Our goal is to lay a scientific foundation for the treatment of those disorders of mental function that depend on our ability to locate ourselves in space and time. The loss of these fundamental abilities is evidence of advanced psychosis or senile dementia. We lay this foundation by: 1) Developing a systematic approach to phenotyping genetically manipulated mice, looking for genetic (heritable) malfunctions in mechanisms that form the foundations of temporal, spatial and numerical cognition. These mechanisms give us our sense of duration, our sense of number, our estimates of rates (how often events of a given kind are to be expected), our sense of distance and our sense of direction. All of these mechanisms require a memory mechanism that carries acquired information forward in time in a behaviorally useful form. That memory mechanism is a major target. 2) Using our approach to test many of the knockout and transgenic strains of mice that figure most prominently in contemporary research on the molecular biology of learning and memory. These tests will either identify mice with genetic alterations that have large effects on our target mechanisms or they may show that many putative memory mutants have nothing wrong with their memory, narrowly defined. Finding mutants that do have the looked-for genetic malfunctions will bring to bear the power of modern molecular biology to elucidate the molecular and cellular mechanisms. The understanding of the molecular and cellular mechanisms at the foundation of cognition is a prerequisite to a fully scientific approach to the understanding and treatment of mental deterioration and mental malfunction.
Specific Aims : 1) Demonstrate the efficacy and efficiency of already developed automated tests for the estimation of - and memory for - duration, number, rate and location in forward and reverse genetic behavioral phenotyping. 2) Develop a compact, automated system for measuring the mouse's ability to estimate distance traveled and to remember distances. 3) Develop and validate an automated system for varying spatial context, which will permit the study of the ubiquitous effects of spatial context on learning and memory. 4) Develop a compact automated system for measuring direction estimation and direction memory. 5) Develop and make generally available a unified software environment for controlling these experiments and analyzing the data from them on line. 6) Integrate these screens into a suite of computer- controlled tests, conducted in a single, compact live-in environment in the minimum possible amount of time, with quantitative, automated, on-line analysis of the behavioral data.
An awareness of where one is in time (year, month, week, day, time-of-day) and space (country, state, city, town, village or county, home or doctor's office or hospital) is a foundation of our mental activity. Our research makes possible the use of genetic and molecular biological methods to find the physical basis for this awareness within the machinery of the brain. It does so by enabling scientists to identify mutant mice that have genetic abnormalities in the underlying brain mechanisms.
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