600 - Mode of respiratory management of preterm lambs affects long-term outcomes of neurobehavior and hippocampal expression of insulin-like growth factor-1 expression and miRNA-23a

Poster Number: 600
Publication Number: 600.1527

Background: Preterm infants who receive invasive mechanical ventilation (IMV) suffer hippocampal dysfunction as evidenced by impaired learning/memory, socialization, and curiosity. Hippocampal functions depend on local expression of insulin-like-1 growth factor (IGF-1) and miRNA-23a. Dysregulation of IGF-1 or miRNA-23a expression associates with cognitive impairment in both humans and rodents. However, the impact of the mode of respiratory management of preterm lambs on neurobehavioral outcomes and hippocampal expression of IGF-1 gene and miRNA-23a are unknown.

Objective: Demonstrate that preterm lambs receiving noninvasive respiratory support (NRS) have better neurodevelopmental outcomes and normalized expression of hippocampal IGF-1 than preterm lambs receiving IMV, which have lower miRNA-23a level.

Design/Methods: Preterm lambs groups were (a) IMV ~7d (n=6), (b) IMV ~3h + NRS ~7d (n=5), or (c) NRS resuscitation (face mask) + NRS ~7d (n=5). Neurobehavioral outcomes for the former preterm (FPT) lambs were tested at 2-months corrected postnatal age (2 moC PNA; eq 1-2y in humans) and 5-moC PNA (eq ~6y in humans). Tests were learning/memory (maze), socialization (non-reflective/reflective surface), and curiosity (novel objects). Hippocampi from the same FPT lambs were analyzed at 5-moC PNA for IGF-1 mRNA and protein levels, and miRNA profiles related to cognitive impairment. The same analyses were made for unventilated term reference lambs (2 and 5 mo PNA; n=4).

Results: Outcomes are reported by lamb and sex because of small sample size and large variability. FPT lambs receiving NRS ~7d spent less time at the non-reflective surface/more time at the reflective surface, and finished the maze faster relative to the 2 IMV FPT groups (Fig 1A). Results for novel object assessment (not shown) provided similar outcomes. The 3 FPT groups had significantly lower abundance of endogenous IGF-1 protein than the term reference group (Fig 1B). Concurrently, the NRS FPT group retained expression of miR-23a whereas both IMV FPT groups had low level of miR-23a (Fig 1C).

Conclusion(s): Preterm lambs managed by NRS demonstrate better neurodevelopmental outcomes and normalized expression of hippocampal IGF-1 and miRNAs associated with appropriate cognition. We speculate that interventions that moderate the impact of IMV on hippocampal IGF-1 mRNA epigenetic profile and miRNAs will decrease the risk of neurodevelopmental impairments in survivors of preterm birth and BPD. Our next step is to determine the epigenetic regulation of the IGF-1 miRNAs.