Sex differences in behavioral outcome following neonatal hypoxia ischemia: Insights from a clinical meta-analysis and a rodent model of induced hypoxic ischemic brain injury Amanda L. Smith a, ⁎, Michelle Alexander a , Ted S. Rosenkrantz b , Mona Lisa Sadek a , R. Holly Fitch a a Department of Psychology, Behavioral Neuroscience Division, University of Connecticut, Storrs, CT 06269, USA b Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030, USA abstract article info Article history: Received 26 September 2013 Revised 1 January 2014 Accepted 2 January 2014 Available online 13 January 2014 Keywords: Hypoxia ischemia Sex differences Prematurity Memory Rapid auditory processing Visual attention Rodent model Hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) is one of the most common injuries among preterm infants and term infants with birth complications. Both populations show cognitive/behavioral deficits, including impairments in sensory, learning/memory, and attention domains. Clinical data suggests a sex difference in HI outcomes, with males exhibiting more severe cognitive/behavioral deficits relative to matched females. Our laboratory has also reported more severe behavioral deficits among male rats with induced HI relative to females with comparable injury (Hill et al., 2011a,b). The current study initially examined published clinical studies from the past 20 years where long-term IQ outcome scores for matched groups of male and fe- male premature infants were reported separately (IQ being the most common outcome measure). A meta- analysis revealed a female “advantage,” as indicated by significantly better scores on performance and full scale IQ (but not verbal IQ) for premature females. We then utilized a rodent model of neonatal HI injury to assess sham and postnatal day 7 (P7) HI male and female rats on a battery of behavioral tasks. Results showed expected deficits in HI male rats, but also showed task-dependent sex differences, with HI males having significantly larger deficits than HI females on some tasks but equivalent deficits on other tasks. In contrast to behavioral results, post mortem neuropathology associated with HI was comparable across sex. These findings suggest: 1) neonatal fe- male “protection” in some behavioral domains, as indexed by superior outcome following early injury relative to males; and 2) female protection may entail sex-specific plasticity or compensation, rather than a reduc- tion in gross neuropathology. Further exploration of the mechanisms underlying this sex effect could aid in neuroprotection efforts for at-risk neonates in general, and males in particular. Moreover, our current re- port of comparable anatomical damage coupled with differences in cognitive outcomes (by sex) provides a framework for future studies to examine neural mechanisms underlying sex differences in cognition and behavior in general. © 2014 Published by Elsevier Inc. Introduction Approximately 12–14% of US births are premature (b 37 weeks ges- tational age (GA)) or very low birth-weight (VLBW, b 1500 g; Kochanek et al., 2012). Within this infant population, hypoxia-ischemia (HI; de- creased blood and/or oxygen to the brain) is a major cause of brain dam- age and associated adverse outcomes (Barrett et al., 2007; Fatemi et al., 2009). The fragility/immaturity of the premature neurovascular system can lead to HI, for example blood pressure fluctuations that rupture cap- illaries and cause intraventricular (IVH) or periventricular (PVH) hem- orrhage (du Plessis and Volpe 2002; Volpe, 2001). These bleeds typically occur in the subependymal germinal matrix, with necrosis and prolonged apoptosis of ventricular zone cells (e.g., glial precursors; du Plessis and Volpe 2002; Volpe, 2001). Reperfusion failure (i.e., capillary collapse) is another common preterm injury, with resulting ischemia often leading to periventricular leukomalacia (PVL; white matter tissue loss around the ventricles; Back et al., 2012; Perlman, 1998). Preterm HI can also follow chronic lung dysfunction (Barrett et al., 2007; Krageloh- Mann et al., 1999; Peterson, 2003). Though less common, HI can also occur in term infants (2–4/1000 full-term births (.2–.4%)), with hypoxic/anoxic injury caused by labor complications, cord compression, placental abnormalities, or prolonged labor (Barrett et al., 2007; Fatemi et al., 2009; Vannucci and Hagberg, 2004; Vannucci and Vannucci, 2005). Neural injury following term HI typically includes diffuse tissue loss (particularly in gray matter; Fatemi et al., 2009; McLean and Ferriero, 2004), as well as altered Experimental Neurology 254 (2014) 54–67 ⁎ Corresponding author at: Dept. of Psychology, Behavioral Neuroscience, University of Connecticut, 406 Babbidge Rd. Unit 1020, Storrs, CT 06269, USA. E-mail address: amanda.l.smith@uconn.edu (A.L. Smith). 0014-4886/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.expneurol.2014.01.003 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr