Modeling the Encephalopathy of Prematurity in Animals: The Important Role of Translational Research

Abstract

Translational research in preterm brain injury depends upon the delineation of the human neuropathology in order that animal models faithfully reiterate it, thereby ensuring direct relevance to the human condition. The major substrate of human preterm brain injury is the encephalopathy of prematurity that is characterized by gray and white matter lesions reflecting combined acquired insults, altered developmental trajectories, and reparative phenomena. Here we highlight the key features of human preterm brain development and the encephalopathy of prematurity that are critical for modeling in animals. The complete mimicry of the complex human neuropathology is difficult in animal models. Many models focus upon mechanisms related to a specific feature, for example, loss of premyelinating oligodendrocytes in the cerebral white matter. Nevertheless, animal models that simultaneously address oligodendrocyte, neuronal, and axonal injury carry the potential to decipher shared mechanisms and synergistic treatments to ameliorate the global consequences of the encephalopathy of prematurity.

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…Various factors are considered to cause preterm brain injury, such as asphyxia, ischemia, hypoxia, and inflammation (5,6,48,49). It is supposed that some of these factors, namely, hypoxia (as indicated in Supplemental Table 6) and inflammation (as indicated in Supplemental Table 7 and Supplemental Figure 10) occur simultaneously with or subsequent to occlusion of the maternal arteries in our mouse model.…”

“…It is supposed that some of these factors, namely, hypoxia (as indicated in Supplemental Table 6) and inflammation (as indicated in Supplemental Table 7 and Supplemental Figure 10) occur simultaneously with or subsequent to occlusion of the maternal arteries in our mouse model. But, our model still does not capture all of these complex etiologies of human extremely preterm infants, and different animal models are required to resolve different questions (6,48). In fact, there are several limitations of our model.…”

“…Recent studies have also suggested perturbed maturation of inhibitory interneurons, caudate projection neurons, and astrocytes by using animal models (14)(15)(16). Furthermore, as an underlying cause of the altered brain growth and subsequent development of cognitive dysfunction, brain injury in premature infants is thought to affect radial neuronal migration in the neocortex (17); however, this idea has not yet been rigorously investigated (6).…”

“…Although the survival rate of extremely preterm infants has improved, many survivors (25%-50%) develop cognitive dysfunction in later life (2)(3)(4). The reason why cognitive impairment is a common neurological outcome following brain injury in extremely preterm infants remains unknown (5,6). Diffuse white matter injury (WMI) has been identified as the most common neuropathology in extremely preterm infants, rather than cystic periventricular leukomalacia, which is frequently present in the injured brains of preterm infants born later than extremely preterm infants (5,7,8).…”

Evolution of T1 Relaxation, ADC, and Fractional Anisotropy during Early Brain Maturation: A Serial Imaging Study on Preterm Infants

“…When performing serial imaging of preterm brain by using specific MR imaging markers, it is important to understand the different processes involved in brain maturation during the last trimester of gestation, such as neuronal differentiation, premyelination with water-content reduction, increase of lipid concentration, maturation of preoligodendrocytes, and finally the beginning of axonal myelination and development of connecting fibers. 5,28 Diffusion and T1 relaxation time are sensitive to changes in tissue water content and compartmentalization. Mean diffusivity reflects intra-and extracellular water mobility and provides information about cellular and axonal density and myelination.…”