Inflammatory mechanisms contribute to long-term cognitive deficits induced by perinatal asphyxia via interleukin-1.

Abstract

Perinatal asphyxia remains a leading cause of neonatal mortality and a major contributor to permanent neurological deficits. Even mild cases can result in long-term neurodevelopmental, cognitive, behavioural and psychiatric disorders. However, the mechanisms underlying asphyxia-induced hypoxic-ischaemic brain injury remain poorly understood, limiting the development of targeted interventions during the critical early plastic period. To explore the behavioural and molecular outcomes of perinatal asphyxia that may model important aspects of neuropsychiatric disorders observed in humans, we utilised a translationally relevant, non-invasive oxygen deprivation model of asphyxia in postnatal day 7 rats. We conducted a comprehensive assessment of asphyxia-induced changes, integrating neurobehavioural profiling (evaluating cognitive, emotional, social and neuromotor functions), microglial morphology analysis, neuroimaging, stress hormone measurement and whole-transcriptome sequencing techniques to elucidate the acute and long-term functional consequences. Consistent with clinical observations, the extensive functional assessment revealed distinct sex-dependent effects, including increased anxiety and impulsivity, attention deficits and impaired inhibitory control, which were observed exclusively in males, with no apparent sensorimotor deficits. This phenotype resembling attention deficit hyperactivity disorder (ADHD) in adult rats was associated with a lasting increase in inhibitory bouton densities in the medial prefrontal cortex. The development of an acute inflammatory response after perinatal asphyxia marked by phenotypic transformation of microglia, paralleled brain perfusion and stress hormone changes. Notably, microglial changes were mitigated by the blockade of proinflammatory interleukin-1 signalling via systemic IL-1 receptor antagonist (IL-1RA) administration in a therapeutically relevant time window. Importantly, early blockade of proinflammatory responses was able to prevent cognitive deficits in adulthood and normalise inhibitory bouton densities. RNA sequencing analysis revealed asphyxia-induced dysregulation of molecular pathways targeting GABAergic signalling, potentially contributing to subsequent morphological and neuropsychiatric alterations. IL-1RA treatment appeared to engage distinct epigenetic regulatory mechanisms, rather than merely reversing these disruptions in the acute post-asphyxia period. Collectively, these findings demonstrate that perinatal asphyxia induces marked behavioural deficits in attention and inhibitory control, paralleled by lasting inhibitory and epigenetic dysregulation, preceded by acute induction of microglia-driven inflammatory processes in the medial prefrontal cortex. Systemic IL-1RA administration may represent a promising therapeutic opportunity to prevent long-term cognitive impairments caused by perinatal asphyxia.