Deciphering Molecular Mechanisms of Post-Stroke Depression in Aged Mice - PROJECT SUMMARY Stroke is the leading cause of adult disability. Over the last 20 years, with the decline in stroke mortality due to improvements in acute care, there has been an increase in the global stroke burden. Most stroke survivors experience varying degrees of motor and neuropsychiatric disorders that significantly impair their quality of life. Post stroke depression (PSD) is a common and serious consequence of stroke that affects many stroke survivors. Women are twice as likely to develop depression after stroke compared to men. Affected individuals are at an increased risk of mortality, recurrent stroke and have delayed functional recovery. Immune dysregulation, microglial hyper-activation, enhanced inflammation, and decreased levels of neurogenesis have been implicated in the pathophysiology of both depression and impaired stroke recovery. These alterations are even more pronounced in aged individuals. This proposal will focus on elucidating the mechanisms underlying the development of depression in aged mice after an ischemic stroke. Oxytocin (OXT) is a neuropeptide that acts as both a hormone and neurotransmitter and is an important regulator of social behavior, learning and memory, maintenance of cardiovascular health. Based on our preliminary studies, and literature, taurine regulates the release of OXT and reduces neuro-inflammation. Taurine is a highly abundant free amino acid in the brain, with multiple functions including a vital role as a neurotransmitter and is capable of reversing stress-induced depressive-behaviors. Interestingly, both OXT and taurine effectively reduce microglial activation, and this raises the intriguing possibility that both are involved in the development of PSD through the modulation of microglia. In this context, we hypothesize that stroke leads to a loss of taurine and OXT with subsequent increase in microglial activation and development of PSD. In our preliminary studies, we have found that taurine and oxytocin levels decline with stroke in both mice and humans. We have also found that chronic oxytocin inhibition leads to depressive-like behaviors in young animals even without brain injury, and inhibition of oxytocin significantly impairs post-stroke recovery. By using wild-type and knockout mice, a variety of pharmacological tools, cell-specific genetic models, and bone marrow chimeras, we will manipulate oxytocin signaling (Aim 1); supplement taurine (Aim 2), and deplete microglia (Aim 3), to determine if these mechanisms are involved in the development of PSD phenotypes in aged mice of both sexes. We will determine the potential of taurine and oxytocin to improve recovery in aged mice after stroke. The results from this study have a high potential for translation into clinical settings, as oxytocin and taurine are in clinical use for other indications.
