PhD Scientific Days 2024

Poster Session I - Neurosciences 2.

Perinatal brain injury leads to sexually dimorphic long-term behavioural deficits in mice

Text of the abstract

Hypoxic-ischaemic encephalopathy caused by perinatal asphyxia (PA) is a leading cause of neonatal mortality and a significant contributor to long-term neuropsychiatric deficits in cases of mild-moderate severity. In utero systemic inflammation is known to enhance PA-vulnerability, contributing to a cumulative negative effect on neuropsychiatric outcome, which often shows sex-dependent manifestations. However, the lack of translational preclinical models is hindering the exploration of causative mechanisms behind inflammatory presensitization-induced increase in PA-sensitivity. Proinflammatory cytokine IL-1β plays a key role in both pathophysiological cascades, possibly contributing to their interactive effects. Here we aimed to determine the long-term behavioural consequences and histological alterations of mild PA in inflammation-sensitized mice of both sexes. For this, C75BL/6 mouse pups received s.c. IL-1β between P2-P6 and/ or a non-invasive PA insult on P7, resulting in treatment groups of IL-1 + PA, IL-1, PA or control. Behavioural consequences were examined in automated (Automated Trainig System, IntelliCage) and classical paradigms through young adulthood. Afterwards, brain tissue was collected and unbiased histological analysis of Iba1(+) microglia was performed. Both sexes exhibited alterations in emotionality (higher anxiety and impulsivity) due to IL-1 and/or PA treatment. Cognitive domains were most significantly affected in males of IL-1 + PA group (diminished learning abilities and cognitive inflexibility). Females were more substantially affected in stress-coping. Histological analysis revealed long-lasting increase in microglia numbers in the mammillary body, basolateral amygdala and multiple thalamic nuclei of males, all related to cognitive and emotional functioning. Our results suggest that early-life inflammation and PA can solely lead to long-term behavioural deficits in a sex-specific manner, with a considerable aggravating effect of an IL-1 mediated inflammatory cascade on PA-vulnerability. Further analysis of long-lasting alterations in microglia functioning is needed to elucidate the underlying mechanisms behind the sexually dimorphic behavioural deficits in adulthood.
Funding: National Laboratory of Translational Neuroscience (Grant# RRF-2.3.1-21-2022-00011) and National Research, Development and Innovation Office (Grant# K135292).