The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.     

Selection for the Predisposition to Catalepsy Enhances Depressive-like Traits in Mice

Immobility reaction or catalepsy is a natural passive defensive (cryptic) behavioral response to the appearance of a predator. Selection for high predisposition to catalepsy has been performed in a population of (CBA × (CBA × AKR)) backcrosses of the crossing between mouse lines prone and resistant to catalepsy (CBA and AKR, respectively). A rapid increase in the number of animals with catalepsy has been observed: from 23% in backcrosses to 71% in the S₃ generation. Selection for catalepsy does not affect mouse anxiety in the open field and plus-maze tests. However, S₈ and S₉ mice are characterized by a decreased motor activity in the open-field test and an increased immobility in the forced swim and tail suspension tests, which is interpreted as an increase in “ depressiveness.” The results indicate that genetically determined catalepsy is related to depressive-like characteristics of defensive behavior.     

Effects of Population Size and Selection Intensity on Short-Term Response to Selection for Postweaning Gain in Mice

The effects of population size and selection intensity on the mean response was examined after 14 generations of within full-sib family selection for postweaning gain in mice. Population sizes of 1, 2, 4, 8 and 16 pair matings were each evaluated at selection intensities of 100% (control), 50% and 25% in a replicated experiment. Selection response per generation increased as selection intensity increased. Selection response and realized heritability tended to increase with increasing population size. Replicate variability in realized heritability was large at population sizes of 1, 2 and 4 pairs. Genetic drift was implicated as the primary factor causing the reduced response and lowered repeatability at the smaller population sizes. Lines with intended effective population sizes of 62 yielded larger selection responses per unit selection differential than lines with effective population sizes of 30 or less.     

Effects of Population Size and Selection Intensity on Correlated Responses to Selection for Postweaning Gain in Mice

Correlated responses to selection for postweaning gain in mice were studied to determine the influence of population size and selection intensity. Correlated traits measured were three-, six- and eight-week body weights, litter size, twelve-day litter weight, proportion infertile matings and two indexes of reproductive performance. In general, the results agreed with observations made on direct response: correlated responses in the body weight traits and litter size increased as (1) selection intensity increased and (2) effective population size increased. Correlated responses in the body weight traits and litter size were positive in the large population size lines (16 pairs), as expected from the positive genetic correlation between these traits and postweaning gain. However, several negative correlated responses were observed at small population sizes (one and two pairs). Within each level of selection intensity, traits generally associated with fitness tended to decline most in the very small populations (one and two pairs) and in the large populations (16 pairs) for apparently different reasons. The fitness decline at the small effective population sizes was attributable to inbreeding depression. In contrast, it was postulated that the fitness decline at the large effective population size was due to selection moving the population mean for body weight and a trait positively correlated genetically with body weight (i.e., percent body fat) away from an optimum.     

After Being Challenged by a Video Game Problem,Sleep Increases the Chance to Solve It

In the past years many studies have demonstrated the role of sleep on memory consolidation. It is known that sleeping after learning a declarative or non-declarative task, is better than remaining awake. Furthermore, there are reports of a possible role for dreams in consolidation of declarative memories. Other studies have reported the effect of naps on memory consolidation. With similar protocols, another set of studies indicated that sleep has a role in creativity and problem-solving. Here we hypothesised that sleep can increase the likelihood of solving problems. After struggling to solve a video game problem, subjects who took a nap (n = 14) were almost twice as likely to solve it when compared to the wake control group (n = 15). It is interesting to note that, in the nap group 9 out 14 subjects engaged in slow-wave sleep (SWS) and all solved the problem. Surprisingly, we did not find a significant involvement of Rapid Eye Movement (REM) sleep in this task. Slow-wave sleep is believed to be crucial for the transfer of memory-related information to the neocortex and implement intentions. Sleep can benefit problem-solving through the generalisation of newly encoded information and abstraction of the gist. In conclusion, our results indicate that sleep, even a nap, can potentiate the solution of problems that involve logical reasoning. Thus, sleep''s function seems to go beyond memory consolidation to include managing of everyday-life events.     

Parsing a Cognitive Task: A Characterization of the Mind's Bottleneck

Parsing a mental operation into components, characterizing the parallel or serial nature of this flow, and understanding what each process ultimately contributes to response time are fundamental questions in cognitive neuroscience. Here we show how a simple theoretical model leads to an extended set of predictions concerning the distribution of response time and its alteration by simultaneous performance of another task. The model provides a synthesis of psychological refractory period and random-walk models of response time. It merely assumes that a task consists of three consecutive stages—perception, decision based on noisy integration of evidence, and response—and that the perceptual and motor stages can operate simultaneously with stages of another task, while the central decision process constitutes a bottleneck. We designed a number-comparison task that provided a thorough test of the model by allowing independent variations in number notation, numerical distance, response complexity, and temporal asynchrony relative to an interfering probe task of tone discrimination. The results revealed a parsing of the comparison task in which each variable affects only one stage. Numerical distance affects the integration process, which is the only step that cannot proceed in parallel and has a major contribution to response time variability. The other stages, mapping the numeral to an internal quantity and executing the motor response, can be carried out in parallel with another task. Changing the duration of these processes has no significant effect on the variance.     

