Social behavior in Fmr1 knockout mice carrying a human FMR1 transgene.

Fragile X syndrome (FXS) results from the loss of expression of the fragile X mental retardation (FMR1) gene. Individuals affected by FXS experience many behavioral problems, including cognitive impairment, hyperactivity, social anxiety, and autistic-like behaviors. A mouse model of Fmr1 deficiency (Fmr1KO) exhibits several similar behavioral phenotypes, including alterations in social behavior. In an earlier study, Fmr1 knockout mice carrying a yeast-artificial chromosome (YAC) transgene that over-expresses normal human FMRP (KOYAC) showed a correction or overcorrection of some behavioral responses, such as hyperactivity and anxiety-related responses. This report presents results from a study examining transgenic rescue of abnormal social responses in Fmr1KO mice. Relative to their wild-type (WT) littermates, Fmr1KO mice made more active social approaches to standard C57BL/6 partner mice in a direct social interaction test, a result consistent with a previous study. KOYAC mice showed fewer active approaches to partners than the WT or Fmr1KO littermates, indicating correction of this phenotype. This finding expands the number of murine behavioral responses caused by Fmr1 deficiency and corrected by overexpression of human FMRP. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversal of sensorimotor gating abnormalities in Fmr1 knockout mice carrying a human Fmr1 transgene.

Fragile X syndrome is caused by a CGG trinucleotide repeat expansion of the FMR1 gene. Individuals with fragile X display several behavioral abnormalities including hyperactivity, social anxiety, autistic-like features, impaired cognitive processing, and impaired sensorimotor gating. The Fmr1KO mouse model of fragile X exhibits several related behavioral phenotypes such as increased activity and altered social interactions. Individuals with fragile X also have impaired sensorimotor gating as measured using the prepulse inhibition of startle response. The authors have recently shown that Fmr1KO mice with a yeast artificial chromosome containing the human FMR1 gene have corrected or overcorrected abnormal behaviors including hyperactivity and altered social interactions. Here the authors present results from a study examining abnormal sensorimotor gating in Fmr1KO mice. Consistent with previous findings, Fmr1KO mice have increased prepulse inhibition. The KO mice with the yeast artificial chromosome containing the human FMR1 gene had levels of prepulse inhibition comparable to WT mice, indicating not only a correction of this phenotype, but also clearly demonstrating that in mice levels of the fragile X mental retardation protein regulate sensorimotor gating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differences in the associability of relevant and irrelevant stimuli.

Pigeons in two experiments were first trained with a set of simple discriminations of the form AX+ CX?, BY+ DY? where A, B, C, and D were relevant, and belonged to one dimension, and X and Y were irrelevant and belonged to a different dimension. They were then tested with a discrimination of the form AX+ AY? BX?. The experiments revealed that the discrimination between AX+ and BX? was acquired more readily than between AX+ and AY?, which indicates that the original training resulted in the associability of the relevant stimuli being greater than that of the irrelevant stimuli. Experiment 2 revealed that the status of other stimuli from the two dimensions influenced these changes in associability. The associability of X and Y was enhanced by making other stimuli from the same dimension relevant, and the associability of A and B was reduced by making other stimuli from the same dimension irrelevant. The associability of the stimuli is attributed to the attention they are paid. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome.

This study assessed social behavior in a mouse model of Fragile X syndrome (FXS), the Fmr1 tm1Cgr or Fmr1 "knockout" (KO) mouse. Both the KO and wild-type (WT) mice preferred to be near a novel conspecific than to be alone. However, during the initial interaction with a novel conspecific, (1) a greater proportion of the KO mice exhibited high levels of grooming; and (2) the average duration of nose contact with the stimulus mouse was significantly shorter for the KO mice, both indicative of increased arousal and/or anxiety. Both groups exhibited a robust novelty preference when the novel animal was a "preferred" mouse. However, when the novel mouse was a "nonpreferred" animal, both groups showed a diminished novelty preference but this effect was more pronounced for the WT mice. This blunted negative reaction of the KO mice to a nonpreferred animal may indicate that they were less proficient than controls in distinguishing between positive and negative social interactions. These findings provide support for the use of this animal model to study the autistic features of FXS and autism spectrum disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mouse model of fragile X syndrome: Behavioral and hormonal response to stressors.

