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

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.

Severe Perinatal Hypoxic-Ischemic Brain Injury Induces Long-Term Sensorimotor Deficits, Anxiety-Like Behaviors and Cognitive Impairment in a Sex-, Age- and Task-Selective Manner in C57BL/6 Mice but Can Be Modulated by Neonatal Handling

“…To the best of our knowledge, there are no reports regarding sex differences in the functional recovery following HI in neonatal handled animals. Nesting environment (Mason et al, 2018), rehabilitative training (Tsuji et al, 2010) or early-life interventions based on environmental rearing conditions (Pereira et al, 2007, 2008; Fan et al, 2011; Rojas et al, 2013, 2015; Nie et al, 2016; Schuch et al, 2016) that share mechanisms of action with NH (Fernández-Teruel et al, 2002), also show sex-specific neuroprotection patterns. In these works, the sex differences analyzed in the recovery of HI after environmental enrichment or rehabilitative training in rats, described partial recovery in working memory in adolescent rats (Pereira et al, 2008) and improved swimming time and length in females but not in males after rehabilitative training (Tsuji et al, 2010).…”

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

“…A total of 40 adolescent (purchased on postnatal day [PND] 32–34, 200–350 g) male Long Evans rats were ordered from Charles River Breeding Laboratories (Wilmington, MA, United States). A power analysis to determine the number of animals required to detect significant differences between groups, was calculated using G*Power software [ 69 ] and was based on past analyses performed in our laboratory [ 70 , 71 ]. Statistical significance was set to p ≤ 0.05, and β = 0.80.…”

Regional Differences in Brain Plasticity and Behaviour as a Function of Sex and Enrichment Type: Oxytocin Matters

“…Social interaction represents an integral component of EE and reveals pronounced sex differences (11,12). Females in general respond more prominently to social enrichment than males (3,4), with some exceptions (13). Neurohormonal disparities and procedural variables contribute to these sexual dimorphisms (14,15).…”