. They seem to adopt the fate of bi-potential stem/progenitor cells similar to that of the expanded CD24(+) CD29(high) stem/progenitor cells from which they are likely to be derived. Our data indicate that decreasing cyclin D1 levels would be an efficient treatment for tumors induced by N1 signaling.

Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors.

Members of the Notch family are involved in the development of breast cancer in animal models and in humans. In young transgenic mice, expressing intracellular activated Notch1 (N1(IC)) in mammary cells, we found that CD24(+) CD29(high) progenitor cells had enhanced survival, and were expanded through a cyclin D1-dependent pathway. This expansion positively correlated with the later cyclin D1-dependent formation of basal-like ductal tumors. This expanded population exhibited abnormal differentiation skewed toward the basal cells, showed signs of pre-malignancy (low PTEN/p53 and high c-myc) and contained stem cells with impaired self-renewal in vivo, and more numerous multipotent, ductal-restricted progenitors. Our data suggest that N1(IC) can favor transformation of progenitor cells early in life through a cyclin D1-dependent pathway.

The interdependence of spatial attention and lexical access as revealed by early asymmetries in occipito-parietal ERP activity.

A test of the possible functional interaction between mechanisms subserving spatial attention and lexical access was devised by displaying one green and one red string of letters, one to the left and one to the right of fixation, and having participants attend to a target string defined by color while ignoring the other distractor string. The target string for a delayed lexical decision task could be a word or a nonword. The distractor was always a word. When the target was a word, target and distractor were associatively related on half of the trials and not related in the other trials. The event-related potential time-locked to the onset of the letter strings produced an N2pc (a greater negativity at scalp sites contralateral to the target relative to the ipsilateral sites arising at about 170 ms poststimulus). N2pc amplitude was reduced when the words were related relative to when they were not related. The results provide direct, online evidence that the rapid activation of meaning by visual words can influence the efficiency of the deployment of spatial attention.

Spatial attention freezes during the attention blink.

A variant of the rapid serial visual presentation paradigm was used to display sequentially two lateral sequences of stimuli, one to the left and one to the right of fixation, embedding two pairs of target stimuli, T1 and T2. T1 was composed of a pair of alphanumeric characters, and subjects had either to ignore T1 or to encode T1 for a delayed response. T2 was a lateral square of a prespecified color. The square had a small gap in one side, and the task for this stimulus was to report which side had the gap. When subjects were required to ignore T1, the T2-locked ERP produced a clear N2pc, that is, a greater negativity at electrode sites contralateral to the position occupied by T2. This N2pc was followed by a sustained posterior contralateral negativity (SPCN). When subjects were required to monitor T1 in addition to T2, both the N2pc and the SPCN components amplitude depended on the difficulty of the task associated with T1. If T1 was composed of digits that had to be encoded for a delayed same/different judgment, both the N2pc and the SPCN components were entirely suppressed. Although attenuated, such components were present when T1 was composed of a pair of symbols that subjects could disregard. The results suggest that a set of mechanisms subserving the allocation of attention in the spatial domain, resulting in the N2pc, suffer significant interference from concurrent cognitive operations required to encode information into visual short-term memory.

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice.

Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHmu-HOX11Tg)-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHmu-HOX11Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesis-block micronucleus assays. Additionally, IgHmu-HOX11Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHmu-HOX11Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHmu-HOX11Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

Expression and analysis of the Epstein-Barr virus BARF1-encoded protein from a tetracycline-regulatable adenovirus system.

Epstein-Barr virus (EBV) has been associated with human cancers of lymphocytic or epithelial origin. Potential functions of the BARF1 early gene in EBV oncogenesis emerged from our observations showing expression of BARF1-encoded protein in nasopharyngeal carcinoma biopsies, and induction of either malignant transformation (in rodent fibroblast and human B cell lines) or immortalization (in monkey primary epithelial cells) following BARF1 transfection. We previously reported expression of the BARF1 product as a cytoplasm/membrane-associated protein from 293-tTA cells infected with a BARF1-recombinant adenovirus. Since constitutive expression of BARF1 from this heterologous system became inefficient, we developed a tetracycline-regulatable recombinant vector expressing BARF1 and green fluorescent protein from a dicistronic message. As here reported, stable and efficient expression of BARF1 from this vector in either permissive or non-permissive cell lines, allowed the first sequencing identification and further molecular characterization of BARF1-encoded protein.