Fragile X syndrome, a form of mental retardation caused by inadequate levels of fragile X mental retardation protein (FMRP), is characterized by extreme sensitivity to sensory stimuli and increased behavioral and hormonal reactivity to stressors. Fmr1 knockout mice lack FMRP and exhibit abnormal responses to auditory stimuli. This study sought to determine whether Fmr1 knockout mice on an F1 hybrid background are normal in their response to footshock. Knockout mice were also examined for signs of hyperexcitation across an extended trial range, and serum corticosterone levels were evaluated in response to various stressors. The ability to acquire conditioned taste aversion was also assessed. Knockout mice exhibited no impairment in associative aversive learning or memory, since they successfully expressed conditioned taste aversion. Footshock-sensitivity, freezing behavior, and corticosterone response to various stressors did not differ between knockout and wild-type mice. However, knockout mice exhibited significantly increased responses during the extended test. The knockout mice’s increased responsiveness to footshock in the extended test may be an indication of increased vulnerability to stress or enhanced emotional reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Quantitative modeling of visual attention processes in patients with Parkinson's disease: Effects of stimulus integrality on selective attention and dimensional integration.

Parkinson's disease (PD) patients and normal controls (NCs) were administered a series of visual attention tasks. The dimensional integration task required integration of information from 2 stimulus dimensions. The selective attention task required selective attention to 1 stimulus dimension while ignoring the other stimulus dimension. Both integral- and separable-dimension stimuli were examined. A series of quantitative models of attentional processing was applied to each participant's data. The results suggest that (a) PD patients were not impaired in integrating information from 2 stimulus dimensions, (b) PD patients were impaired in selective attention, (c) selective attention deficits in PD patients were not due to perceptual interference, and (d) PD patients were affected by manipulations of stimulus integrality and separability in much the same way as were NCs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of the entorhinal cortex in a process of attentional modulation: Evidence from a novel variant of an IDS/EDS procedure.

Novel behavioral assays were used to assess the role of the entorhinal cortex in modulating attention to components of stimulus compounds. In Stage 1, rats received discrimination training with compounds constructed from 3 dimensions (auditory, visual, and tactile); in each compound the combination of components from 2 dimensions (e.g., auditory and visual) were relevant to the solution of the discrimination, and the remaining dimension (e.g., tactile) was irrelevant. In Stage 2, rats received a different discrimination in which the relevant dimensions were either congruent (auditory and visual) or incongruent (auditory and tactile) with those that were relevant in Stage 1. Sham-operated rats acquired the congruent discrimination more rapidly than the incongruent discrimination—a finding indicative of a process of attentional modulation—whereas rats with excitotoxic lesions of the entorhinal cortex acquired both discriminations equally readily. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The modulation of fragile X behaviors by the muscarinic M4 antagonist, tropicamide.

Muscarinic acetylcholine receptors (mAChR) are G protein–coupled receptors (M1–M5), grouped together into two functional classes, based on their G protein interaction. Although ubiquitously expressed in the CNS, the M4 protein shows highest expression in the neostriatum, cortex, and hippocampus. Electrophysiological and biochemical studies have provided evidence for overactive mAChR signaling in the fragile X knock-out (Fmr1KO) mouse model, and this has been hypothesized to contribute to the phenotypes seen in Fmr1KO mice. To address this hypothesis we used an M4 antagonist, tropicamide, to reduce the activity through the M4 mAChR and investigated the behavioral response in the Fmr1KO animals. Data from the marble-burying assay have shown that tropicamide treatment resulted in a decreased number of marbles buried in the wild-type (WT) and in the knockout (KO) animals. Results from the open field assay indicated that tropicamide increases activity in both the WT and KO mice. In the passive avoidance assay, tropicamide treatment resulted in the improvement of performance in both the WT and the KO animals at the lower doses (2 and 5 mg/kg), and the drug was shown to be important for the acquisition and not the consolidation process. Lastly, we observed that tropicamide causes a significant decrease in the percentage of audiogenic seizures in the Fmr1KO animals. These results suggest that pharmacological antagonism of the M4 receptor modulates select behavioral responses in the Fmr1KO mice. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Discrimination of Multidimensional Visual Stimuli by Mice: Intra- and Extradimensional Shifts.

