Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice.

Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus.

Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague-Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naïve controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2-like antagonist eticlopride during cocaine conditioning, but not by co-administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits.

Discovering that the shoe fits: the self-validating role of stereotypes.

Stereotypes can influence social perceptions in many ways. The current research examined a previously unexplored possibility-that activation of a stereotype can validate thoughts about other people when the thoughts are stereotype consistent (i.e., that stereotype activation can increase people's confidence in their previous stereotype-consistent thoughts). Given previous results for other forms of metacognition, this thought validation from stereotype activation should be most likely when people have the cognitive capacity to carefully process individuating information. In two experiments, participants were given information about a target person and then a description designed to activate a stereotype. When processing capacity was high, confidence in thoughts was greater when the initial information produced thoughts consistent, rather than inconsistent, with the stereotype that was later activated, and higher confidence in thoughts was associated with stronger perception-consistent recommendations related to the target. When processing capacity was low, an activated stereotype served its familiar heuristic role in judgment, and thought confidence played no role in judgment-related recommendations.

Source entitativity and the elaboration of persuasive messages: the roles of perceived efficacy and message discrepancy.

Compared with nonentitative groups, entitative targets are considered to elicit more elaborative processing because of the singularity or unity they represent. However, when groups serve as sources of persuasive messages, other dynamics may operate. The current research suggests that entitativity is intrinsically linked to perceptions of a group's efficacy related to the advocacy, and this efficacy combines with the position of the appeal to determine message elaboration. When messages are counterattitudinal, entitative (efficacious) sources should elicit greater processing than nonentitative groups because of concern that the entitative sources may be more likely to bring about the negative outcomes proposed. However, when appeals are proattitudinal, sources low in entitativity (nonefficacious) should initiate more elaboration due to concern that they may be unlikely to facilitate the positive outcomes proposed. These hypotheses were supported in a series of studies. Preliminary studies established the entitativity-efficacy relation (Studies 1A and 1B). Primary persuasion studies showed that manipulations of source entitativity (Studies 2 and 3) and source efficacy (Studies 4A and 4B) have opposite effects on processing as a function of message discrepancy.

Attitudinal ambivalence and message-based persuasion: motivated processing of proattitudinal information and avoidance of counterattitudinal information.

Attitudinal ambivalence has been found to increase processing of attitude-relevant information. In this research, the authors suggest that ambivalence can also create the opposite effect: avoidance of thinking about persuasive messages. If processing is intended to reduce experienced ambivalence, then ambivalent people should increase processing of information perceived as proattitudinal (agreeable) and able to decrease ambivalence. However, ambivalence should also lead people to avoid processing of counterattitudinal (disagreeable) information that threatens to increase ambivalence. Three studies provide evidence consistent with this proposal. When participants were relatively ambivalent, they processed messages to a greater extent when the messages were proattitudinal rather than counterattitudinal. However, when participants were relatively unambivalent, they processed messages more when the messages were counterattitudinal rather than proattitudinal. In addition, ambivalent participants perceived proattitudinal messages as more likely than counterattitudinal messages to reduce ambivalence, and these perceptions accounted for message position effects on amount of processing.

Positive Stereotype Validation: The Bolstering Effects of Activating Positive Stereotypes After Intellectual Performance.

Past research has found that members of stigmatized groups may feel more certain of poor performance when negative stereotypes are made accessible after finishing a task (i.e., stereotype validation). However, no research to date has identified the potential effects of activating positive stereotypes after performance. Based on past research and theory, we hypothesized that such positive stereotype validation may serve to bolster-rather than hinder-important beliefs related to one's abilities and future task performance. Across three studies, the accessibility of positive group stereotypes was manipulated after participants completed an initial test on a topic. Consistent with predictions, the activation of positive, self-relevant stereotypes after the initial test was found to increase how certain participants were that they performed well on it. Furthermore, these increases in evaluative certainty predicted more positive ability beliefs, higher expectations for future performance, and better performance on a follow-up test that participants completed.

Not all stereotyping is created equal: differential consequences of thoughtful versus non-thoughtful stereotyping.

Much research emphasizes heuristic use of stereotypes, though stereotypes have long been considered as capable of influencing more thoughtful processing of social information. Direct comparisons between thoughtful and non-thoughtful stereotyping are lacking in the literature. Recent research in attitude change emphasizes the different consequences of judgments arising from relatively thoughtful versus non-thoughtful processes. Therefore, increased thought could not only fail to decrease stereotyping but might also create stereotypic perceptions that are more likely to have lasting impact. The current studies demonstrate thoughtful and non-thoughtful stereotyping within the same setting. More thoughtful stereotyping is more resistant to future attempts at change and to warnings of possible bias. Implications are discussed for the typical research questions asked after observing stereotypic judgements.

Stereotype validation: the effects of activating negative stereotypes after intellectual performance.

