PhD Scientific Days 2022

Neurosciences II.

Neuroinflammation Causes Long-term Cognitive Deficits and Prefrontal Cortex-Dependent Functional Changes in a Rat Model of Perinatal Asphyxia

Text of the abstract

Introduction: Perinatal asphyxia (PA) is a leading cause of neonatal mortality and a major contributor to later-manifesting psychiatric and behavioural disorders, e.g. ADHD. Still, the underlying mechanisms of PA-induced brain injury remain elusive, hindering the development of targeted therapeutic strategies.
Aim: We explored the short- and long-term neuropshychiatric outcome and underlying neurobiological mechanisms of PA in rats, using a novel PA insult model.
Method: For the insult, 7 days old rat pups were treated with a special gas mixture (4% O2, 20% CO2) for 15 minutes in normothermia. To assess the behavioural consequences of PA, rats were subjected to extensive motor, emotional and cognitive testing from infancy through adulthood. To address the behavioural alterations on a histological level, immunohistochemistry (IHC) and STORM microscopy were performed in relevant brain regions. Acute brain perfusion changes were studied with SPECT and MRI imaging. Based on neuroimmunological findings, interleukin-1 receptor antagonist (IL-1RA) treatment was administered acutely after PA.
Result: PA resulted in elevated anxiety, marked motor impulsivity and hippocampus (HC)- and prefrontal cortex (PFC)-dependent cognitive deficits (spatial learning, memory, attention disturbances), indicating ADHD-like features. IHC confirmed acute neuroinflammation in the PFC and HC, partially preserved through adulthood. STORM imaging revealed a permanent disruption of excitatory/inhibitory balance in the PFC. Reduced whole brain blood volume and brainstem perfusion were observed 24h after PA. IL-1RA administration significantly ameliorated attention deficit in adulthood.
Conclusion: PA leads to acute brain perfusion changes and lasting local inflammation in the PFC and HC, paralleled by excitatory/inhibitory dysregulation and marked region-dependent emotional and cognitive deficit. Furthermore, IL-1RA may provide a treatment opportunity for PA-induced cognitive deficits.
Funding: Our research was funded by the Hungarian Scientific Research Fund (Grants No. K109743, NN114607 and K135292); the Hungarian Brain Research Program (Grant No. KTIA_13_NAP-A-I/2 and NAP 2017-1.2.1-NKP-2017-00002; the Lendület (Momentum) Program of the Hungarian Academy of Sciences; ERC-CoG 724994-MicroCONtACT; ERC-2013-AdG 341116-PressBirth and Behavior Study Unit of Institute of Experimental Medicine.