Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus

The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1^N598R allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.According to Hebb''s postulate, neurons require a molecular mechanism to detect synchronous activity in order to change the strength of synaptic connectivity (Hebb 1949). NMDA receptors (NMDARs) are molecular coincidence detectors, and selective NMDAR antagonists block the induction of long-term potentiation (LTP) in both the dentate gyrus (DG) and CA1 regions of the hippocampus (Bliss and Collingridge 1993; Martin et al. 2000). NMDARs have been long known for their role in spatial learning, but more recently have been implicated in other forms of cognitive function and dysfunction (Gruart et al. 2006; Whitlock et al. 2006; Castner and Williams 2007; Kristiansen et al. 2007; Wilson and Linster 2008).Neuronal NMDARs are hetero-tetrameric ligand-gated ion channels typically comprised of two types of subunits. Two copies of the mandatory GluN1 subunit (or NR1 subunit [Collingridge et al. 2009] encoded by Grin1) are associated with two copies from the GluN2 family, GluN2A–D (or NR2A–D). The GluN1 subunit is expressed ubiquitously both spatially and temporally throughout the developing and adult brain. Global knockout mice models of the GluN1 subunit are postnatally lethal within hours after birth (Forrest et al. 1994; Li et al. 1994), and cell-specific GluN1 mice knockouts (Tsien et al. 1996; Nakazawa et al. 2002; McHugh et al. 2007; Niewoehner et al. 2007) have provided insights on how specific synapses and regional neuronal networks are dependent on NMDAR function.The early postnatal lethality of the global GluN1 knockout is in contrast to the null mutants of the four AMPA receptor genes and other major synaptic proteins, such as αCaMKII (Silva et al. 1992a,b; Jia et al. 1996; Zamanillo et al. 1999; Meng et al. 2003). This can be at least partially explained by the absence of any close GluN1 homologs, which could functionally compensate for the absence of the GluN1 subunit. Recombinant expression studies defined the GluN1 subunit as a mandatory component of NMDARs. This constellation provides a specific opportunity to test whether different local neuronal subnetworks are affected differentially by mutant Grin1 alleles associated with subtle alterations of the functional properties of NMDARs.GluN1 subunits with the N598R point mutation (GluN1^R) yield functional NMDARs that are Mg²⁺ insensitive and Ca²⁺ impermeable (Burnashev et al. 1992; Mori et al. 1992). The Grin1^N598R allele that codes for GluN1^R subunits is a gain-of-function mutation that is dominant lethal, even in heterozygous and hemizygous lines (Single et al. 2000; Rudhard et al. 2003). NMDARs with GluN1^R subunits do not act as coincidence detectors and, interestingly, mice expressing exclusively the GluN1^R allele lack whisker-related pattern formation in the neonate brainstem (Rudhard et al. 2003).To investigate the functional importance of GluN1 subunits with the N598R point mutation, we took advantage of the generation of a variant mutant line of mice (GluN1^Rneo/+) expressing a minority (around 10%) of these mutant NMDARs. Even though the majority of the NMDARs are normal, all neurons expressing NMDARs will contain a subset of receptors carrying this mutation.Therefore, this mouse model is an ideal candidate to study the impact of subtle alterations of NMDAR function on different neuronal networks, such as those comprising the hippocampal formation.Studies examining region-specific targeted disruption of GluN1 expression in subregions of the hippocampus have revealed subtle yet important contributions of this NMDAR subunit in synaptic plasticity and spatial learning and memory. CA1-restricted knockout of GluN1 expression in the hippocampus caused impaired spatial learning and memory as well as reduced CA1-LTP (Tsien et al. 1996). In the case of the disruption of GluN1 expression in the DG region of the hippocampus, more subtle behavioral impairments were apparent, including the inability to discriminate between two similar contexts (pattern separation) and deficits in spatial working memory despite normal LTP in the CA1 region (McHugh et al. 2007; Niewoehner et al. 2007).Our GluN1^Rneo/+ mice differ from the region-specific GluN1 mutant mice in that they express the mutant hypomorph at the same level in different subregions of the hippocampus. Interestingly, we found that this allele leads to substantial differences in short- and long-term plasticity between area CA1 and the DG of the hippocampus. The specific impairment in the DG was accompanied by impaired spatial recognition, spatial learning, reversal learning, and retention. Our data establish the possibility of a circuit-specific phenotype caused by a mutant variant of a globally expressed major nonredundant synaptic protein.     

