A neonatal piglet model for investigating brain and cognitive development in small for gestational age human infants

• Published in: PloS one Vol. 9; no. 3; p. e91951
• Main Authors: Radlowski, Emily C, Conrad, Matthew S, Lezmi, Stephane, Dilger, Ryan N, Sutton, Brad, Larsen, Ryan, Johnson, Rodney W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.03.2014; Public Library of Science (PLoS)
• Subjects: Abnormalities; Age; Animal cognition; Animal sciences; Animals; Animals, Newborn; Anisotropy; Archives & records; Attention deficit hyperactivity disorder; Biology and Life Sciences; Birth weight; Body Weight; Brain; Brain - anatomy & histology; Brain - growth & development; Brain - physiology; Brain research; Cages; Child Development; Cognition - physiology; Cognitive ability; Cognitive development; Corpus callosum; Diffusion Tensor Imaging; Disease; Fetuses; Gestational age; Hogs; Humans; Infant, Newborn; Infant, Small for Gestational Age - growth & development; Infants; Investigations; Magnetic resonance; Magnetic resonance imaging; Magnetic Resonance Spectroscopy; Maze Learning; Medical imaging; Medicine and Health Sciences; Memory; Metabolism; Metabolites; Milk; Models, Animal; Morphometry; Neonates; Neural networks; Neuroimaging; Neurosciences; Newborn babies; NMR; Nuclear magnetic resonance; Organ Size; Pediatrics; Research and Analysis Methods; Small for gestational age; Spatial discrimination learning; Spatial memory; Spectroscopy; Studies; Substantia alba; Substantia grisea; Swine; Trends; United States > US; Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091951

The piglet was investigated as a potential model for studying brain and cognitive deficits associated with being born small for gestational age (SGA). Naturally farrowed SGA (0.7-1.0 kg BW) and average for gestational age (AGA, 1.3-1.6 kg BW) piglets were obtained on postnatal day (PD) 2, placed in individual cages, and provided a nutritionally adequate milk replacer diet (285 ml/kg/d). Beginning at PD14, performance in a spatial T-maze task was assessed. At PD28, piglets were anesthetized for magnetic resonance (MR) imaging to assess brain structure (voxel-based morphometry), connectivity (diffusion-tensor imaging) and metabolites in the hippocampus and corpus callosum (proton MR spectroscopy). Piglets born SGA showed compensatory growth such that BW of SGA and AGA piglets was similar (P>0.05), by PD15. Birth weight affected maze performance, with SGA piglets taking longer to reach criterion than AGA piglets (p<0.01). Total brain volume of SGA and AGA piglets was similar (P<0.05), but overall, SGA piglets had less gray matter than AGA piglets (p<0.01) and tended to have a smaller internal capsule (p = 0.07). Group comparisons between SGA and AGA piglets defined 9 areas (≥ 20 clusters) where SGA piglets had less white matter (p<0.01); 2 areas where SGA piglets had more white matter (p<0.01); and 3 areas where SGA piglets had more gray matter (p<0.01). The impact of being born SGA on white matter was supported by a lower (p<0.04) fractional anisotropy value for SGA piglets, suggesting reduced white matter development and connectivity. None of the metabolites measured were different between groups. Collectively, the results show that SGA piglets have spatial learning deficits and abnormal development of white matter. As learning deficits and abnormalities in white matter are common in SGA human infants, the piglet is a tractable translational model that can be used to investigate SGA-associated cognitive deficits and potential interventions.