Anatomy and Pharmacology of Fear-Potentiated Startle

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This is a competing renewal for a 10-year MERIT Award competitively reviewed last in 1990. Because of delays in grant transfer and lab construction after my recent move to Emory University, I received a one- year extension,which accounts for why this application is being submitting at this time. The overall goals of this project are to understand neural systems involved in conditioned fear using the fear potentiated startle test as a measure. Progress over the last 10 years has focused on the amygdala and its direct projection to a critical part of the acoustic startle pathway. In this application we will evaluate the role of the mesencephalic reticular formation, near the border of the deep white layers of the superior colliculus (deep SC/Me), in fear potentiated startle. We will also test whether fear potentiated startle results from activation of GABA containing neurons in the lateral division of the CeA (lateral CeA), which then inhibit GABA containing projection neurons in the medial CeA, thereby disinhibiting the deep SC/Me, leading to an increase in startle. During the prior grant period we found that over-expression of CREB (cAMP response element binding protein) dramatically increased fear conditioning. Here we propose to localize more exactly within the basolateral amygdala (Bla) where over-expression of CREB will facilitate fear conditioning using viral vector gene transfer. We also found that experimental extinction (presentation of lights in the absence of shock following fear conditioning) led to an upregulation of gephyrin mRNA, critical for the inhibitory neurotransmitters glycine and GABA. Here we will determine whether treatments that block (local APS or Map kinase inhibitors in Bla) or facilitate (D-cyclpserine given systemically or directly into Bla) will alter gephyrin mRNA upregulation. We also found fear conditioning induced several genes within and afferent to the amygdala. Here we will determine whether treatments that block (local APS or Map kinase inhibitors in Bla) or facilitate acquisition (HSV-CREB) of fear potentiated startle will block or facilitate gene expression in amygdala and other areas. Finally, we will employ a discrimination procedure we developed to determine or GABA antagonists or inactivation of the hippocampus, septal nucleus, bed nucleus stria terminalis or frontal cortex will affect discrimination, inhibition and generalization. The work is relevant to human anxiety disorders and promises to elucidate critical events in the formation and elimination of fear and anxiety.