Functional correlates of central white matter maturation in perinatal period in rabbits

Abstract

Anisotropy indices derived from diffusion tensor imaging (DTI) are being increasingly used as biomarkers of central WM structural maturation, myelination and even functional development. Our hypothesis was that the rate of functional changes in central WM tracts directly reflects rate of changes in structural development as determined by DTI indexes. We examined structural and functional development of four major central WM tracts with different maturational trajectories, including internal capsule (IC), corpus callosum (CC), fimbria hippocampi (FH) and anterior commissure (AC). Rabbits were chosen due to perinatal brain development being similar to humans, and four time points were studied: P1, P11, P18 and adults. Imaging parameters of structural maturation included fractional anisotropy (FA), mean and directional diffusivities derived from DTI, and T2 relaxation time. Axonal composition and degree of myelination were confirmed on electron microscopy. To assess functional maturation, conduction velocity was measured in myelinated and non-myelinated fibers by electrophysiological recordings of compound action potential in perfused brain slices. Diffusion indices and T2 relaxation time in rabbits followed a sigmoid curve during development similar to that for humans, with active changes even at premyelination stage. The shape of the developmental curve was different between the fiber tracts, with later onset but steeper rapid phase of development in IC and FH than in CC. The structural development was not directly related to myelination or to functional development. Functional properties in projection (IC) and limbic tracts (FH) matured earlier than in associative and commissural tracts (CC and AC). The rapid phase of changes in diffusion anisotropy and T2 relaxation time coincided with development of functional responses and myelination in IC and FH between the second and third week of postnatal development in rabbits. In these two tracts, MRI indices could serve as surrogate markers of the early stage of myelination. However, the discordance between developmental change of diffusion indices, myelination and functional properties in CC and AC cautions against equating DTI indices changes as biomarkers for myelination in all tracts.

Rabbit neurospheres as a novel in vitro tool for studying neurodevelopmental effects induced by intrauterine growth restriction

“…Yet commercially available hNPCs are derived from healthy individuals, and hNPCs from IUGR individuals are such an extremely scarce material that they are unviable to establish a permanent research model for mechanistic investigations. Therefore, and considering that the rabbit in vivo model previously developed in BCNatal mimics the neurodevelopmental features of human IUGR individuals better than other rat in vivo models, and that rabbits are perinatal brain developers 50 similar to humans and unlike rodents, 51 we decided to establish a rabbit neurosphere culture for the first time. The combination of a 3D in vitro neurodevelopmental testing strategy, with the clinically relevant IUGR experimental animal model allowed us to study IUGR neurodevelopmental consequences by decomposing them into basic neurodevelopmental processes, which are evaluated separately.…”

Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain

“…The rabbit has frequently been used to study the effect of perinatal insults, including prematurity 19 , intraventricular hemorrhage 70,71 , hypoxia 69 , and infection 16 , on neurodevelopment. Despite being relatively immature at birth, rabbits show a large repertoire of spontaneous behaviors (motor activities and reflex responses) that are well characterized [72][73][74][75] and can be reproducibly tested. Furthermore, rabbits have a placental structure (hemodichorial, i.e.…”

Concurrent decrease of brain white matter tracts' thicknesses and fractional anisotropy after antenatal hypoxia‐ischemia detected with tract‐based spatial statistics analysis

“…While providing a method to statistically assess group differences in WM tracts' diffusion properties, such as FA and directional diffusivities, the traditional TBSS approach lacks the ability to compare another important metric of WM tracts, such as tract volume or cross‐section area. Changes to cross‐section areas of WM tracts are important indicators of normal maturation, axonal loss or neurodegeneration after brain injury, or compensatory increase . Importantly, changes in diffusion properties, presumably indicating microstructural injury, may be temporally discordant with volumetric changes.…”