This is an application for a MERIT extension to study neuroanatomical, cellular and molecular mechanisms involved in conditioned fear, anxiety, extinction and learned safety, 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 by eliciting the reflex in the presence of a light or odor previously paired with a shock (fear- potentiated startle). During the previous grant period we delineated a new connection between the medial nucleus of the amygdala and the acoustic startle pathway critical for fear-potentiated startle, discovered a new method to try to understand the neural basis of conditioned fear vs. anxiety, analyzed the differential roles of NMDA-2A and 2B receptors in the acquisition vs. expression of fear-potentiated startle, uncovered a role for brain derived neurotropin in the development of both fear conditioning and extinction,as well as observing interactions between cholecystokinin and cannabinoid receptors in extinction. One of the most vexing problems in studying the cellular and molecular mechanisms of learning and memory in a complex organism is the problem of signal-to-noise ratio. Given billons of neurons and trillions of synapses, how will we ever be able to figure out at a cellular level the molecular events necessary for memory formation and storage? By using genetically engineered mice, namely mice in which the promoter for a particular olfactory sensory receptor (m71) is fused to the gene that codes for either green fluorescent protein or B- galactosidase, in combination with olfactory-mediated fear-potentiated startle using acetophenone as the conditioned stimulus, we hope to overcome some of these problems. We will use manganese(Mn) enhanced MRI,in conjunction with standard histological techniques, to trace brain circuits involved in conditioned fear, extinction, and conditioned inhibition, using a small animal, 9.4 T magnet. Other studies will evaluate changes in M71 axon number following fear conditioning and whether the amygdala modulates these changes. Other studies will evaluate the role of corticotropin releasing factor receptors in the amygdala or bed nucleus of the stria terminalis in fear vs. anxiety and other studies will use high speed voltammetry to assess changes in glutamate release in the acoustic startle pathway during fear-potentiated startle testing.
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