There is an urgent need for more targeted therapies to treat Panic Disorder (PD), a mental disorder which is characterized by recurring and often unexpected panic attacks. The NIMH estimates that 6 million Americans currently suffer from PD, with about one-third of patients becoming housebound due to the severity of their symptoms. Although it is a widespread mental illness, there is a dearth of medical therapies to treat the disorder. Many patients are prescribed anti-depressants, which do not specifically target the symptoms of PD, have numerous negative side effects, and can lead to the exacerbation of panic attacks in some individuals. Alternatively, benzodiazapenes, often prescribed as anti-anxiety medication, are extremely powerful drugs that can only be used for short periods of time and put one at risk for developing dependence. The lack of available therapies stems, in part, from the paucity of knowledge of the underlying neurological basis of anxiety disorders. Although previous research has shown that the brain stem and the limbic system are involved in PD, very little is known about the specific circuits responsible for mediating the various aspects of the disorder. Recent studies have found hypocretin-releasing neurons in the lateral hypothalamus to be necessary for the onset and maintenance of PD. Dr. de Lecea and his colleagues have previously studied the role hypocretin plays in setting an arousal threshold. This suggests hypocretin is involved in anxiety disorders, which are associated with a state of hyper-arousal. Hypocretin is also known to be involved in regulating many of the physiological alterations which accompany panic attacks, including increased breathing and heart rate and exaggerated responses to interoceptive stimuli. This proposal hypothesizes that different subpopulations of neurons in the lateral hypothalamus have distinct electrophysiological properties and adaptations in response to anxiety-provoking stimuli. Experimentally I plan to investigate, through projection-specific optogenetic activation, the role each subpopulation may play in mediating anxiety-like behaviors. Furthermore, preliminary studies on a group of nucleus solitarious tract neurons (A2), which receive innervation from hypocretin cells in the lateral hypothalamus, have revealed that activation of these cells instigat anxiety-like behaviors. By studying the projections of these neurons, this project seeks to identify and characterize the synaptic targets of A2 neurons which contribute to anxiety disorders. These proposed molecular and cellular studies will provide very useful and highly novel information, both for improving our knowledge of the circuitry of PD and for identifying new drug targets to develop more effective treatments for anxiety disorders.