A visual discrimination protocol similar to that used with monkeys was adapted to measure attentional set-shifting in mice. An automated touchscreen procedure with compound visual stimuli was used to train mice to attend to 1 of 2 stimulus dimensions (lines or shapes). On a 2nd problem with new stimuli, the mice were required to attend to the same dimension (intradimensional [ID] shift) or switch to the previously irrelevant dimension (extradimensional [ED] shift). Mice readily learned the initial compound discrimination and following shift problem, but there was no ID-ED difference. The fact that mice can be tested with stimuli and task sequences similar to those used with primates suggests that this method can be used to directly compare higher cognitive functions in diverse species. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Executive functions in the heterozygous reeler mouse model of schizophrenia.

Deficits in working memory and executive functions are now considered among the most reliable endophenotypes for schizophrenia. To determine whether cognitive deficits exist in mouse models of the disease, the authors trained heterozygous reeler (+/rl) mice on a series of visual discriminations similar to those used to test executive abilities in primates. These mice resemble schizophrenia patients in that both have reduced levels of reelin protein and altered gamma aminobutyric acid neurotransmission in the prefrontal cortex. The +/rl mice showed a selective deficit in reversal learning, with a pattern of errors that suggested impaired visual attention rather than a deficiency in perseveration and inhibitory control. These results show that cognitive dysfunction may serve as a useful biomarker in mouse models of neuropsychiatric disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early social deprivation disrupts attentional, but not affective, shifts in rats.

This study examined the effects of early social deprivation in rats in 2 dissociable forms of inhibitory control of behavior that operate at 2 different levels of response selection: reversing the assignment of stimulus–reward associations within perceptual dimensions (affective shifts) and switching selective attention from 1 perceptual dimension to another (attentional shifts). Isolated Ss (isolates) and social controls (socials) were individually trained to spatial and nonspatial visual discrimination criteria on a radial arm maze. Whereas isolates and socials differed in neither acquisition nor reversal of both versions of the task, isolates were selectively impaired in shifting from spatial to nonspatial discrimination and vice versa. These findings demonstrate that isolation rearing selectively disrupts inhibitory control in attentional selection but leaves inhibitory control in affective processing intact. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of learned irrelevance in attentional set-shifting impairments in Parkinson's disease.

In this study, the cognitive and neurochemical factors underlying learned irrelevance, one of the mechanisms thought to be responsible for attentional set-shifting deficits in Parkinson's disease (PD), were investigated. In a visual discrimination learning task, the extent to which a target dimension was irrelevant prior to an extra-dimensional shift was varied. Twenty patients with PD and 22 healthy participants performed the task twice, with patients tested on and off L-dopa. The patients made more errors than control participants in the condition in which the target dimension was completely irrelevant prior to the extradimensional shift, but not when it was partially reinforced. Moreover, L-dopa had no effect on the patients' task performance, despite improving their working memory. These results confirm that learned irrelevance is a significant factor in accounting for attentional set-shifting deficits in patients with PD, although unlike other executive impairments in this group, the phenomenon appears to be unrelated to their central dopaminergic deficit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquired distinctiveness is controlled by stimulus relevance not correlation with reward.

In 2 experiments, the relationship between the role of a stimulus in signaling trial outcome and the attention paid to it was investigated. In Exp 1, an intradimensional–extradimensional shift effect was shown in pigeons using autoshaping. In Exp 2, pigeons were trained with a biconditional discrimination, using stimulus compounds varying on 3 dimensions (color, orientation, and position), 2 of which were relevant to the solution of the discrimination, and 1 of which was irrelevant. Acquisition of a subsequent biconditional discrimination was more rapid if the same stimulus dimensions were relevant to the solution of both discriminations than if a previously irrelevant discrimination became relevant. These results indicate that the amount of attention paid to a stimulus is determined by its relevance to the solution of a discrimination, and not by its correlation with reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory and control of attention in persons with Alzheimer's disease and mild cognitive impairment.

