Ischemic stroke (or Stroke) is one of the major causes of death and disability in our Veterans, and a huge economic burden in the U.S. While Veterans in all age groups are affected by stroke, recent studies suggest that the prevalence of stroke is higher in middle-aged Veterans returning from combat. The most common artery that is blocked and causes stroke is the middle cerebral artery (MCA). Blockade of MCA causes ischemia that affects major brain regions, including cortex, striatum and hippocampus. While patients suffering from stroke display multitude of symptoms, including hemiplegia or hemiparesis, dysphagia, cognitive impairments, the most persistent and debilitating symptoms observed in stroke patients are sleep disturbances, including insomnia, excessive daytime sleepiness and reduced REM sleep. In addition, these sleep disturbances are associated with worse motor outcomes and slower functional recovery post-stroke. In contrast, attenuation of sleep disturbances in stroke patients is associated with faster recovery and promotes neurorehabilitation. Overall, sleep disturbances are unique, novel, and modifiable treatment target that can potentially improve outcomes in stroke patients, provided that we understand the neuroanatomical substrates responsible for sleep disturbances. However, the paucity of animal models mimicking sleep disturbances in human stroke is the major limiting factor. Development of appropriate animal models will enhance our understanding towards the underlying sleep-wake substrates and mechanisms affected by stroke and help in the development of novel and targeted therapeutic strategies to treat sleep disturbances and accelerate recovery and rehabilitation post-stroke. Recently, we have observed that 1h of middle cerebral artery occlusion (MCAO) in middle-aged (9 - 12 months) C57BL/6J mice mimics major symptoms of human stroke including altered sleep-wake rhythm along with sensorimotor and cognitive deficits. We propose to use this mouse model along with a combination of multidisciplinary approaches, such as behavioral (sleep deprivation), pharmacological (orexin receptor antagonist) and novel non-traditional (Designer Receptor Exclusively Activated by Designer Drug; DREADD), to test our hypothesis “Stroke disrupts sleep homeostasis and circadian processes to cause chronic sleep disturbances that are responsible for preventing post-stroke recovery and rehabilitation.” Two aims are designed: Aim 1: proposes that stroke in mice will disrupt sleep homeostasis and altered circadian genes expression in select brain regions (but not in suprachiasmatic nucleus) to cause circadian desynchrony resulting in a) sleep disturbances observed in human stroke patients as evident by excessive daytime sleepiness during the active (dark) period coupled with insomnia-like symptoms (reduced quality and quantity of sleep) and reduced REM sleep during the light (sleep) period, b) sensorimotor, memory and cognitive deficits and c) altered syn...