We propose to use trace eyelid conditioning to study the neural mechanisms operating in prefrontal cortex to mediate working memory. We have demonstrated that trace eyelid conditioning in rabbit is a working memory task that involves the persistent activity of the so called "delay cells" of prefrontal cortex. There are many fundamental questions about delay cells and the mechanisms of working memory that have remained unanswered largely owing to limitations of studies in primates: the traditional system for working memory studies. Specifically, working with trace conditioning in rabbits makes it feasible to study the origins of delay cell activity in PFC: what roles are played by learning? what are the inputs to PFC that are necessary for delay cells? Because recordings are feasible in rabbits completely na?ve to the task, which is not feasible with primates, such questions become feasible and affordable to answer. We will use recordings from PFC neurons to determine how delay cell activity arises and to characterize the rules that govern changes in delay cell responding as task demands are changed. Rabbit studies also make feasible analysis of the pathways projecting to prefrontal cortex that are involved in trace conditioning and delay cell activity. The completion of these studies will therefore yield fundamental new insights into the mechanisms responsible for the formation of working memories and their modulation by changes in environmental demands. Such knowledge will greatly facilitate our ability to develop strategies for the prevention or treatment of a host of neurological disorders that appear to relate to working memory deficits, including attention disorders and age-related dementias.
These studies investigate the mechanisms in prefrontal cortex of working memory. Working memory deficits are known to be associated with attention disorders such as ADD and ADHD, and with forms of age-related senility including Alzheimer's disease. As such, understanding the normal operation of working memory mechanisms is as fundamental to the treatment and prevention of these disorders as understanding how a car works is to being a car mechanic.
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