Central processing overlap modulates P3 latency.

Two experiments examined the issue of the functional mechanisms exerting a modulatory effect on the latency of the P3. In experiment 1, using a psychological refractory period (PRP) paradigm, two sequential stimuli (T(1) and T(2)) were presented in each trial at varying stimulus onset asynchronies (SOAs), each requiring a speeded choice response. Substantial lengthening of the reaction time to T(2) was observed as SOA decreased (i.e., PRP effect). A systematic investigation of the T(2)-locked P3 component amplitude and latency was undertaken to discover whether either of these P3 parameters was correlated with the PRP effect. The results showed lengthening of the T(2)-locked P3 component latency as SOA was decreased, and, across subjects, a positive correlation between the PRP effect and P3 latency lengthening. No SOA-dependent P3 amplitude variation was observed. In experiment 2, the P3 component was measured under single-task conditions. P3 amplitude was higher under single-task than under dual-task conditions, but no SOA-dependent latency variations were observed in this experiment. Overall, the results of both experiments support the notion that part of the processing reflected in P3 activity occurs at or after the locus of the PRP effect, thus suggesting strongly that central mechanisms are involved in P3 latency variations.

Unitary attention in callosal agenesis.

The interhemispheric organisation of two specific components of attention was investigated in three patients affected by partial or complete agenesis of the corpus callosum. A visuospatial component of attention was explored using a visual search paradigm in which target and distractors were displayed either unilaterally within a single visual hemifield, or bilaterally across both visual hemifields in light of prior work indicating that split-brain patients were twice as fast to scan bilateral displays compared to unilateral displays. A central component of attention was explored using a psychological refractory period (PRP) paradigm in which two visual stimuli were presented laterally at various stimulus onset asynchronies (SOAs), with each stimulus associated with a different speeded two-alternative choice task. The stimulus-response compatibility in the second task was systematically manipulated in this paradigm, in light of prior work indicating that split-brain patients exhibited a close-to-normal PRP effect (i.e., slowing of the second response as SOA is decreased), with, however, abnormally decreasing effects of the manipulation of the response mapping on the second task speed as SOA was decreased. The present results showed that, although generally slower than normals in carrying out the two tasks, the performance of each of the three acallosal patients was formally equivalent to the performance of a matched control group of normal individuals. In the visual search task, the search rate of the acallosal patients was the same for unilateral and bilateral displays. Furthermore, in the PRP task, there was more mutual interference between the lateralised tasks for the acallosal patients than that evidenced in the performance of the matched control group. It is concluded that the visuospatial component and the central component of attention in agenesis of the corpus callosum are interhemispherically integrated systems.

Electrophysiological evidence of visual encoding deficits in a cross-modal attentional blink paradigm.

Two experiments are reported in which two target stimuli, T1 and T2, were presented at variable stimulus onset asynchronies (SOAs). In Experiment 1, T1 and T2 were visual stimuli embedded in a rapid serial visual presentation (RSVP) stream of distractors. Participants were asked to report T1 and T2 at the end of the stream. In Experiment 2, T1 was an auditory stimulus, and T2 a visual stimulus embedded in an RSVP stream. Participants made a speeded discriminative response to T1, and reported T2 at the end of the stream. An attentional blink (AB) effect was observed in both experiments: T2 report suffered at short SOA compared to long SOA. During the AB, the amplitude of the P300 component of the event-related potential (ERP) locked to T2 onset was sensibly reduced in both experiments. Behavioral and ERP results were very similar across the two experiments. Implications for models of the AB effect are discussed.

Four-dot masking produces the attentional blink.

When two target stimuli (T1 and T2) are presented sequentially within half a second of each other, identification accuracy is often poor for T2. This phenomenon, known as attentional blink (AB), can be observed generally only if the stimulus terminating the presentation of T2 acts as an interruption mask. Recent evidence suggests that even four small dots surrounding a target item can exert masking effects, provided the target onset occurs at an unattended spatial location. In order to test whether an AB could be observed under conditions of four-dot masking of T2, five rapid serial visual presentation streams of letters were synchronously displayed on each trial of the present experiment. T1 and T2 were digits presented at unpredictable locations and unpredictable temporal intervals. T2 was followed by either a blank field, a letter, or four-dots. No AB was observed when T2 was not masked, but robust and equally sized ABs were observed when T2 was followed by both the letter mask and the four-dots.

Assessing the emetic potential of PDE4 inhibitors in rats.

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck.

The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important determinant of AIDS pathogenesis. We have previously reported that HIV-1 Nef is responsible for the induction of a severe AIDS-like disease in CD4C/HIV transgenic (Tg) mice. To understand the molecular mechanisms of this Nef-induced disease, we generated Tg mice expressing a mutated Nef protein in which the SH3 ligand-binding domain (P(72)XXP(75)XXP(78)) was mutated to A(72)XXA(75)XXQ(78). This mutation completely abolished the pathogenic potential of Nef, although a partial downregulation of the CD4 cell surface expression was still observed in these Tg mice. We also studied whether Hck, one of the effectors previously found to bind to this PXXP motif of Nef, was involved in disease development. Breeding of Tg mice expressing wild-type Nef on an hck(-/-) (knockout) background did not abolish any of the pathological phenotypes. However, the latency of disease development was prolonged. These data indicate that an intact PXXP domain is essential for inducing an AIDS-like disease in CD4C/HIV Tg mice and suggest that interaction of a cellular effector(s) with this domain is required for the induction of this multiorgan disease. Our findings indicate that Hck is an important, but not an essential, effector of Nef and suggest that another factor(s), yet to be identified, may be more critical for disease development.

Distinct regulatory elements are required for faithful expression of human CD4 in T cells, macrophages, and dendritic cells of transgenic mice.

To identify the regulatory elements controlling expression of the human CD4 (hCD4) gene in different cell types of the immune system, deletion and chimeric (human/murine) reporter genes were constructed and tested in transgenic (Tg) mice. Regulatory elements required for the proper hCD4 expression in the immature double-positive thymic T cells were identified in the enhancer and in the 3' end of intron 1. Expression of hCD4 in macrophages is controlled by at least 2 sets of regulatory elements: one present in front of exon 1 and the second at the 5' end of intron 1. The hCD4 elements required for expression on both myeloid and lymphoid CD8alpha(+) dendritic cells (DCs) from lymph node and thymus were found to be different from those required for macrophage expression. The results indicate that expression of hCD4 in T cells, macrophages, and DCs is controlled by distinct regulatory elements.

Cross-modal attentional deficits in processing tactile stimulation.

In order to substantiate recent theorization on the possible links between the causes of the attentional blink and the psychological refractory period phenomena (e.g., Jolicoeur, 1999a), four experiments are reported in which two target stimuli, T1 and T2, were presented in different modalities at varying stimulus onset asynchronies (SOAs), with each stimulus being associated with a distinct task, Task1 and Task2. In Experiment 1, T1 was a tone, and Task1 was a speeded vocal response based on pitch. T2 was a brief press applied to either of two distal fingerpads, and Task2 was a speeded manual response based on tactile stimulus location. In Experiment 2, the same T1 as that used in Experiment 1 was presented, and in Task1 the subject either made a speeded vocal response based on pitch or ignored T1. T2 was a masked tactile stimulation, and Task2 was an unspeeded manual discrimination of the tactile stimulation location. This Task2 was maintained in Experiments 3 and 4. The auditory T1 was replaced with a white digit embedded in a rapid serial visualization presentation of a stream of black letters, and in Task1 the subject either made an unspeeded decision based on T1 identity or ignored T1. In all the experiments, the results showed an SOA-locked impairment in Task2. As SOA was decreased, reaction times in the speeded Task2 of Experiment 1 increased, and accuracy in the unspeeded Task2 of Experiments 2-4 decreased. The SOA-locked impairment was almost eliminated when T1 could be ignored or was absent. The results are discussed in terms of central processing limitations as the cause of such effects.