实验动物屏障环境中化学消毒剂的选用

消毒工作是实验动物管理中的一项关键环节。掌握正确的消毒方法,对实验动物管理场所的生物安全和环境安全管理具有积极地意义。本文总结了使用化学消毒剂的方法和经验以供实验动物工作者借鉴。     

Sarm1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice

Postoperative cognitive dysfunction (POCD) is a common phenomenon among elderly patients with unclear etiology. Sterile alpha and TIR motif-containing 1 (Sarm1) plays important roles in neuroinflammation and cognitive function, and activates Calpain which has been shown to promote POCD through TrkB cleavage. This study aims to test the hypothesis that Sarm1 is involved in POCD through regulating Calpain activity. Wild type and Sarm1 knock out mice were exposed to isoflurane. Mouse cognitive function was determined by Morris water maze test. Neuroinflammation was determined by Iba1 and GFAP protein levels and mRNA expression of proinflammatory cytokines. Calpain activation was determined by αII-spectrin degradation and TrkB cleavage. Mitogen-activated protein kinase (MAPK) signaling was determined by c-Jun N-terminal kinase and cJun phosphorylation both in vivo and in vitro by Western blot and immunofluorescence staining. We found that Sarm1 deletion suppressed isoflurane induced cognitive impairment and neuroinflammation. Deletion of Sarm1 inhibited isoflurane induced αII-spectrin degradation and TrkB cleavage, which indicates suppression of Calpain activation. Finally, deletion of Sarm1 suppressed isoflurane induced MAPK signaling both in vivo and in vitro. Our findings suggest that isoflurane anesthesia induced cognitive impairment is prevented by Sarm1 deletion in mice, making Sarm1 a potent therapeutic target for treating or preventing POCD.

     

Need for Cognitive Closure Modulates How Perceptual Decisions Are Affected by Task Difficulty and Outcome Relevance

The aim of this study was to assess the extent to which Need for Cognitive Closure (NCC), an individual-level epistemic motivation, can explain inter-individual variability in the cognitive effort invested on a perceptual decision making task (the random motion task). High levels of NCC are manifested in a preference for clarity, order and structure and a desire for firm and stable knowledge. The study evaluated how NCC moderates the impact of two variables known to increase the amount of cognitive effort invested on a task, namely task ambiguity (i.e., the difficulty of the perceptual discrimination) and outcome relevance (i.e., the monetary gain associated with a correct discrimination). Based on previous work and current design, we assumed that reaction times (RTs) on our motion discrimination task represent a valid index of effort investment. Task ambiguity was associated with increased cognitive effort in participants with low or medium NCC but, interestingly, it did not affect the RTs of participants with high NCC. A different pattern of association was observed for outcome relevance; high outcome relevance increased cognitive effort in participants with moderate or high NCC, but did not affect the performance of low NCC participants. In summary, the performance of individuals with low NCC was affected by task difficulty but not by outcome relevance, whereas individuals with high NCC were influenced by outcome relevance but not by task difficulty; only participants with medium NCC were affected by both task difficulty and outcome relevance. These results suggest that perceptual decision making is influenced by the interaction between context and NCC.     

Identification of an Astrovirus Commonly Infecting Laboratory Mice in the US and Japan

Mice (Mus musculus) are the most commonly used laboratory animals. Viral metagenomics on tissues of immunodeficient mice revealed sequences of a novel mammalian astrovirus. Using PCR, we screened mice from 4 breeders, 4 pharmaceutical companies, 14 research institutes and 30 universities in the US and Japan. Mice from one US breeder tested positive while none from Japanese breeders were positive for MuAstV. Mice in over half of the universities (19/30), institutes (7/14) and pharmaceutical animal facilities (2/4) investigated revealed the presence of MuAstV. Nine mice strains tested positive including both immunodeficient strains (NSG, NOD-SCID, NSG-3GS, C57BL6-Timp-3 ^−/−, and uPA-NOG) and immunocompetent strains (B6J, ICR, Bash2, BALB/c). Our data indicates that MuAstV has a wide geographical, institutional and host strain distribution. Comparison of the MuAstV RdRp sequences showed numerous mutations indicating ongoing viral divergence in different facilities. This study demonstrates the need for metagenomic screening of laboratory animals to identify adventitious infections that may affect experimental outcomes.     

