University of Vermont COBRE 1 (P20 RR016435)
 "Center for Neuroscience Excellence"

Research Project 2: "Molecular and Genetic Analysis of Learned Fear Reduction in Mice"
 Investigator: William Falls, Ph.D.

 A single traumatic experience can result in the development of over generalized fear, as observed in Posttraumatic Stress Disorder (PTSD). To understand PTSD and related disorders, basic research has focused on identifying the neural systems that are responsible for the acquisition of Pavlovian conditioned fear. Clinically, a major problem seen in these disorders is an inability to inhibit the traumatic memories and the associated fear. Hence, an important area of inquiry concerns the way unwanted memories can be reduced or inhibited and why this is so difficult following traumatic fear conditioning. The long-term goals of the P.I.'s research are to identify and examine the neural systems involved in the reduction of fear.

Recent advances in molecular and genetic techniques have provided an unprecedented opportunity to examine the molecular basis of fear and their use in examining the reduction of fear has great potential. Experiments will examine the reduction of fear using an extinction procedure in which conditioned fear to a tone is reduced when the tone is repeatedly presented in the absence of shock. The modulation of extinction will also be examined using renewal and reinstatement procedures in which extinguished fear to a tone is recovered when the tone is presented outside of the extinction context (renewal) and extinguished fear to a tone is recovered when the tone is subsequently presented in an aversive context (reinstatement). In Specific Aim 1 studies will parametrically examine extinction, renewal and reinstatement in C57BL/6 and DBA/2 mice. These mice differ on several neurobiological variables that are expected to influence renewal and reinstatement. In Specific Aim 2, studies will explore the contribution of the hippocampus and amygdala to extinction, renewal and reinstatement through the use of reversible lesions and intra-cerebral infusions of specific protein kinase inhibitors. In Specific Aim 3 studies will examine the contribution of CREB to the learned reduction of fear by examining extinction, renewal and reinstatement in mice transgenic for an inducible repressor of CREB. In Aim 4 studies will examine amygdala and hippocampal levels of several kinases that are known to be involved in learning and memory to determine if they are associated with extinction, renewal and reinstatement. This project will be the first to systematically evaluate the reduction of fear in mice and the molecular correlates of extinction. The results of this work will provide important new information that will further our understanding of PTSD and related disorders and may lead to new and more effective treatments for these disorders.