Co-Principal Investigators/ProgramDirectors (Last, First, Middle): Shekhar, Anantha; Johnson, Philip L. Project Summary/Abstract: Panic disorder (PD) is a severe anxiety disorder characterized by recurrent panic attacks affecting about 2-5% of the population with agoraphobia present in half of PD subjects, and results in severe disability in about a third of those subjects.  Selective serotonin reuptake inhibitors (SSRI?s) are the gold standard for treating PD, but the mechanisms of action are poorly understood.  Recent evidence has identified that orexin hypothalamic neurons are one of the key regulators of a coordinated panic response and that patients with panic do indeed have high levels of orexin in their cerebrospinal fluid.  Our preclinical work has identified that orexin plays critical role in panic in models of pathological panic, but little is known about how serotonin regulate this system in the context of panic and phobias.  In order to address this gap in knowledge, we will employ traditional pharmacological and immunohistochemical techniques with novel opto- and chemo-genetic techniques to: Aim 1) elucidate the role of midbrain serotonergic system projection to the panic-ON hypothalamic OX system in regulating normal panic; Aim 2) how disruption of this system results in PD-like pathology; and Aim 3) how ventromedial prefrontal cortical projections to this serotonergic system also regulates panic.  We will measure behavioral and cardiovascular panic/fear responses with additional molecular and electrophysiological endpoints.  The proposed project will test a clear hypothetical model, basedlargely on empirical data from our own laboratories for the neural circuits and mechanisms underlying development of acute and chronic panic-like states.  This proposal is innovative because it uses state-of-the-art approaches to, for the 1st time, investigate the functional properties of subpopulations of serotonergic neurons withinthe DRN and MRN relevant to specific symptoms of severe anxiety disorders.  If our hypotheses are further supported by the aims proposed here, it will emphasize the need to develop successful therapies for anxiety disorders that have the ability to inhibit panic and fear learning circuits by modulating these distinct functional subsets of serotonergic neurons.  PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page