Provisional QTL for Circadian Period of Wheel Running in Laboratory Mice: Quantitative Genetics of Period in RI Mice

Wheel running was monitored in B X D recombinant inbred (RI) mice under dark-dark (DD) conditions, and the mean circadian period was calculated for each strain. There were significant differences for this trait among B X D recombinant inbred strains (p <. 0001) and a narrow-sense heritability of 21%. Analysis of strain means and variances indicates that at least four segregating loci contribute to the genetic variance for the free-running circadian period in this population. Correlation of the strain means for the circadian period of wheel running for each RI strain against the distribution of markers at over 1500 loci along the mouse genome identified a number of provisional quantitative trait loci (QTL). There were provisional QTL for wheel running atp <. 001 on chromosome 11 and atp <. 01 on chromosomes 1, 6, 9, 17, and 19. Most were in agreement with a second analysis done under similar conditions.     

Correlation between Brain Weight and the Pattern of Behavior Changes in Response to Ethanol Injections in Laboratory Mice

The effects of ethanol injections on the F₂ offspring of the cross between large-brain (LB) and small-brain (SB) mouse strains selected for high and low relative brain weights, respectively, have been studied. The parental strains have significantly differed in brain weight for many generations. The effects of ethanol (2.4 g/kg) have been compared in four subpopulations of mice that differ pairwise in brain weight. One pair of subpopulations has been derived from the hybrid group and the other, from generation 22 of selection of the parental strains. The results of ANOVA have demonstrated that brain weight is related to the behavioral response to ethanol injections. The parameters of stereotyped behavior, which increased in after ethanol injections and reflected the decrease in exploratory activity, were different in mice with high and low relative brain weights. The pattern of behavioral changes after ethanol injections is the second (after increased learning ability) behavioral trait found to be correlated with brain weight.     

Poor Long-Term Efficacy of Prevnar-13 in Sickle Cell Disease Mice Is Associated with an Inability to Sustain Pneumococcal-Specific Antibody Titers

Background

One of the most common causes of morbidity and mortality in children with sickle cell disease (SCD) is infection with the pneumococcal bacterium (Streptococcus pneumoniae). Unfortunately, the polysaccharide-conjugate vaccine appears to be less effective in individuals with SCD when compared to the general population. We sought to better understand the relative efficacy of pneumococcal vaccination in a SCD mouse challenge model.

Methods

Transgenic control and SCD mice were monitored for mortality after intranasal pneumococcal infection or pneumococcal vaccination with Prevnar-13 and type-matched challenge. Anti-pneumococcal antibody titers were measured by ELISA and opsonophagocytosis was measured in vitro.

Results

Mortality after pneumococcal infection was similar between control and SCD mice. However, after three intramuscular polysaccharide-conjugate vaccinations, all control mice were protected following high-dose intranasal infection, whereas 60% of SCD mice died. Anti-pneumococcal antibody titers showed initial IgG and IgM responses in both groups, but waning titers were observed in the SCD group, even after boosting. When functionally assayed in vitro, serum from SCD mice 13 weeks after a second booster shot maintained little to no ability to opsonize pneumococci, while serum from control mice sustained a significantly higher capacity opsonization. Thus, it appears that SCD mice do not maintain antibody responses to pneumococcal polysaccharides after Prevnar-13 vaccination, thereby leaving them susceptible to mortality after type-matched infection.

Conclusion

Our results emphasize the need to better understand the correlates of immune protection in SCD so that pneumococcal vaccines can be improved and mortality reduced in this susceptible population.     

Polymorphism of Unique Noncoding DNA Sequences in Wild and Laboratory Mice

Two DNA probes, D17Tu1 and D17Tu2, were isolated from a genomic DNA library containing only two mouse chromosomes, one of which is chromosome 17, carrying the major histocompatibility complex (H-2), as well as the t complex genes. The D17Tu1 probe was mapped to the centromeric region of chromosome 17 and the D17Tu2 probe to the S region of the H-2 complex. Neither of the two probes appeared to detect any genes, but both contained unique, nonrepetitive sequences. Typing of DNA obtained from a large panel of mice revealed the presence of four D17Tu1 patterns in inbred mouse strains, one very common, one less common, and two present in one strain each. The two common patterns could not be detected in appreciable frequencies in the European wild mice tested (one of the two patterns was, however, found in Australian wild mice). Conversely, the patterns found frequently in European wild mice are absent in the laboratory mice. We therefore conclude that wild mice from the sampled regions of Europe could not have provided the ancestral stocks from which inbred strains were derived. Only one D17Tu1 pattern was found in all the populations of Mus musculus tested, while eight patterns were found in Mus domesticus, with virtually all the populations being polymorphic. We suggest that this difference reflects different modes in which the two species colonized Europe. The distribution of the D17Tu2 patterns in inbred strains correlates with the distribution of H-2 haplotypes.