Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia

Aaron Bradford; Miranda Hernandez; Elaine Kearney; Luke Theriault; Yow-Pin Lim; Barbara S Stonestreet; Steven W Threlkeld

doi:10.3390/brainsci10120999

Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia

Brain Sci. 2020 Dec 17;10(12):999. doi: 10.3390/brainsci10120999.

Authors

Aaron Bradford¹, Miranda Hernandez¹, Elaine Kearney¹, Luke Theriault¹, Yow-Pin Lim^{2

3}, Barbara S Stonestreet⁴, Steven W Threlkeld¹

Affiliations

¹ Neuroscience Program, School of Health Sciences, Regis College, 235 Wellesley Street, Weston, MA 02493, USA.
² ProThera Biologics, Inc., 349 Eddy Street, Providence, RI 02903, USA.
³ Department of Pathology and Laboratory Medicine, The Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI 02903, USA.
⁴ Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA.

Abstract

Hypoxic-Ischemic (HI) brain injury in the neonate contributes to life-long cognitive impairment. Early diagnosis and therapeutic interventions are critical but limited. We previously reported in a rat model of HI two interventional approaches that improve cognitive and sensory function: administration of Inter-alpha Inhibitor Proteins (IAIPs) and early experience in an eight-arm radial water maze (RWM) task. Here, we expanded these studies to examine the combined effects of IAIPs and multiple weeks of RWM assessment beginning with juvenile or adolescent rats to evaluate optimal age windows for behavioral interventions. Subjects were divided into treatment groups; HI with vehicle, sham surgery with vehicle, and HI with IAIPs, and received either juvenile (P31 initiation) or adolescent (P52 initiation) RWM testing, followed by adult retesting. Error rates on the RWM decreased across weeks for all conditions. Whereas, HI injury impaired global performance as compared to shams. IAIP-treated HI subjects tested as juveniles made fewer errors as compared to their untreated HI counterparts. The juvenile group made significantly fewer errors on moderate demand trials and showed improved retention as compared to the adolescent group during the first week of adult retesting. Together, results support and extend our previous findings that combining behavioral and anti-inflammatory interventions in the presence of HI improves subsequent learning performance. Results further indicate sensitive periods for behavioral interventions to improve cognitive outcomes. Specifically, early life cognitive experience can improve long-term learning performance even in the presence of HI injury. Results from this study provide insight into typical brain development and the impact of developmentally targeted therapeutics and task-specific experience on subsequent cognitive processing.

Keywords: Inter-alpha Inhibitor Proteins; early behavioral intervention; eight-arm water maze; encephalopathy; hypoxia-ischemia; immune modulator; inflammation; working memory.

Grants and funding

R15 HD077544/HD/NICHD NIH HHS/United States