The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6.

The mechanisms responsible for degeneration of germinal centers (GC) and follicular dendritic cell (FDC) networks during progression to AIDS remain elusive. Here, we show that CD4(+) T cells from CD4C/HIV-1 Tg mice, which develop a severe AIDS-like disease, express low levels of CD40 ligand. Accordingly, GC formation, FDC networks, and immunoglobulin isotype switching are impaired in these animals. However, Tg B cells respond to in vitro CD40 stimulation. Total serum IgG levels are reduced in Tg mice, whereas total IgM levels are increased with a significant amount showing DNA specificity. IFN-gamma- and IL-6-deficient CD4C/HIV Tg mice also develop the AIDS-like disease and produce auto-Ab. Thus, CD4C/HIV Tg mice have immune dysfunction accompanied by autoimmune responses.

Pathogenesis of defective retroviruses.

Concerns about the presence of contaminating defective retroviruses in cells used for vaccine preparations have been raised. These concerns mainly reflect the fact that (i) most species harbour several copies of endogenous defective and/or non-defective retroviral sequences in their genome; (ii) these sequences have frequently been found to participate in recombination events giving rise to novel viral entities; and (iii) several strains of defective retroviruses have been shown to be pathogenic. Here, a brief description of the main features of defective retroviruses is provided. In addition, the characteristics and plasticity of defective retroviruses are illustrated with a defective retrovirus inducing a mouse disease, murine AIDS (MAIDS).

Interactions between search mechanisms in conjunction search.

We report the results of a technique designed to measure interactions between different visual search processes. We interrupted pop-out search before it produced a detection response, by adding extra distractors to the display so that a target initially defined by a single feature difference (e.g., a yellow horizontal line among yellow vertical lines) could then only be found on the basis of the conjunction of two features (a yellow horizontal line among yellow vertical lines and pink horizontal lines; difficult search). This technique has been used to measure the duration of the perceptual components of pop-out search, independent of over-all response time, for targets presented among different sets of distractors. In addition, when pop-out failed because it was interrupted, past work has shown that it nevertheless provided useful information to the processes responsible for difficult search. That is, partial pop-out assisted difficult search, when extra distractors made search difficult because the target was between the two types of distractors in the relevant feature space (Olds, Cowan, & Jolicoeur, 2000a,b,c). The present results demonstrate that partial pop-out also assists difficult search when difficult search is a conjunction search, and therefore these interactions may occur at a stage where information from different feature dimensions is combined.

Selective influence of second target exposure duration and task-1 load effects in the attentional blink phenomenon.

The purpose of the experiments was to constrain the locus of interference in the attentional blink (AB) paradigm. Two visual stimuli, T1 and T2, were shown 300 msec apart, and each was followed by a mask. T1 was an "H," an "S," an "&," or a blank field; T2 consisted of five letters. In Task1, blank fields and & characters could be ignored, whereas Hs and Ss had to be identified and reported. Task2 was always to report as many letters as possible from T2. Task2 performance was lower when T1 had to be reported, as expected from the attentional blink phenomenon (AB). The exposure duration of T2 was also manipulated. More letters could be reported as exposure duration was increased. However, this effect was additive with manipulations of Task1 processing load that produced the AB effect. Log-linear analyses assuming that effects of T2 exposure duration and Task1 load effects occur at functionally distinct stages of processing provided satisfactory fits to the results, suggesting that none of the AB effect occurs as early as those of T2 exposure duration. The results suggest that the locus of the AB effect is later than the stage(s) of processing affected by exposure duration.

Tracking visual search over space and time.

Visual perception consists of early preattentive processing and subsequent attention-demanding processing. Most researchers implicitly treat preattentive processing as a domain-dependent, indivisible stage. We show, however, by interrupting preattentive visual processing of color before its completion, that it can be dissected both temporally and spatially. The experiment depends on changing easy (preattentive) selection into difficult (attention-demanding) selection. We show that although the mechanism subserving preattentive selection completes processing as early as 200 msec after stimulus onset, partial selection information is available well before completion. Furthermore, partial selection occurs first at locations near fixation, spreading radially outward as processing proceeds.