Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species

Abstract

Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.

Keywords: 5-HT; 5-hydroxytryptamine; Agamma-Aminobutyric acid; Brain development; CNS; Central nervous system; GAB; GCL; Gd; HI; HIE; Human; Hypoxia-ischemia; IL; Immature; MRI; N-methyl-D-aspartate; NMDA; OL; Rodent; SGZ; SVZ; TBI; Traumatic brain injury; gestation day; granule cell layer; hypoxia-ischemia/hypoxic-ischemic; hypoxic-ischemic encephalopathy; interleukin; magnetic resonance imaging; oligodendrocyte; pnd; postnatal day; pre-OL; pre-oligodendrocyte; subgranular zone; subventricular zone; traumatic brain injury.

Fig. 1

Temporal changes in postnatal brain development in rodents and humans, as assessed by magnetic resonance imaging. (a) Total mouse brain volumes on the left vertical axis (also expressed as % adult volume; right axis) measured between embryonic day 12 and pnd 60. Measurements were fitted to a sigmoidal model with a 95% confidence interval (long dash lines) and 95% prediction band (short dash lines). Reprinted from Chuang et al. (2011), with permission from Elsevier. (b) Total human brain volumes measured between 3 monthsand30yearsofage, in a total of 71 males (females follows a similar trajectory; data not shown). Black dots represent the observed data; the black line indicates the estimated median growth curve, and gray lines represent a set of 100 credible growth curves as determined by simulations. Reprinted from Groeschel et al. (2010), with permission from Elsevier. (c) Fractional anisotrophy (FA) in the corpus callosum of rats between pnd 0 and pnd 56 (n = 4–6/time point). bcc, gcc and scc represent the body, genu and splenium of the corpus callosum, respectively. From Bockhorst et al. (2008); reprinted with permission from Wiley Interscience. (d) FA in the corpus callosum of human patients aged 5–83 years (n = 403); males and females are indicated by blue and red dots, respectively. Note that FA typically peaks at ∼20-30 years of age (early adulthood), which is roughly comparable to ∼pnd 60 in rodents. From Lebel et al. (2012); reprinted with permission from Elsevier.

Fig. 2

The time course of key neurodevelopmental processes in humans, during gestation and up to 20 years of age (not to scale), with the associated changes in white and gray matter volumes over time. Adapted from Lenroot and Giedd (2006). Note that there may be considerable variability in developmental timing between different cortical and subcortical regions.

Fig. 3

BrdU/NeuN double-labeling to identify newly generated neurons in the granule cell layer of the mouse hippocampus. In the absence of injury (control), neurogenesis is several-fold higher in the younger (pnd 9) brains compared to at pnd 21. However, the response to hypoxia-ischemia (HI) is paradoxical-neurogenesis is decreased after injury at pnd 9, but increased in the pnd 21 injured brain. H: hypoxia only. Asterisks indicate statistical significance compared to age-matched controls. Modified from Qiu et al. (2007).

Fig. 4

Traumatic or hypoxic-ischemic injury to the early postnatal brain can impact many key neurodevelopmental processes which are undergoing maturation changes during this time, resulting in functional consequences including sensorimotor, psychosocial and cognitive deficits.