With regard to intellectual performance, a large body of research has shown that stigmatized group members may perform more poorly when negative, self-relevant stereotypes become activated prior to a task. However, no research to date has identified the potential ramifications of stereotype activation that happens after-rather than before-a person has finished performing. Six studies examined how postperformance stereotype salience may increase the certainty individuals have in evaluations of their own performance. In the current research, the accessibility of gender or racial stereotypes was manipulated after participants completed either a difficult math test (Studies 1-5) or a test of child-care knowledge (Study 6). Consistent with predictions, stereotype activation was found to increase the certainty that women (Studies 1, 2, 4, and 5), African Americans (Study 3), and men (Study 6) had toward negative evaluations of their own test performance. These effects emerged when performance-related perceptions were stereotype consistent rather than inconsistent (Studies 1-6) and were found to be most pronounced among those who were highly identified with the stereotyped group (Study 5). Furthermore, greater certainty-triggered by negative stereotypes-predicted lowered domain-relevant beliefs (Studies 1, 2, 3, and 6) and differential exposure to domain-relevant stimuli (Studies 4 and 5).

Differential effects of cocaine exposure on the abundance of phospholipid species in rat brain and blood.

BACKGROUND: Lipid profiles in the blood are altered in human cocaine users, suggesting that cocaine exposure can induce lipid remodeling. METHODS: Lipid changes in the brain tissues of rats sensitized to cocaine were determined through shotgun lipidomics using electrospray ionization-mass spectrometry (ESI-MS). We also performed pairwise principal component analysis (PCA) to assess cocaine-induced changes in blood lipid profiles. Alterations in the abundance of phospholipid species were correlated with behavioral changes in the magnitude of either the initial response to the drug or locomotor sensitization. RESULTS: Behavioral sensitization altered the relative abundance of several phospholipid species in the hippocampus and cerebellum, measured one week following the final exposure to cocaine. In contrast, relatively few effects on phospholipids in either the dorsal or the ventral striatum were observed. PCA analysis demonstrated that cocaine altered the relative abundance of several glycerophospholipid species as compared to saline-injected controls in blood. Subsequent MS/MS analysis identified some of these lipids as phosphatidylethanolamines, phosphatidylserines and phosphatidylcholines. The relative abundance of some of these phospholipid species were well-correlated (R(2) of 0.7 or higher) with either the initial response to cocaine or locomotor sensitization. CONCLUSION: Taken together, these data demonstrate that a cocaine-induced sensitization assay results in the remodeling of specific phospholipids in rat brain tissue in a region-specific manner and also alters the intensities of certain types of phospholipid species in rat blood. These results further suggest that such changes may serve as biomarkers to assess the neuroadaptations occurring following repeated exposure to cocaine.

Source Credibility and Persuasion: The Role of Message Position in Self-Validation.

Highly credible communicators have been found to elicit greater confidence and attitudes that are based more on recipients' thoughts (i.e., self-validation) compared with non-credible sources. However, source credibility may produce different effects on thought confidence and persuasion depending on the position of an advocacy. When messages are proattitudinal, credible sources should initiate self-validation because recipients may be motivated to confirm (bolster) their existing views. Conversely, when appeals are counterattitudinal, recipients may be motivated to defend their opinions and disconfirm information. In these contexts, greater self-validation may emerge when a communicator lacks rather than possesses credibility. When a message was counterattitudinal and contained weak arguments, evidence of self-validation was found with low source credibility (Studies 1 and 2) and among participants high in defense motivation (Study 2). In response to strong, proattitudinal arguments, findings were consistent with high credibility producing self-validation when bolstering motivation was high (Study 3).

Hirano body expression impairs spatial working memory in a novel mouse model.

INTRODUCTION: Hirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer's disease or frontotemporal lobar degeneration-tau. While Hirano body ultrastructure and protein composition have been well studied, little is known about the physiological function of Hirano bodies in an animal model system. RESULTS: Utilizing a Cre/Lox system, we have generated a new mouse model which develops an age-dependent increase in the number of model Hirano bodies present in both the CA1 region of the hippocampus and frontal cortex. These mice develop normally and experience no overt neuron loss. Mice presenting model Hirano bodies have no abnormal anxiety or locomotor activity as measured by the open field test. However, mice with model Hirano bodies develop age-dependent impairments in spatial working memory performance assessed using a delayed win-shift task in an 8-arm radial maze. Synaptic transmission, short-term plasticity, and long-term plasticity was measured in the CA1 region from slices obtained from both the ventral and dorsal hippocampus in the same mice whose spatial working memory was assessed. Baseline synaptic responses, paired pulse stimulation and long-term potentiation measurements in the ventral hippocampus were indistinguishable from control mice. In contrast, in the dorsal hippocampus, synaptic transmission at higher stimulus intensities were suppressed in 3 month old mice with Hirano bodies as compared with control mice. In addition, long-term potentiation was enhanced in the dorsal hippocampus of 8 month old mice with Hirano bodies, concurrent with observed impairment of spatial working memory. Finally, an inflammatory response was observed at 8 months of age in mice with Hirano bodies as assessed by the presence of reactive astrocytes. CONCLUSION: This study shows that the presence of model Hirano bodies initiates an inflammatory response, alters hippocampal synaptic responses, and impairs spatial working memory in an age-dependent manner. This suggests that Hirano bodies may promote disease progression. This new model mouse provides a tool to investigate how Hirano bodies interact with other pathologies associated with Alzheimer's disease. Hirano bodies likely play a complex and region specific role in the brain during neurodegenerative disease progression.

