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Research Areas:

1) Molecular Mechanisms of Fear Learning. Specifically, we are interested in the genes and proteins that are involved in the acquisition and consolidation of fear and extinction of fear using wild-type and genetically altered mouse models.
a. Role of Growth Factors in fear learning. We have shown through a variety of studies that BDNF and its receptor TrkB, are involved in fear conditioned learning within the amygdala (Rattiner et al., 2004; Rattiner et al., submitted).
b. Role of specific cell-types within amygdala in fear learning. We are currently creating several different BAC-transgenic mice, which when combined with transgenic lentiviruses should allow cell-type and regional specific control of gene expression within the amygdala.
c. Role of inhibitory synapses in fear learning. We have demonstrated that there is a rapid downregulation of the GABAA receptors within the amygdala following fear conditioning (Chhatwal et al., submitted). We have previously examined fear conditioning in mice that are mutant for the GAD65 subtype of GABA-producing enzyme (Heldt et al., 2004). We have submitted an R01 to NIDA to examine the similarities between stress-dependent GABAA desensitization and a similar process that occurs with substance use as a potential way of understanding stress-induced reinstatement and relapse (Ressler, NIH R01, submitted)

2) Molecular Mechanisms of Olfactory learning. The olfactory system is the most robust sensory system to mediate fear learning in rodents. We have built upon original work performed in the Davis lab to examine olfactory fear learning and olfactory discrimination in mice. We believe that the use of transgenic mice in which specific olfactory 'labeled lines' are genetically labeled will allow novel and powerful approaches to understanding how the amygdala modulates sensory systems during fear learning.
a. Use of a genetically 'labeled-line' mouse to examine effects of odorant-specific learning. We have made a transgenic animal that allows cellular visualization of 1 out of 1000 glomeruli within the olfactory bulb that has a known odorant ligand. This model potentially will allow a greater molecular and cellular understanding of olfactory learning at the bulb, piriform cortex, and potentially amygdala levels (Ressler, NIH R21 under revision).
b. Mechanisms of olfactory - mediated aversive vs. appetitive learning. These animals will also be used to examine Pavlovian fear conditioning (Jones, submitted) in contrast to appetitive pairing to food and sex. Pair bonding will be performed in collaboration with Larry Young who studies mechanisms of pair bonding in mice and voles (Hammock et al., Abstract, FENS, 2004).

3) Molecular and circuitry regulation of prepulse inhibition and models of psychosis, such as Paranoid Schizophrenia (a disorder of psychotic and delusional fear).
a. Knockout of the GAD65 gene induce PPI deficits. We have found that mice with targeted deletion of the GAD65 gene have deficits in prepulse inhibition, although they have no abnormalities in fear conditioning (Heldt et al., 2004).
b. Site- and time-specific rescue of the GAD65 gene - effects on PPI. We have created a lentivirus that expresses a reporter gene and the wild-type GAD65 allele. This will be used to examine whether replacement of wild-type GAD65 within certain brain regions will 'rescue' the PPI deficit.
c. Stress-dependent deficits in PPI and Dopamine regulation following lesions of the habenula. We have found that the habenula, which is activated in an activity-dependent manner with fear conditioning, is not actually required for fear conditioning, but instead appears to be important for stress-dependent regulation of monoamine systems and also contributes to regional deficits in GAD67 expression (Heldt et al., submitted).

4) Translational research examining blockade of fear and enhancement of extinction in humans.
a. In collaboration with Michael Davis and Barbara Rothbaum, we have shown that D-cycloserine, which we previously demonstrated enhanced extinction of fear in rats (Walker et al., 2002), also enhances extinction of specific fears in human subjects (Ressler et al., 2004). Future studies aim to look at how general an effect this is in other phobic disorders and eventually within patients with PTSD.
b. A number of ongoing studies are examining the prevalence and comorbidity of PTSD within the inner city in downtown Atlanta (Schwartz et al., 2004; Schwartz et al., submitted). These studies hope to be the stepping off point for larger research programs examining the interaction of stress, environment, and genetics on the development of PTSD and depression in this population (Cubells, NIH R01, submitted). We also hope that as research in this clinic matures, we will be able examine some of the translational approaches, e.g. D-cycloserine, to study enhancement of extinction for treatment of PTSD using exposure therapy.