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Stress exacerbates many psychiatric conditions, and repeated stress contributes to the pathogenesis of disorders such as Post Traumatic Stress Disorder, Panic Disorder and Major Depressive Disorder. The orexin (hypocretin) system is highly reactive to stress, and regulates many physiological processes that are altered in stress-related mental illness, including sleep/wake patterns, appetite and cognition. Changes in orexin levels have been reported in major depression and anxiety disorders, and polymorphisms in the orexin 1 receptor are associated with anxiety spectrum disorders, particularly in women. The orexin system is therefore an attractive target for treating stress-related disorders. Orexinergic neurons have wide projection targets across the nervous system, including hypothalamus, thalamus, cortex, brain stem and spinal cord. The projections to other hypothalamic neurons and subcortical arousal centres are important for modulating arousal, appetite and activity of the Hypothalamic Pituitary Adrenal Axis. The roles of projections to cortical circuits remain less well understood, but may be involved in regulating cortical arousal and the cognitive responses to stress and could represent promising targets for drug development to treat stress-related cognitive dysfunction. The aim of this project is to resolve the mechanisms by which orexinergic neurons directly modulate cortical network activity, using optogenetic stimulation of orexinergic projections in ex vivo cortical brain slices in combination with patch-clamp recordings, multiphoton imaging and high density multielectrode arrays.