Neonatal Hypoxic-Ischemic Encephalopathy Yields Permanent Deficits in Learning Acquisition: A Preclinical Touchscreen Assessment

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a common problem worldwide for infants born at term. The impact of HIE on long-term outcomes, especially into adulthood, is not well-described. To facilitate identification of biobehavioral biomarkers utilizing a translational platform, we sought to investigate the impact of HIE on executive function and cognitive outcomes into adulthood utilizing a murine model of HIE. HIE mice (unilateral common carotid artery occlusion to induce ischemia, followed by hypoxia with a FiO 2 of 0.08 for 45 min) and control mice were tested on discrimination and reversal touchscreen tasks (using their noses) shown to be sensitive to loss of basal ganglia or cortical function, respectively. We hypothesized that the HIE injury would result in deficits in reversal learning, revealing complex cognitive and executive functioning impairments. Following HIE, mice had a mild discrimination impairment as measured by incorrect responses but were able to learn the paradigm to similar levels as controls. During reversal, HIE mice required significantly more total trials, errors and correction trials across the paradigm. Analysis of specific stages showed that reversal impairments in HIE were driven by significant increases in all measured parameters during the late learning, striatal-mediated portion of the task. Together, these results support the concept that HIE occurring during the neonatal period results in abnormal neurodevelopment that persists into adulthood, which can impact efficient associated learning. Further, these data show that utilization of an established model of HIE coupled with touchscreen learning provides valuable information for screening therapeutic interventions that could mitigate these deficits to improve the long-term outcomes of this vulnerable population.

Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury

“…This model encompasses the FIRS, SIRS and placental pathology common in preterm infants with CHORIO [ 62 ], including acutely elevated IL-1β, TNF-α, IL-6, IL-10, and CXCL1 in serum [ 59 , 62 , 64 , 110 ]. Reflecting the significant inflammation transduced through the placental–fetal brain axis, rats with CHORIO grow up to have complex gait abnormalities, cognitive and executive function abnormalities and white matter injury in adulthood [ 59 – 61 , 64 , 111 ]. The systemic inflammation associated with CHORIO causes PBMC hyper-reactivity at P7 (term-equivalent human age) and P21 (toddler-equivalent human age) [ 59 ].…”

Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia‐ischemia

“…The anatomical complexity of the PPN and large variability in ChAT+ neuron counts in the PPN may obscure an effect of HI. Nevertheless, impairments in cognitive flexibility after neonatal HI (Maxwell et al., 2020) can be explained by the observed injury to striatal ChAT+ interneurons.…”

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…The clinical definition of hypoxic-ischemic encephalopathy (HIE) is “asphyxia of the umbilical blood supply to the human fetus occurring at 36 gestational weeks or later” ( Millar et al, 2017 ). This is one of the most common causes of long-term neuronal impairment in children ( Perlman, 1997 , 2006 ; Maxwell et al, 2020 ). Studies have shown that the incidence rate of HIE for full-term newborns with more than 36 weeks gestational age is 3/1,000 ( Knox et al, 2013 ; Hagberg et al, 2015 ), and this is approximately 7/1,000 for premature fetus within the gestational age of 33–35 weeks ( Chalak et al, 2012 ).…”