Role of Trkb in Anxiety Following Neonatal Hypoxic Ischemia

Nur Sena Cagatay, University of Wisconsin-Madison, WI, United States; TEMOUR SHEIKH, University of Wisconsin-Madison, United States; Ela Bicki, University of Wisconsin-Madison, United States; Onur Taparli, University of Wisconsin-Madison, United States; MARGARET B HACKETT, University of Wisconsin-Madison, United States; SEFER YAPICI, University of Wisconsin-Madison, United States; Nazli Deveci, University of Wisconsin-Madison, United States; BURAK OZAYDIN, University of Wisconsin-Madison, United States; PETER A FERRAZZANO, University of Wisconsin-Madison, United States; JON E. LEVINE, University of Wisconsin-Madison, United States; Pelin Cengiz, University of Wisconsin-Madison, United States

Background: Neonatal hypoxic ischemic (HI) encephalopathy may lead to anxiety, risk taking behavior, and memory deficits in children. We have previously shown that tyrosine kinase B (TrkB) mediated neuroprotection is estrogen receptor (ER) alpha dependent in the hippocampus and female biased following neonatal HI. The severity of injury to the limbic system which regulates emotion, behavior, long-term memory and olfaction may correlate closely with the outcomes of neonatal HI. Recently, we have identified a sex difference in risk taking behavior post HI and 7,8 DHF therapy in our long term behavioral studies. Our MRI data implicates areas of the limbic system as responsible for the observed behavioral outcomes.

Objectives: To determine the neurotherapeutic efficacy of 7,8 DHF in anxiety and risk taking behavior following HI in males and females. In addition, to identify the region of the limbic system that plays a role in the observed behavioral outcomes.

Design/Methods: HI was induced in postnatal (P) day 9 C57BL/6J mice using Vannucci’s HI model. Mice were treated with 7,8 DHF (5mg/kg, i.p.) or vehicle control starting at 10 min post-HI and daily for 7 days. At P60+, mice underwent elevated plus maze (EPM) testing for 15 minutes. Five min segments of EPM video recordings were analyzed using AnyMaze software. Percent (%) time spent in the open arm is reported as mean ± SEM. ANOVA was used to analyze the EPM data. MRI was performed under anesthesia following EPM testing using a 4.7-tesla small animal MRI. Various brain regions were segmented using ITK-SNAP. The % injury to the region of interest was calculated and correlated with each 5 min segment of the EPM test using linear regression.

Results: Sham mice gradually spent less time in the open arm (OA) in the 10-15 segment of the EPM test (p < 0.05). Female mice spent statistically significantly more time in the OA in the 10-15 min segment of the test which was recovered by 7,8-DHF therapy (p < 0.05) post-HI to sham level. Male mice demonstrated the complete opposite of female behavior post-HI and post-treatment. The % time spent in the OA positively correlated with the piriform cortex injury (R2: 0.7, p< 0.001).

Conclusion: HI induces risk taking behavior in female mice which recovers with TrkB agonist therapy. Different pathways may be involved in neural circuitry regulating the male and female anxiety/risk taking behavior. However, our results suggest that injury to the limbic system, specifically to the piriform/amygdalar area, may be regulating the anxiety/risk taking behavior following neonatal HI.