Shaking into deficits: investigating behavioural and neuropathological outcomes associated with a novel preclinical model of infant abusive head trauma.

Abstract

Abusive head trauma (AHT) resulting from violent shaking and whiplash-induced brain injury by a caregiver, is the leading cause of abusive mortality and morbidity in children. Cerebral oedema is common in survivors of AHT. While many children may initially appear behaviourally asymptomatic or present with non-specific symptoms following the AHT, deficits often emerge later in childhood. Additionally, AHTs are frequently repetitive, with a single child likely to experience multiple AHTs. Despite the prevalence of AHT, the mechanisms that lead to brain pathology and the latent emergence of behavioural deficits are poorly understood, and there is a paucity of preclinical, small animal models to investigate the biology and cumulative effects of repetitive injuries. This study aimed to develop a preclinical model of repetitive AHT and subsequently examine alterations in gene expression, cell types, and early adolescent behaviour. Mice were placed on a 400 rpm shaking device for 60s. This was repeated one, three, or five times throughout the neonatal development period (postnatal days (P)8-12). Injured mice initially displayed no overt behavioural changes compared to uninjured controls; however, in adolescence (P40-45) they later developed deficits in socialisation and thermal nociception. Further, alterations in the expression of genes involved in growth, cell damage, and development were observed in the brains of injured mice, along with an increase in white matter cells and evidence of blood-brain barrier leakage. This novel preclinical model of AHT provides a valuable platform for exploring diagnostic biomarkers and potential therapeutic interventions for children with an AHT.