Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species
Introduction
Rodent models of ischemic and traumatic brain injury are frequently used in research laboratories, both to investigate the underlying mechanisms of injury vulnerability and evaluate potential therapeutic approaches. Perinatal hypoxic-ischemic encephalopathy (HI or HIE) accounts for 25% of developmental disabilities in children, occurring in 1% of all full-term births (Shevell et al., 2000). Perinatal asphyxia-induced brain injury is one of the most common causes of morbidity and mortality in term and preterm neonates, accounting for 23% of neonatal deaths globally (Lawn et al., 2005). Neonatal stroke, a cerebrovascular event which occurs between 28 weeks gestation and one postnatal month of age, may be either hemorrhagic or HI in origin and has been associated with consequences including cerebral palsy and behavioral abnormalities (Lee et al., 2005, Lynch, 2009). Traumatic brain injury (TBI) is a leading cause of long-term neurocognitive and psychosocial deficits in infants and young children worldwide (Mazzola and Adelson, 2002, Selassie et al., 2008), with an estimated 475,000 cases of TBI in 0–14 year old children each year in the US (Langlois et al., 2005). Rates are highest in children under 4 years of age, and TBI sustained during early childhood typically results in poorer outcomes and longer recovery times compared to children who sustain injury in later childhood or adolescence (Catroppa et al., 2008, Duval et al., 2008). Regardless of the injury type or mechanism, traumatic and ischemic injuries share many common pathological mechanisms (Kochanek, 1993), and it is increasingly evident that the developing brain responds differently to injury compared to the adult brain (Babikian et al., 2010, Blomgren et al., 2007, Claus et al., 2010, Giza et al., 2007, Hu et al., 2000, Potts et al., 2006, Qiu et al., 2007, Zhu et al., 2009, Zhu et al., 2005). It is thus crucial that we gain a better understanding of the unique properties intrinsic to the developing brain and its response to insult (Giza et al., 2009). The number of paradigms to model the injured immature brain is growing, using different animals of varying ages (Balduini et al., 2000, Bittigau et al., 2003, Claus et al., 2010, Ikonomidou and Kaindl, 2011, Tai et al., 2009, Zhu et al., 2005). Yet questions of comparability across species continue to create controversy. Which ages in rodents best correspond to the premature, newborn at term, infant, child and adolescent human? Which aspects of brain development are most essential to equate to humans when using an animal model? Keeping in mind that no given model is likely to fully mimic the human disease or condition, we suggest that it is most important to accurately define and correlate general mechanisms of injury and neuroprotection, which are often dependent on the maturation stage of the nervous system (Hagberg et al., 2002a).
Here, we will review key events that accompany brain development in both rodents and humans to identify temporal ‘benchmarks’ where there is heightened vulnerability to injury during infancy, childhood and adolescence. Developmental changes in neuroanatomy, cell proliferation, synaptogenesis and myelination will be discussed, as well as differential immune responses seen at different ages. Lastly, the emergence of age-dependent behaviors in rodents and humans will be considered in relation to ongoing developmentally regulated molecular and anatomical changes. The impact of TBI or HIE at different developmental processes will be highlighted throughout, to emphasize the complex interplay between injury mechanisms superimposed upon maturation-related changes in brain structure and function.
Section snippets
Gross neuroanatomy
The first major event of central nervous system (CNS) development in all vertebrates is the formation of a specialized fold of ectodermal tissue called the neural tube, from which the spinal cord and brain subsequently differentiate. Neural tube formation occurs approximately mid-gestation in rodents, on gestational day (gd) 10.5–11 and 9–9.5 in rats and mice, respectively, with birth typically occurring on gd 20–21. In humans, this event occurs earlier during prenatal development, between gd
Cell proliferation
The generative capacity of the immature brain varies by brain region and cell type. In general, cell proliferative processes between rodents and humans are remarkably parallel, although the time scales are substantially different (Bayer et al., 1993). The neonatal mammalian brain contains a temporary ‘subplate zone,’ a layer of glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurons between the immature cerebral cortex and white matter regions, which acts as a source of new neurons
Synaptogenesis and neurotransmission
Synaptogenesis refers to the biochemical and morphological changes which enable the formation of synapses between neurons. Across mammalian species, neurons present at birth undergo a period of overproduction of their arborization and synaptic contacts to increase synaptic density, followed by an elimination or pruning phase of refinement. This activity-dependent pruning of excess synapses is hypothesized to contribute to plasticity and be a mechanism by which the cortical circuitry is refined,
Myelination
The formation of myelin sheaths, generated by interfascicular oligodendrocytes in the CNS, is essential for the propagation and speed of neurotransmission in the mammalian brain. It is now generally accepted that myelination is a prolonged process which continues well into childhood and adolescence in specific brain regions (Fig. 2). An increased understanding of oligodendrocyte maturation stages in the normally developing human and rodent brain over the past decade has also highlighted the
Innate and adaptive immunity
The immune system can have a profound effect on brain development, function and behavior, including modulation of brain activities such as temperature, sleep patterns and feeding behaviors (Steinman, 2004). On a global level, it has been suggested that the worldwide distribution of cognitive ability is determined in part by variation in the intensity of infectious diseases (Eppig et al., 2010). Of particular relevance to the developing brain, it has recently been demonstrated that microglia
Blood-brain barrier development
Historically, barrier mechanisms in the neonatal brain were commonly considered to be immature and leaky. It is now known that the blood-brain barrier is established and functional during embryogenesis in both rodents and humans, and is tightly regulated by pericyte-endothelial cell interactions (Daneman et al., 2010, Saunders et al., 2012). The blood-brain barrier and choroid plexus of the developing mammalian brain contain some features which are not seen later during adulthood, such as a
Age-dependent behavioral phenotypes
The species comparisons presented here thus far have been based on anatomical, molecular and biochemical changes across brain development. Equally important are age-dependent behaviors which can be assessed when modeling human brain injury in rodents. Although it is unrealistic to explicitly link biological processes of CNS development with the behavioral capacities they control, certain behaviors can in fact be temporally correlated with the maturation of specific neuronal regions or
Future research
While there is a strong foundation for the use of age-specific rodent models to study injury to the developing human brain, there remain areas of research that require further elucidation. With the exception of neuroanatomical changes measured by MRI, there is a notable paucity of detailed mouse studies in many aspects of brain maturation and developmental behaviors, particularly in terms of neuronal proliferation and synaptogenesis. Findings in rats are commonly presumed to apply equally
Concluding remarks
The pronounced differences between rodents and humans should be considered when comparing the maturational age of the CNS during normal and disrupted development. However, there is also considerable cross-species alignment in terms of key developmental milestones, behavioral phenotypes and regional vulnerability to brain injury. It is now generally accepted that the maturation state of the brain, and in particular, specific processes of synaptogenesis and myelination, rather than chronological
Acknowledgements
Support was provided by NIH/NINDS RO1 NS050159 and NS077767, a Sir Keith Murdoch Fellowship from the American Australian Association, and the Neurobehavioral Core for Rehabilitation Research at the University of California San Francisco. The authors report no conflicts of interest.
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