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Front. Behav. Neurosci. | doi: 10.3389/fnbeh.2018.00221

Nesting Environment Provides Sex-Specific Neuroprotection in a Rat Model of Neonatal Hypoxic-Ischemic Injury

 Briana Mason1, 2,  L.G. Rollins2, 3,  Evans Asumadu1, 2, Christina Cange1, 2,  Najah Walton1, 2 and  S T. Donaldson1, 2*
  • 1Developmental and Brain Sciences, Department of Psychology, University of Massachusetts Boston, United States
  • 2Clinical Psychology Program, University of Massachusetts Boston, United States
  • 3Warren Alpert Medical School, Brown University, United States

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 (PND35-50). 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 (PND35-37), both male and female CN-raised animals demonstrated faster latency to find the hidden platform during hidden platform trials (PND 38-42) and appeared to freely explore the MWM pool during an additional probe trial (PND43). Moreover, after sacrifice (PND60), 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.

Keywords: Rice-Vanucci P7 HI model, Long Evans rats, environmental enrichment, Morris water maze, Neurogenesis, Neonatal Hypoxic Ischemic Injury, Hippocampus

Received: 23 May 2018; Accepted: 03 Sep 2018.

Edited by:

Walter Adriani, Istituto Superiore di Sanità (ISS), Italy

Reviewed by:

Giovanni Laviola, Istituto Superiore di Sanità (ISS), Italy
Sung-Rae Cho, Yonsei University, South Korea  

Copyright: © 2018 Mason, Rollins, Asumadu, Cange, Walton and Donaldson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. S T. Donaldson, PH.D.., University of Massachusetts Boston, Developmental and Brain Sciences, Department of Psychology, 100 Morrissey Boulevard, Boston, 02125, Massachusetts, United States,