Project Summary The Triple Risk Model describes SIDS occurrences when an intrinsically vulnerable infant experiences an exogenous insult resulting in a chronically hypoxic/hypercapnic environment particularly during a critical developmental period. SIDS pathophysiology includes evidence of chronic hypoxia exposure, brainstem gliosis and serotonergic abnormalities, as well as respiratory/autonomic dysfunction and carotid body abnormalities. Although animal models have been instrumental in advancing our understanding of SIDS, the lack of models that recapitulate the hallmark features has hindered our ability to confirm SIDS pathophysiology and resolve the major hypothetical/proposed features. We resolved this hurdle after discovering a rat model that closely simulates postnatal hypoxia component of SIDS as an exogenous stressor in a vulnerable neonate. In this model, prolonged/sustained (days) hypoxia exposure during a uniquely critical period of postnatal development results in spontaneous unexplained death several days later. Importantly, in both published and preliminary studies (this proposal) the model recapitulates ALL of the aforementioned SIDS features. Here, using our novel model, we propose the novel hypothesis that the hallmark brainstem abnormalities (microglia and 5-HT) in SIDS is in response to chronic disruption of carotid body afferent inputs into the brainstem. We propose that these disrupted inputs over several days are sufficient to elicit a localized brainstem microglial response (as seen in SIDS), ultimately leading to the fatal abnormalities in brainstem neurochemistry in key respiratory/autonomic control regions. A particularly novel component of our proposal is the discovery of a microglial inhibitor, which prevents the adverse effects of hypoxia exposure, thus for the first time in any setting, we may be on the path to a preventative measure against SIDS. We also propose that aberrant expression of several components of the extracellular matrix may be a new central (brainstem) and peripheral (carotid body) pathophysiological mechanism in SIDS. Finally, given the compelling similarities in our model with SIDS cases, we are poised to assess serum and urine biomarkers for identifiers of at-risk infants and predictors of later mortality. Overall, this proposal will: 1) be fundamental to our understanding of respiratory and autonomic dysfunction associated with SIDS, 2) provide a mechanistic perspective on the root cause of the common brainstem abnormalities, 3) discover potentially new SIDS pathophysiology (per the requirements of the NOSI, and 4) reveal a glimmer of hope at a prophylactic treatment toward SIDS prevention.