(Administrative Supplement; R01 HL139685) The developmental stage of the brain at the stroke onset plays key role in injury. Inflammation is a hallmark of perinatal brain injury, both in early injury and repair. The long-term goal of funded Parent R01 HL139685 is to identify how deficiency/enrichment in n3-Polyunsaturated Fatty Acids (n3-PUFA, i.e., Omega-3 fatty acids and derivatives/metabolites) in a diet during gestation and during early postnatal period affects brain injury in neonatal mice subjected to stroke or bacterial stimuli and whether n3-PUFA enhance brain repair after perinatal stroke by modifying S1P/S1PR2 signaling at the immune-neurovascular axis. While during submission we proposed to examine effects of two diets, basic and n3-PUFA enriched diets, during funded period, using three diets?imbalanced, balanced or enriched in n3-PUFA diets? we discovered highly significant differences in lipid composition profiles in the brain, blood and erythrocytes under physiological conditions in neonates born from mothers maintained on n3-PUFA enriched diet, in brain cytokine expression following acute bacterial infection, and significantly attenuated neuroinflammatory response and injury after acute neonatal stroke in pups maintained during gestation/postnatal on n3-PUFA enriched diet. In the Supplement, we propose to examine effects of imbalanced, balanced and n3-PUFA enriched diets during gestation/postnatal period on physiological brain lipid composition, cytokine profiles, social interactions, anxiety and cognitive behavior during young adulthood (Supplemental Aim 1), evaluate the underlying mechanisms in vivo by examining brain connectivity and vascular development/complexity during young adulthood (Supplemental Aim 2), and, in pups subjected to stroke/sham surgery, examine effects of n3-PUFA enriched diet on brain lipid composition, inflammatory status and behavior outcomes (Supplemental Aim 3). We will use state-of-the-art methodologies in vivo (MR tractography, ?vascular painting?) and post vivo (mass spec, multiplexing) and unique neonatal stroke model. The scientific premise of these studies is in enhancing the understanding of how n3-PUFA deficient/imbalanced diet during pregnancy/nursing deranges lipid composition/signaling and alters immune responses, affecting brain function and connectivity in early adulthood. These results have far reaching translational impact for human health.
Stroke in the term newborn occurs in 1 in 4,000 live births. Most of these infants survive with significant long-term disabilities, and there are no treatments available to ameliorate their suffering and decrease the enormous cost to families and society. The proposed studies will identify previously unknown effects and mechanisms of gestational/perinatal deficiency in dietary Omega-3 fatty acids (n3-PUFA) on brain function and social and cognitive behavior in young adulthood.
| Mallard, Carina; Ek, C Joakim; Vexler, Zinaida S (2018) The myth of the immature barrier systems in the developing brain: role in perinatal brain injury. J Physiol 596:5655-5664 |
| Mallard, Carina; Tremblay, Marie-Eve; Vexler, Zinaida S (2018) Microglia and Neonatal Brain Injury. Neuroscience : |
| Salehi, Arjang; Jullienne, Amandine; Wendel, Kara M et al. (2018) A Novel Technique for Visualizing and Analyzing the Cerebral Vasculature in Rodents. Transl Stroke Res : |
