This is a Research Career Scientist application to study neuroanatomical and neurochemical mechanisms involved in conditioned fear and anxiety, using the acoustic startle reflex in rats. Acoustic startle is a short latency reflex mediated by a simple neural pathway. Startle amplitude can be increased be eliciting the reflex in the presence of a light previously paired with a shock (fear-potentiated startle).This effect can be blocked by drugs which reduce anxiety clinically, by lesions of the amygdala or lesions that prevent visual information from reaching the amygdala. Low level electrical stimulation of they amygdala markedly increases acoustic startle amplitude via a direct project from the amygdala to the acoustic startle circuit. Fear-potentiated also can be readily measured in humans using anticipation of shock as the fear-provoking manipulation. Thus, fear-potentiated startle can be measured in both rats and humans where much of the neural circuitry in rats has been delineated. A major problem in many types of anxiety disorders is an inability to inhibit fear or anxiety. We have developed procedures to measure inhibition of fear-potentiated in both rats and humans using a conditioned inhibition paradigm. The present proposal will evaluate the role of excitatory amino acid receptors in the acquisition of conditioned inhibition by locally infusing N-methyl-D-aspartate (NMDA) vs. non--NMDA antagonists into amygdala nuclei before conditioned inhibition training sessions. Other studies will evaluate whether the amygdala vs. other target areas is the site where a conditioned inhibitor acts to decrease fear. Other studies will evaluate how activation of the amygdala increases startle via its direct projection to the startle pathway. Another use of the startle reflex has been to assess sensory gating, which is abnormal in schizophrenia and disrupted by dopamine agonists in rats. We have found that dopamine agonists affect auditory transmission at the cochlea, the very earliest part of the auditory system. Studies will test whether this could explain disruption of sensory gating via actions on the olivary cochlear bundle.
