Panic disorder is a common psychiatric illness with a lifetime prevalence of about 4.5%. The hallmark of the disorder is recurring panic attacks, which can appear suddenly and unexpectedly, consisting of pronounced fear, as well as cardiovascular and respiratory responses. The initial pathology in these patients appears to be an alteration somewhere in the central neural pathways regulating normal panic responses, thus rendering the patients susceptible to unprovoked panic symptoms when exposed to ordinarily mild interoceptive stressors. Understanding the neuronal underpinnings of panic attacks would significantly improve the outcomes and treatment. The neurotransmitter hypocretin (Hcrt), also known as orexin, has been recently linked to hyperarousal, anxiety and panic, but the specific effector circuits are unknown. Anatomical and functional evidence suggests that one of the possible Hcrt/orexin targets are norepinephrine (NE)-containing neurons in the brainstem. Here, we will test the overall hypothesis that Hcrt/orexin acts through ventral norepinephrine A2 neurons and their efferents to produce different components of the anxiety and panic responses. We will use anatomical tracing and optogenetic tools to obtain a functional map of the neuronal circuitry connecting A2 neurons with several of its anatomical targets, namely the paraventricular hypothalamic nucleus (PVN) and the bed nucleus of the stria terminalis (BNST). We will also determine the connectivity between these circuits and the arousal promoting Hcrt/orexin neurons in the lateral hypothalamus. Our experiments will increase our understanding of the circuitry associated with anxiety with cellular specificity and may lead to potentially more selective treatments for anxiety and panic disorders.
We will test the overall hypothesis that Hcrt/orexin acts through ventral norepinephrine A2 neurons and their efferents to produce different components of the anxiety and panic responses. Our experiments will increase our understanding of the circuitry associated with anxiety with cellular specificity and may lead to potentially more selective treatments for anxiety and panic disorders.
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