Evaluating the message or the messenger? Implications for self-validation in persuasion.

Characteristics of persuasive message sources have been extensively studied. However, little attention has been paid to situations when people are motivated to form an evaluation of the communicator rather than the communicated issue. We postulated that these different foci can affect how a source validates message-related cognitions. Participants focused on the source (Studies 1 and 2) or the issue (Study 2) while reading weak or strong message arguments. Later, the communicator was described as low or high in credibility. When focused on the source, highly motivated participants were more confident and their attitudes were more reflective of thoughts when argument quality matched (e.g., weak arguments-low credibility) rather than mismatched (e.g., weak arguments-high credibility) source credibility. Conversely, when participants were focused on the issue, self-validation was greater when credibility was high rather than low-regardless of argument quality. Implications of these findings for the study and practice of persuasion are discussed.

Feeling conflicted and seeking information: when ambivalence enhances and diminishes selective exposure to attitude-consistent information.

To date, little research has examined the impact of attitudinal ambivalence on attitude-congruent selective exposure. Past research would suggest that strong/univalent rather than weak/ambivalent attitudes should be more predictive of proattitudinal information seeking. Although ambivalent attitude structure might weaken the attitude's effect on seeking proattitudinal information, we believe that conflicted attitudes might also motivate attitude-congruent selective exposure because proattitudinal information should be effective in reducing ambivalence. Two studies provide evidence that the effects of ambivalence on information choices depend on amount of issue knowledge. That is, ambivalence motivates attitude-consistent exposure when issue knowledge is relatively low because less familiar information is perceived to be effective at reducing ambivalence. Conversely, when knowledge is relatively high, more unambivalent (univalent) attitudes predicted attitude-consistent information seeking.

Source expertise and persuasion: the effects of perceived opposition or support on message scrutiny.

Compared to nonexperts, expert sources have been considered to elicit more processing of persuasive messages because of expectations that the information is likely to be valid or accurate. However, depending on the position of an advocacy, source expertise could activate other motives that may produce a very different relation from that found in past research. When messages are counterattitudinal (disagreeable), experts should motivate greater processing than nonexpert sources because of expectations that they will likely provide robust opposition to one's existing views. In contrast, when advocacies are proattitudinal (agreeable), nonexpert rather than expert sources should elicit more scrutiny because of perceptions that they will likely provide inadequate support to recipients' current views. Two studies offer evidence consistent with these predictions. Manipulations of source expertise created different expectations regarding the strength of opposition or support, and these perceptions accounted for effects of source expertise on the amount of message scrutiny.

Comparative transcriptional profiling of two human embryonic stem cell lines.

Human embryonic stem cells (ESCs) have generated enormous interest due to their ability to self-renew and produce many different cell types. In conjunction with microarray technology, human ESCs provide a powerful tool for employing a systems-based approach to deciphering the molecular mechanisms that control pluripotency and early development. Recent work has focused on defining "stemness" and pluripotency based on different experimental and analytical approaches in both mouse and human ESCs. Using a mixed linear model statistical approach, we report a stringent direct comparison between data sets obtained from two human ESCs (BG01 and H1) in order to obtain a list of genes that are enriched in ESCs. In addition, we used another pluripotent population derived from BG01 ESCs to obtain a list of genes that we consider important to the maintenance of pluripotency. A total of 133 genes overlapped between the three pluripotent populations. A majority of the 133 genes were classified under the key functional categories of cell-cycle regulation, signaling, and regulation of transcription. Key genes expressed were Oct4, Sox2, LeftyA, and Fgf2. Also found to be enriched in all three populations is FLJ10713, a gene encoding a hypothetical protein of unknown function that has been shown in earlier studies to possess a homolog in mouse ESCs and also to cluster tightly with Oct4 in human ESCs. Although there were many genes unique to each pluripotent population, they shared similarities based on functional ontologies that define pluripotency. The significance of our studies underscores the need for direct comparison of stem cell populations that share biological similarities using uniform stringent analytical approaches, in order to better define pluripotency. Our findings have important implications for the maintenance of pluripotency and in developing directed differentiation strategies for various regenerative applications.