NEURAL SUBSTRATES OF SUSTAINED VERSUS PHASIC FEAR

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent findings suggest that the neural substrates of phasic (short-duration onset responses) and sustained (longer-duration responses) startle increases may be partially different. Other findings suggest that the sustained component may be especially relevant clinically. The central goals of this project are to develop better animal models of clinical anxiety (based on sustained fear);to develop a greater understanding of the neural substrates of sustained and phasic fear, how they are similar and how they are different;and to identify potential targets for therapeutic intervention. During the first several months of this project, we completed experiments which compared the predictive validity of these two measures. Thus, several drug treatments that either are or are not clinically effective for anxiety reduction were evaluated for their effects on phasic and sustained startle increases. In general, we found that the effects on sustained startle increases more accurately predicted their clinical effects than their effects on phasic startle potentiation. This suggests that sustained fear paradigms may be better models of at least some types of clinical anxiety and perhaps therefore, more useful for evaluating novel compounds for anxiolytic activity. We have also collected initial data showing that prefrontal cortex lesions exacerbate sustained startle fear while having no effect on phasic fear. These results suggest a key role for the prefrontal cortex in controlling anxiety. Other activities have been devoted to optimizing procedures that will be used in years 2-5 of this project (e.g., lesions of the bed nucleus of the stria terminalis).