Behavioral and histological outcomes following neonatal HI injury in a preterm (P3) and term (P7) rodent model

Abstract

Hypoxia-ischemia (HI) occurs when blood and/or oxygen delivery to the brain is compromised. HI injuries can occur in infants born prematurely (<37 weeks gestational age) or at very low birth weight (<1500 grams), as well as in term infants with birth complications. In both preterm and term HI populations, brain injury is associated with subsequent behavioral deficits. Neonatal HI injury can be modeled in rodents (e.g., the Rice-Vannucci method, via cautery of right carotid followed by hypoxia). When this injury is induced early in life (between postnatal day (P)1–5), neuropathologies typical of human preterm HI are modeled. When injury is induced later (P7–12), neuropathologies typical of those seen in HI term infants are modeled. The current study sought to characterize the similarities/differences between outcomes following early (P3) and late (P7) HI injury in rats. Male rats with HI injury on P3 or P7, as well as sham controls, were tested on a variety of behavioral tasks in both juvenile and adult periods. Results showed that P7 HI rats displayed deficits on motor learning, rapid auditory processing (RAP), and other learning/memory tasks, as well as a reduction in volume in various neuroanatomical structures. P3 HI animals showed only transient deficits on RAP tasks in the juvenile period (but not in adulthood), yet robust deficits on a visual attention task in adulthood. P3 HI animals did not show any significant reductions in brain volume that we could detect. These data suggest that: 1) behavioral deficits following neonatal HI are task-specific depending on timing of injury; 2) P3 HI rats showed transient deficits on RAP tasks; 3) the more pervasive behavioral deficits seen following P7 HI injury were associated with substantial global tissue loss; and 4) persistent deficits in attention in P3 HI subjects might be linked to neural connectivity disturbances rather than a global loss of brain volume, given that no such pathology was found. These combined findings can be applied to our understanding of differing long-term outcomes following neonatal HI injury in premature versus term infants.

Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats

“…Moreover, overall significant adult deficits were seen (Group A) on SG 0-100 and SG 0-10 (HI subjects again significantly impaired compared to shams; Figure 2a and b). This finding is consistent with prior evidence that behavioral HI deficits persist into adulthood [39, 41-43, 45], suggesting a lack of recovery of function in P7 HI animals. This is supported by correlations that reveal a significant correlation for performance on long duration silent gaps in the juvenile and long duration silent gaps in adulthood, in HI animals (p=.05).…”

“…Anatomic results were consistent with prior reports from our lab, which showed that the hippocampus, cortex and ventricles of HI animals were all significantly compromised compared to sham animals [29, 41-43, 45]. Photomicrographs depict the severity of the HI injury in this study, but also indicate substantial variability (Figure 8).…”

“…All subjects (n=48) were tested on juvenile auditory processing (silent gap (SG) 0-100 ms and SG 0-10 ms) to replicate previous findings [29, 39, 44, 45]. Following testing, animals were randomly split into two Groups (A, B; n=12 sham/HI each).…”

Models of hypoxia and ischemia-induced seizures

“…For models of neonatal HIE, pups of P7 to P10 are used as this age is thought to correspond with a human near 32-36 weeks of gestation. Damage in rats resulting from the HI has been found to be a function of age of treatment and over the first one to two weeks of postnatal life there is an increase in tissue vulnerability to hypoxic-ischemic insults (Alexander et al, 2014;Grafe, 1994;Towfighi et al, 1997;Yager and Thornhill, 1997). Mice have also been used and this has opened the paradigm up for potential use with the wide array of genetic models available in that species (Ditelberg et al, 1996;Ferriero et al, 1996).…”

Sexual dimorphism and brain lateralization impact behavioral and histological outcomes following hypoxia–ischemia in P3 and P7 rats

“…HIP7 causes delays 55 in reflex maturation, motor coordination deficits (Lubics 56 et al, 2005), and also anxiety-related and cognitive 57 impairments in early and late development (Ikeda et al,58 2001; Pereira et al, 2007;Hill et al, 2010;Arteni et al, 59 2010; Sanches et al, 2012). Anatomical and growing impairments (Tai et al, 2009), spatial and 76 aversive memory impairments (Huang et al, 2009;77 Sanches et al, 2013a,b;Alexander et al, 2013), as well 78 as sensorimotor deficits after HIP3 injury (Fan et al,79 2005; Cengiz et al, 2011;Alexander et al, 2014). 80 Recent findings of our research group showed effects 81 of hemispheric brain lateralization on biochemical, 82 histological and behavioral impairments using HIP7 and 83 HIP3 injury models (Arteni et al, 2010;Sanches et al, 84 2013a,b), and such effects showed to also depend on 85 the age of animals at injury.…”