The following aims are developed as the logical next step based on published and unpublished findings from the parent grant (initiated by the late Dr. Traystman) to assess sex-specific signaling following pediatric (juvenile mice) cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Pediatric cardiac arrest is surprisingly common and remains poorly understood and understudied. We made significant progress on the major aims of the previous grant cycle and obtained important new preliminary data that form the foundation for the current aims. We take advantage of our novel juvenile mouse cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to assess functional outcomes and recovery following CA/CPR. Emerging evidence from our laboratory, and others, indicate that alterations in the surviving functional networks contribute to cognitive deficits. Synaptic plasticity, in the form of strengthening following physiological stimuli (long-term potentiation; LTP) is a well-established cellular model of learning and memory. Deficits in hippocampal LTP correlate with memory impairments in adult and juvenile mice and therefore, we focus on therapies that target reversing synaptic plasticity deficit to enhance functional recovery (neuro-restoration). We recently made the remarkable observation that juvenile mice exhibit endogenous neuro-restoration; recovery LTP and memory function 14-30 days after CA/CPR, which we do not observe in adults exposed to the same injury. Our data indicates that the impairments and endogenous recovery of synaptic plasticity and memory function in juvenile mice correlates with expression of brain derived neurotrophic factor (BDNF). Further, we show that stimulation of BDNF-TrkB signaling facilitates recovery of hippocampal function. The recovery in hippocampal function we observed in juveniles corresponds with hormonal maturation that occurs between PND28-56. Our preliminary data indicates that gonadectomy of juvenile male (CAST) and female (OVX) mice prevents recovery of LTP (and recovery of BDNF levels) following CA/CPR. Further, we observed that replacement of sex steroids (estrogen in females and testosterone in males) restores endogenous neuro- restoration in CAST/OVX juvenile mice. Importantly, we observe that estrogen stimulates BDNF expression in juvenile females but not males and that brain estrogen does not facilitate recovery of LTP in males. Therefore, our overarching hypothesis is that 1) increased steroid levels in the brain during puberty facilitate endogenous neuro-restoration following juvenile CA/CPR through activation of sex-specific signaling (Aim 2 male-specific androgen signaling and aim 3 female-specific estrogen receptor signaling) that converges on BDNF and other plasticity gene expression to enhance synaptic plasticity. The proposed research will contribute to our understanding of the mechanisms of functional impairments and recovery following cardiac arrest in the pediatric age group, an understudied population. In particular, this project extends our long-standing research focus regarding sex-specific signaling and the interaction between age, sex, sex steroids and outcomes following brain injury. Further, our studies will extend our focus on developing therapeutic strategies to restore synaptic function within surviving brain networks, rather than attempting to protect neurons from ischemic injury, which may impact treatments of patients of all ages.

Public Health Relevance

Cardiac arrest is an important cause of mortality and poor neurological outcome in children, with approximately 16,000 arrests occurring each year in the US. Unfortunately, there are currently no drugs available in the United States to improve outcome and quality of life following cardiac arrest in children. The proposed studies will characterize the response of childhood brain to cardiac arrest and demonstrate that puberty provides insights into enhanced recovery observed in children compared to adults.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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University of Colorado Denver
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Orfila, James E; McKinnon, Nicole; Moreno, Myriam et al. (2018) Cardiac Arrest Induces Ischemic Long-Term Potentiation of Hippocampal CA1 Neurons That Occludes Physiological Long-Term Potentiation. Neural Plast 2018:9275239
Orfila, James E; Grewal, Himmat; Dietz, Robert M et al. (2017) Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke. J Cereb Blood Flow Metab :271678X17750761
Quillinan, Nidia; Herson, Paco S; Traystman, Richard J (2016) Neuropathophysiology of Brain Injury. Anesthesiol Clin 34:453-64
Terry, Peter B; Traystman, Richard J (2016) The Clinical Significance of Collateral Ventilation. Ann Am Thorac Soc 13:2251-2257
Dietz, R M; Deng, G; Orfila, J E et al. (2016) Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in sex-dependent manner. Neuroscience 325:132-41
Deng, G; Yonchek, J C; Quillinan, N et al. (2014) A novel mouse model of pediatric cardiac arrest and cardiopulmonary resuscitation reveals age-dependent neuronal sensitivities to ischemic injury. J Neurosci Methods 222:34-41
Deng, Guiying; Carter, Jessica; Traystman, Richard J et al. (2014) Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation. J Neuroimmunol 274:132-40
Herson, Paco S; Traystman, Richard J (2014) Animal models of stroke: translational potential at present and in 2050. Future Neurol 9:541-551
Herson, Paco S; Bombardier, Chris G; Parker, Susan M et al. (2013) Experimental pediatric arterial ischemic stroke model reveals sex-specific estrogen signaling. Stroke 44:759-63
Planas, Anna M; Traystman, Richard J (2011) Advances in translational medicine 2010. Stroke 42:283-4

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