Second-generation high-throughput forward genetic screen in mice to isolate subtle behavioral mutants.

Forward genetic screens have been highly successful in revealing roles of genes and pathways in complex biological events. Traditionally these screens have focused on isolating mutants with the greatest phenotypic deviance, with the hopes of discovering genes that are central to the biological event being investigated. Behavioral screens in mice typically use simple activity-based assays as endophenotypes for more complex emotional states of the animal. They generally set the selection threshold for a putative mutant at 3 SDs (z score of 3) from the average behavior of normal animals to minimize false-positive results. Behavioral screens using a high threshold for detection have generally had limited success, with high false-positive rates and subtle phenotypic differences that have made mapping and cloning difficult. In addition, targeted reverse genetic approaches have shown that when genes central to behaviors such as open field behavior, psychostimulant response, and learning and memory tasks are mutated, they produce subtle phenotypes that differ from wild-type animals by 1 to 2 SDs (z scores of 1 to 2). We have conducted a second-generation (G2) dominant N-ethyl-N-nitrosourea (ENU) screen especially designed to detect subtle behavioral mutants for open field activity and psychostimulant response behaviors. We successfully detect mutant lines with only 1 to 2 SD shifts in mean response compared with wild-type control animals and present a robust statistical and methodological framework for conducting such forward genetic screens. Using this methodology we have screened 229 ENU mutant lines and have identified 15 heritable mutant lines. We conclude that for screens in mice that use activity-based endophenotypic measurements for complex behavioral states, this G2 screening approach yields better results.

Sex, strain, and estrous cycle influences on alcohol drinking in rats.

Although women appear to be more vulnerable to alcohol-induced pathophysiology than men, the neurobiological basis for sex differences is largely unknown, partially because most studies on alcohol drinking are conducted in male subjects only. The present study examined sex differences in alcohol consumption in two rat strains, Long Evans and Wistar, using multiple behavioral paradigms. The effects of the estrous cycle on alcohol consumption were monitored throughout the study. The results indicated that females drank more alcohol than males when given either continuous or intermittent access to alcohol (vs. water) in their home cages (voluntary drinking). Under operant conditions, no sex or strain differences were found in drinking prior to development of alcohol dependence. However, upon dependence induction by chronic, intermittent alcohol vapor exposure, Wistar rats of both sexes substantially escalated their alcohol intake compared with their nondependent drinking levels, whereas Long Evans rats only exhibited a moderate escalation of drinking. Under these conditions, the estrous cycle had no effect on alcohol drinking in any strain and drinking model. Thus, strain, sex, and drinking conditions interact to modulate nondependent and dependent alcohol drinking. The present results emphasize the importance of including sex and strain as biological variables in exploring individual differences in alcohol drinking and dependence.

Display dimensionality and conflict geometry effects on maneuver preferences for resolving in-flight conflicts.

OBJECTIVE: Two experiments explored the effects of display dimensionality, conflict geometry, and time pressure on pilot maneuvering preferences for resolving en route conflicts. BACKGROUND: With the presence of a cockpit display of traffic information (CDTI) that provides graphical airspace information, pilots can use a variety of conflict resolution maneuvers in response to how they perceive the conflict. Inconsistent preference findings from previous research on conflict resolution using CDTIs may be attributable to inherent ambiguities in 3-D perspective displays and/or a limited range of conflict geometries. METHODS: Pilots resolved predicted conflicts using CDTIs with three levels of display dimensionality; the first had two 2-D orthogonal views, the second depicted the airspace in two alternating 3-D perspective views, and the third had a pilot-controlled swiveling viewpoint. RESULTS: Pilots demonstrated the same preferences that have been observed in previous research for vertical over lateral maneuvers in low workload and climbs over descents for level-flight conflicts. With increasing workload the two 3-D perspective displays, but not the 2-D displays, resulted in an increased preference for lateral over vertical maneuvers. Increased time pressure resulted in increased vertical maneuvers, an effect again limited to the two 3-D perspective displays. CONCLUSION: Resolution preferences were more affected by workload and time pressure when the 3-D perspective displays were used, as compared with the 2-D displays, although overall preferences were milder than in previous studies. APPLICATION: Investigating maneuver preferences using the strategic flight planning paradigm employed in this study may be the key to better ensure pilot acceptance of computer-generated resolution maneuvers.

Effects of battlefield display frames of reference on navigation tasks, spatial judgements, and change detection.

This paper describes an experiment which illustrates the cause of 'cognitive tunnelling' as it affects information gathering and perception-based task performance in computer-generated terrain displays of varying frames of reference. Cognitive tunnelling refers to the effect where observers focus attention on information from specific areas of a display to the exclusion of information presented outside these areas. Previous research suggests that cognitive tunnelling is induced by more immersive or egocentric visual displays. Results from our preceding study suggested that an immersed split-screen display induces cognitive tunnelling and results in poorer information extraction and situation awareness than an exocentric display of the same information. The current study determined that failure of the observers to integrate information across the two views of the immersed display led to the cognitive tunnelling effect. Cognitive tunnelling was also affected by primacy of information initially presented within the larger egocentric view in the immersed display.