The goal of the present study was to assess 3 attentional control processes--divided attention, manipulation capacities, and inhibition--in persons with mild cognitive impairment (MCI) and with mild Alzheimer's disease (AD). Manipulation capacities were tested by comparing immediate serial recall with alphabetical-order recall of words. Divided attention was tested with the Brown-Peterson procedure, in which participants divide their attention between simple addition tasks and consonant trigrams over delays. Inhibition was tested with the Hayling procedure, in which participants complete sentences with words irrelevant to their context. Persons with AD showed severe impairment on the 3 attentional control components. Persons with MCI exhibited impaired performance on the Brown-Peterson procedure but normal performance on the other 2 tasks. With AD and MCI participants, there was a negative correlation between general cognitive deficits and impairment on attentional control tasks, indicating that attentional control deficits increase in the MCI/AD continuum. When separating MCI with and without significant subsequent decline, those with subsequent decline showed impaired performance on both the Brown-Peterson procedure and manipulation task. These data suggest that control of attention tasks can track AD at a preclinical stage and that impairment increases gradually during the preclinical phase of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Restricted stimulus control and inferred attentional deficits in autistic and retarded children.

Seven autistic, 7 Down's syndrome, and 7 normal children (mean CAs 83.1, 65.7, and 45.3 mo; mean MAs 42, 36.7, and 50.6 mo; mean IQs 46.3, 45.3, and 98.6, respectively) were initially trained on a single dimension, simultaneous match-to-sample problem. Following criterion performance, each S's simultaneous matching of 4 new dimensions (2 attributes/dimension) was assessed in order to clarify the relation between autism, retardation, and attentional deficits. The Down's syndrome Ss matched significantly fewer attributes than did the autistic and normal Ss, who were equivalent in their performances. Based on these results, it is suggested that Down's syndrome and not autistic children suffer from attentional deficits. Performance in this simultaneous match-to-sample paradigm, which better assesses attentional mechanisms, was related to performances in previous serial and simultaneous discrimination paradigms, in which autistic children reportedly evidenced overselective attention. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome.

On a series of attention tasks, male mice with a mutation targeted to the fragile X mental retardation 1 (Fmrl) gene (Fmrl knockout [KO] mice) committed a higher rate of premature responses than wild-type littermates, with the largest differences seen when task contingencies changed. This finding indicates impaired inhibitory control, particularly during times of stress or arousal. The KO mice also committed a higher rate of inaccurate responses than controls, particularly during the final third of each daily test session, indicating impaired sustained attention. In the selective attention task, the unpredictable presentation of potent olfactory distractors produced a generalized disruption in the performance of the KO mice, whereas for controls, the disruption produced by the distractors was temporally limited. Finally, the attentional disruption seen following an error was more pronounced for the KO mice than for controls, further implicating impaired regulation of arousal and/or negative affect. The present study provides the first evidence that the Fmrl KO mouse is impaired in inhibitory control, attention, and arousal regulation, hallmark areas of dysfunction in fragile X syndrome. The resistance to change also seen in these mice provides a behavioral index for studying the autistic features of this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis.

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (     

Attention and brain function in Alzheimer's disease: A review.

Cognitive and neuroscience studies point to a selective impairment of attentional functions in Alzheimer's disease (AD). Prominent deficits occur in the shifting and division of attention, whereas phasic arousal and focused attention to stimulus features are only minimally affected in the early stages of AD. Macroscopic processing interpretations of these results—global cognitive impairment, generalized cognitive slowing, processing resource deficit, and failure of central executive control ("dysexecutive" syndrome)—are discussed. An alternative approach is based on the identification of component attentional operations and their mediation by corticocortical and subcortical networks. This analysis suggests that attention represents the first cognitive indicator of neocortical dysfunction in early AD. Disconnection between frontal and posterior parietal areas may mediate the selective disruption of attentional functions in AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional MRI reveals spatially specific attentional modulation in human primary visual cortex

Selective visual attention can strongly influence perceptual processing, even for apparently low-level visual stimuli. Although it is largely accepted that attention modulates neural activity in extrastriate visual cortex, the extent to which attention operates in the first cortical stage, striate visual cortex (area V1), remains controversial. Here, functional MRI was used at high field strength (3 T) to study humans during attentionally demanding visual discriminations. Similar, robust attentional modulations were observed in both striate and extrastriate cortical areas. Functional mapping of cortical retinotopy demonstrates that attentional modulations were spatially specific, enhancing responses to attended stimuli and suppressing responses when attention was directed elsewhere. The spatial pattern of modulation reveals a complex attentional window that is consistent with object-based attention but is inconsistent with a simple attentional spotlight. These data suggest that neural processing in V1 is not governed simply by sensory stimulation, but, like extrastriate regions, V1 can be strongly and specifically influenced by attention.     

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)