Over 19 million U.S. citizens suffer from some form of anxiety disorder, including post-traumatic stress disorder [PTSD], generalized anxiety, and panic. As such, one major goal of mental health research is to identify the neural substrates underlying the development, manifestation and control of these debilitating illnesses. The objective of the studies described in this proposal is to examine the role of the transcription factor cAMP response element-binding protein (CREB) in the acquisition and expression of fear and anxiety- like behaviors. Because the involvement of CREB in the regulation of mood has been linked to its activity in specific brain areas, the focus of these studies is on the function of CREB in the bed nucleus of the stria terminalis (BNST), a key component of the brain circuitry implicated in the control of anxiety states. Our specific hypothesis is that CREB function in the BNST controls the level of fear and anxiety in animals. This hypothesis is based on the observation that extremely fearful animals have a significant reduction in the level of phosphorylated (activated) CREB (pCREB) in the BNST. Using viral-mediated gene transfer techniques, we will examine the behavioral effects of directly altering the function of CREB in the BNST of rats. Following intra-BNST infusions of herpes simplex virus (HSV)-based vectors that either increase CREB function (HSV-CREB) or decrease CREB function (HSV-mCREB), behavior will be tested in two assays believed to model different anxiety disorders: fear-potentiated startle (a model of PTSD) and the elevated plus-maze'(a model of generalized anxiety). In three Specific Aims, we will examine if alterations in CREB function in the BNST predispose an animal to develop abnormal levels of fear (Aim 1) or if these alterations affect the manifestation of fear and anxiety (Aims 2 and 3). Ultimately, these studies may lead to new insights into the etiology and treatment of anxiety disorders. ? Relevance: The development and manifestation of behavioral symptoms of some anxiety disorders (e.g. post-traumatic stress disorder [PTSD], generalized anxiety disorder, panic) is likely due to changes in the function of intracellular signals occurring within key brain regions. This research will examine if the function of one such molecule, CREB, acting in a specific brain region (the BNST), can directly affect fear and anxiety levels in animals. Such studies may ultimately lead to the development of novel and effective treatments for human anxiety disorders ? ?
| Meloni, Edward G; Reedy, Catherine L; Cohen, Bruce M et al. (2008) Activation of raphe efferents to the medial prefrontal cortex by corticotropin-releasing factor: correlation with anxiety-like behavior. Biol Psychiatry 63:832-9 |
