Exposure to enriched environment and parental care ameliorates brain pathology and behavioral impairment after germinal-matrix intraventricular hemorrhage

Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications associated with prematurity. GM-IVH commonly results in neurodevelopmental impairments or neuropsychiatric disorders. However, GM-IVH has no successful treatment. Previous studies have shown that early intervention programs may have beneficial effects in preterm newborns (PT). Similarly, enriched environments (EE) increase neurogenesis and behavioral alterations in animal models. Therefore, we propose the study of the effects of long-term exposure to a complex EE in a murine model of induced GM-IVH. We analyzed brain pathological features and feasible markers of GM-IVH, as well as behavioral outcomes. In parallel, we analyzed the same plasma markers in PT with GM-IVH that followed an intervention program including parental bonding and stimulation. EE exposure limited brain atrophy, maintained the neuronal density, limited axonal damage and increased the neuronal complexity. Furthermore, neurogenesis was promoted and the inflammatory process was attenuated. Importantly, after the exposure to EE, cognition was improved, and the peripheral markers of brain damage, UCHL1 and plasma gelsolin, were also ameliorated. In line with this, plasma UCHL1 was early increased in patients with GM-IVH while plasma gelsolin was reduced and an overall reduction of peripheral markers was observed with time, both in Controls and in patients with GM-IVH. On the other hand, plasma tau levels were significantly reduced in those patients with GM-IVH that received parental support and nurturing environment. Altogether, our data show an improvement of pathological hallmarks, peripheral biomarkers and cognitive impairment associated with GM-IVH and support the beneficial effects of early intervention programs.