Change in school ethnic diversity and intergroup relations: The transition from segregated elementary to mixed secondary school for majority and minority students

This research examined the impact of a change in school diversity on school children's intergroup relations. A longitudinal survey tracked 551 White British and Asian British students (M_age = 11.32) transitioning from elementary (time 1) to secondary (time 2) school in an ethnically segregated town in the United Kingdom. We estimated a multivariate, multilevel model. A cross-sectional comparison of segregated schools and a mixed elementary school at time 1 revealed that both Asian and White British in the mixed school reported more positive intergroup relations. A longitudinal analysis found that the transition from segregated elementary to mixed secondary schools was associated with Asian British developing more positive intergroup relations. White British reported overall less positive intergroup relations, although only trust decreased; evidence from other measures remains inconclusive. The findings are important for understanding early stages of diversity exposure, and the impact of changing diversity levels on majority and minority groups.     

Serum testosterone,cortisol, glucose,and ethanol in males arrested for spouse abuse

Concentrations of ethanol, testosterone, cortisol, and glucose were determined in serum obtained from 16 males taken into police custody after incidents of spouse abuse. The mean blood ethanol level at the time of arrest was 33.3 ± 2.6 mM. Serum testosterone levels were significantly lower and cortisol levels higher at the time of police intervention (within 1 hour of the incident) compared to control data collected later from the subjects when sober. Offenders did not differ from a group of nonviolent pub patrons at similar blood ethanol levels (35.9 ± 4.5 mM) with respect to serum testosterone, cortisol, or glucose, but their sober state cortisol and glucose concentrations were significantly higher compared to a control group of nonalcoholic men. Intoxication or acute hormonal changes were thus not specifically associated with violent behaviour. Provocative cues, however, may have been more frequent in the offender families, as Straus Conflict Tactics data showed that offenders and victims resorted to verbal aggression significantly more often than control families. The significantly elevated cortisol and glucose concentrations in offenders when sober compared to nonviolent controls could be viewed as direct effects of life stress, or as indirect effects of stress mediated by learned escape drinking. Excessive drinking as well as spouse abuse could be maladaptive coping strategies that principally serve to maintain the status quo, physiologically as well as psychologically. © 1992 Wiley-Liss, Inc.     

Supervenience and infinitary property-forming operations

This paper provides an account of the closure conditions that apply to sets of subvening and supervening properties, showing that the criterion that determines under which property-forming operations a particular family of properties is closed is applicable both to the finitary and to the infinitary case. In particular, it will be established that, contra Glanzberg, infinitary operations do not give rise to any additional difficulties beyond those that arise in the finitary case.     

The zoom lens of attention: Simulating shuffled versus normal text reading using the SWIFT model

Assumptions on the allocation of attention during reading are crucial for theoretical models of eye guidance. The zoom lens model of attention postulates that attentional deployment can vary from a sharp focus to a broad window. The model is closely related to the foveal load hypothesis, i.e., the assumption that the perceptual span is modulated by the difficulty of the fixated word. However, these important theoretical concepts for cognitive research have not been tested quantitatively in eye movement models. Here we show that the zoom lens model, implemented in the SWIFT model of saccade generation, captures many important patterns of eye movements. We compared the model's performance to experimental data from normal and shuffled text reading. Our results demonstrate that the zoom lens of attention might be an important concept for eye movement control in reading.     

A combined planning and self-efficacy intervention to promote physical activity: a multiple mediation analysis

Many individuals are motivated to improve their physical activity levels, but often fail to act upon their intention. Interventions fostering volitional strategies, such as action planning, coping planning, and self-efficacy beliefs, can help to translate intentions into behavior. This study examines the effectiveness and the mechanisms of a combined planning and self-efficacy intervention to promote physical activity among motivated individuals. Participants (N = 883) were randomly assigned to the intervention or to a waiting-list control condition. Multivariate analysis of variance revealed that the intervention resulted in significantly more physical activity, higher levels of action planning, coping planning, and volitional self-efficacy beliefs (p < 0.01). In addition, multiple mediation analysis showed that action planning, coping planning, and volitional self-efficacy mediate between the intervention and physical activity. The study shows that the intervention successfully fostered physical activity and unfolds the underlying self-regulatory mechanisms of the intervention's effectiveness.     

