Abstract
Hypoxic-ischemic (HI) encephalopathy is a devastating injury that occurs when the fetal brain is deprived of oxygen and blood to a degree that may lead to neurological damage, seizing and cerebral palsy. In rodents, early environmental enrichment that promotes maternal care-taking behavior (mCTB) can improve neurobehavioral outcomes and protect against neurological decline. We hypothesized that an enhanced nesting environment would improve mCTB as measured by pup weight gain, and support greater HI recovery in developing rats. Pregnant dams (E15-16) were introduced to either control Standard Facility (SF) housing or closed nestbox (CN) conditions and maintained in larger cages through pup weaning. On postnatal day (PND) 7, male and female Long-Evans rat pups (N = 73) were randomly sorted into one of two surgical conditions: control and HI. HI pups received isoflurane anesthesia and right carotid artery ligation, a 2-h rest followed by 90 min exposure to a moist hypoxic (92% N, 8% O2) chamber. Pups (PND 8) were weighed daily, and tested on the Morris Water Maze (MWM) task (PND 35-50). Results demonstrate significant differences afforded to male and female pups based on weight measure, where CN-rearing modifies pre-weaning adolescent weights in females and increases post-weaning weights in males and females by an average of 10 g. Following successful MWM training and acquisition (PND 35-37), both male and female CN-raised animals demonstrated faster latency to find the hidden platform (HP) during HP trials (PND 38-42) and appeared to freely explore the MWM pool during an additional probe trial (PND 43). Moreover, after sacrifice (PND 60), CN rearing created sex-specific alterations in brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) immunopositive cell staining of the dorsomedial striatum and CA1 of the hippocampus. CN-rearing afforded HI males higher BDNF levels in the striatum and produced greater GDNF levels in the hippocampus of HI-injured females. These results suggest that early life environmental enrichment positively modifies nesting environment, increases weight gain, as well as spatial learning and memory in a sex-specific directionality. Our findings also implicate correlative changes in corticolimbic neurotrophin protein levels in the CN-reared animals that may contribute to these benefits.
Highlights
Neonatal Hypoxic-ischemic encephalopathy (HIE) is a serious neurological injury resulting from oxygen and glucose deprivation during birth
In closed nestbox (CN) animals, all animals had both right and left hippocampi, each displayed a disparity between right and left hippocampi, with the right measuring smaller than the left
For females exposed to hypoxic ischemic (HI), those reared in CN demonstrated cognitive abilities similar to those of non-injured females, in contrast to HI females reared in Standard Facility (SF) housing that demonstrated significant functional impairment and diminished weight gain
Summary
Neonatal Hypoxic-ischemic encephalopathy (HIE) is a serious neurological injury resulting from oxygen and glucose deprivation during birth. Using the Rice-Vannucci method (Vannucci et al, 1999), the most prevalent rodent model of neonatal HIE, the injury is modeled in rats at postnatal day (PND) 7 by ligation of the right common carotid artery followed by oxygen deprivation. This model simulates both morphometric and functional sequalae of term neonatal hypoxic ischemic (HI) injury, including spatial and working memory deficits (Smith et al, 1991; Balduini et al, 2000; de Paula et al, 2009). As a result of HI, early cell death occurs in the neocortex, and a second wave of cell death occurs from 12 h to 24 h after oxygen deprivation, targeting subcortical structures including the hippocampus, striatum and thalamus (Azzarelli et al, 1996; Northington et al, 2007)
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