407 - Therapeutic Hypothermia Demonstrates Sex-Dependent Improvement in Sensorimotor and Temporospatial Organization in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy

Poster Number: 407
Publication Number: 407.236

Angela Saadat, Eastern Virginia Medical School, Norfolk, VA, United States; Ashley Blackwell, Eastern Virginia Medical School, Norfolk, VA, United States; Haree Pallera, Eastern Virginia Medical School, Virginia Beach, VA, United States; Tushar A. Shah, Eastern Virginia Medical School, Norfolk, VA, United States

Background: Neonatal hypoxic ischemic encephalopathy (HIE) leads to lifelong cognitive and motor deficits, which are characteristically heterogeneous and more pronounced in males. Therapeutic hypothermia (TH) is the standard of care treatment in neonatal HIE and has demonstrated sexually dimorphic effects on neuroprotection.

Objective: To measure the effects of TH on functional deficits in neonatal HIE with particular attention to gender differences, utilizing a combination of established and novel neurobehavioral assays.

Design/Methods: Using the Vannucci model of neonatal HIE, term-equivalent male and female rat pups (P12) were randomized to Sham (Control), NT (Normothermia, HIE) and TH (31°C for 6h). Behavioral tests were conducted in adolescence to early adulthood (weeks 6-12) to assess cognitive abilities (dark and light open field, novel object recognition (NOR) and food protection tests) and sensorimotor abilities (rotarod, string-pull, food handling and beam walking tests). In addition to the traditional NOR, beam-walk and rotarod tests, we employed string pulling (tests sensorimotor integration where rats make rhythmic head, body, bilateral forearm and skilled hand movements to reel in a string), food protection (tests convergence in spatial and temporal processing, attentional and motivational deficits after food restriction) and open field test (tests locomotion motivated by exploration in dark and lit environments, anxiety)

Results: NT rats showed deficits in recognition memory (less time associating with the novel object in the NOR test, p=0.0347), learning (higher number of failures during habituation in the string pulling test, p=0.0478), temporospatial organization (increased number of food items stolen in the food protection test, p< 0.0001), fine motor ability (increased time needed to complete string pulling, p=0.018, and decreased food handling behavior, p=0.0223) and gross motor ability (increased latency to fall in the rotarod test, p=0.0047) compared to sham animals. TH-treated rats performed significantly better than NT rats, to levels comparable to shams, in learning (p=0.048), fine motor ability (p=0.007) and body mass (p=0.025). Improvement in temporospatial organization in the food protection test was detected only in female TH-treated rats (p=0.003) and gross motor improvement in the rotarod test was detected only in TH treated males (p=0.023)Conclusion(s): TH provides partial functional neuroprotection in neonatal HIE with notable gender differences. This expanded battery of neurobehavioral assays may help unravel subtle functional deficits after brain injury.