Views on aging and emotional benefits of physical activity: Effects of an exercise intervention in older women

Objectives

This intervention study evaluated the effects of exercise in old age on views on one’s own aging and on direct approach motivation for physical activity. It further examined the mechanism between these variables.

Design

Two hundred forty-seven healthy women aged 70−93 years were randomized to an exercise course (n = 86), an active (n = 85), or a passive control group (n = 76) for a 6-month participation in Berlin, Germany. Activity interventions (3 × 1.5 h/wk) were conducted using standardized manuals.

Method

Group differences in changes of views on aging and direct approach were evaluated by analyses of covariance adjusted for baseline. A mediating effect of direct approach between exercise participation and views on aging was tested with percentile-based bootstrapping.

Results

In contrast to both the active and the passive control groups, higher direct approach, F(2, 226) = 6.97, p = .001, and less aging dissatisfaction, F(2, 225) = 5.39, p = .005, were observed in the exercise group after 6 months. Exercise had an indirect beneficial effect on aging dissatisfaction through direct approach, B = −0.31, 95% CI = −0.68 to −0.05.

Conclusion

In women above 70 years, exercise participation increases direct approach motivation which in turn leads to lower aging dissatisfaction. This shows that exercise holds the potential to overcome subjective ageist bias.     

Affective and health-related outcome expectancies for physical activity in older adults

This study tests the effects of affective and health-related outcome expectancies on physical exercise, assuming stronger direct and indirect (via intention) effects from affective outcome expectancy to physical exercise than from health-related outcome expectancy to exercise. Physical exercise and social cognitive variables were assessed at baseline, and 6- and 12-month follow-up in 335 older adults (60-95 years of age). Applying structural equation modelling, there was a direct effect from affective, but not from health-related outcome expectancy on intentions and behaviour. Also, the indirect effect from self-efficacy on physical exercise via affective outcome expectancy was significant, whereas the mediation via health-related outcome expectancy was not. These findings emphasise the relative importance of affective versus health-related outcome expectancies in predicting intentions and physical exercise in older adults and highlight the importance to separate these facets at a conceptual level to enhance both theory development and health promotion.     

Fixation positions after skipping saccades: A single space makes a large difference

During reading, saccadic eye movements are generated to shift words into the center of the visual field for lexical processing. Recently, Krügel and Engbert (Vision Research 50:1532?C1539, 2010) demonstrated that within-word fixation positions are largely shifted to the left after skipped words. However, explanations of the origin of this effect cannot be drawn from normal reading data alone. Here we show that the large effect of skipped words on the distribution of within-word fixation positions is primarily based on rather subtle differences in the low-level visual information acquired before saccades. Using arrangements of ??x?? letter strings, we reproduced the effect of skipped character strings in a highly controlled single-saccade task. Our results demonstrate that the effect of skipped words in reading is the signature of a general visuomotor phenomenon. Moreover, our findings extend beyond the scope of the widely accepted range-error model, which posits that within-word fixation positions in reading depend solely on the distances of target words. We expect that our results will provide critical boundary conditions for the development of visuomotor models of saccade planning during reading.     

A Great Many Things to Do and Not a Minute to Spare: Can Feedback From Supervisors Moderate the Relationship Between Skill Variety,Time Pressure,and Employees' Innovative Behavior?

Workplace changes necessitate employees' innovative behavior. Developing and implementing new ideas can be enhanced by focusing on situational characteristics and adjusting them to improve employees' working conditions. To date, mostly interactions between situational and personal characteristics on innovative behavior have been researched. This study focused explicitly on the interaction between 3 situational characteristics: time pressure, skill variety, and feedback from supervisors. A questionnaire study was administered to 81 employees (age range 40–64 years) from different organizations. Results indicated direct positive correlations between time pressure and skill variety with idea generation and implementation. Feedback from supervisors moderated the positive relationships while controlling for effects of creative thinking abilities. Implications are explored.