Neuronal Cell Death, Connectomics, and Proteinopathy in Human Neonatal Hypoxic–Ischemic Encephalopathy and Related Animal Models

Hypoxic–ischemic encephalopathy (HIE) is a form of brain damage in infants caused by reduced blood and oxygen supply to the brain, occurring in about 1–3 infants per 1,000 live term births in America and Western Europe. Damage can be mild, moderate, or severe and can cause death or long-term neurological, cognitive, and behavioral disabilities. Worldwide nearly 1 million infants die each year from HIE after perinatal asphyxia. Hypothermia (HT) is the only approved treatment for neonatal HIE in western countries. However, about one third of the infants who receive whole-body or head cooling still have moderate-to-severe impairments in executive, visuospatial, and motor functions, language, and emotional maturity years later. A better understanding of the process of neonatal brain degeneration and the mechanisms of HT neuroprotection and persistence of injury will help to develop additional therapeutics. We explore four key mechanistic aspects of neonatal brain injury to potentially catalyze progress: connectivity or connectomics; proteinopathy; cell death; and the proteasome. In this chapter we discuss these four aspects of neonatal brain injury and their possible interrelations.