Neonatal hypoxia-ischemia (H/I) remains a major health issue with limited therapeutic approaches. The life long consequences to both infant and caregivers demands we increase our knowledge regarding the origins, consequences and prevention of brain damage around the time of birth. Clinical evidence increasingly points to the cerebellum as a region that is profoundly but more diffusely impacted by neonatal H/I and this damage reverberates as additional damage ensues to the regions with which it shares reciprocal connections. Yet the cerebellum has been largely ignored in preclinical models of neonatal H/I. This proposal models H/I in the term human infant, a time of heightened sensitivity for the cerebellum. Insults that occur during narrow sensitive periods can have enduring effects by derailing dynamic developmental processes that can never be reset. Often neonatal H/I is compounded by earlier, and perhaps undetected, neuroinflammation. Thus we propose to conduct an in-depth first-of-its-kind analysis of the developing cerebellum after neonatal H/I with and without prior inflammation. We attack the question with three Specific Aims. SA1: Develop an animal model of term H/I with and without prior inflammation that has construct validity for clinical evidence of cerebellar damage in newborns. SA2: Integrate neuroanatomical, metabolic, signal transduction and behavioral endpoints relevant to cerebellar damage in this animal model. SA3: Test the neuroprotective effects of agents that inhibit neuroinflammation, restore metabolism and/or prevent dysregulated signal transduction and thereby create a preclinical foundation for translation in the immediate future.
These aims will be achieved via four independent projects and synergy assured by provision of animals, histology and behavioral testing from the Animal and Behavioral Core (Core B). Each project is headed by an expert PI. Project I (McCarthy) - microglia as the brain's innate immune system and their role in normal cerebellar development and impact on damage, Project II (McKenna) - metabolism and its response to and role in damage, and Project III (Bearer) - lipid rafts as essential signaling elements disrupted by H/I and inflammation. Project IV (Waddell), an R03 pilot project, explores the novel use of eye blink conditioning, a well known cerebellar controlled learning paradigm, to assess the cognitive impact of neonatal H/I. Microglia both respond to and produce inflammation which can, if not arrested, become a run away and enduring pathological response. Metabolism and energy use is an important determinant of damage following H/I, with high energy areas at greater risk, including the cerebellum. Use of MALDI-MSI imaging will provide detailed high resolution relevant to lipids, neurotransmitters, oxidative stress and metabolism. Lipid rafts are critical components of neural development yet they have been largely unexplored in the context of H/I. All experiments include equal numbers of males and females. Together these projects will highlight new therapeutic targets that can be easily implemented in current clinical practice.
The proposed studies jointly focus on the integration of inflammation and hypoxia-ischemia to exacerbate brain damage in neonates in the understudied cerebellum. This brain region is fundamental to motor as well as cognitive, communicative and emotional behaviors and developmentally yoked with the prefrontal cortex, compounding and expanding injury foci. Complementary multidisciplinary approaches will quantify the mode and magnitude of injury and identify mechanisms to provide nodal points for prevention, intervention and regeneration. Careful attention to the impact of being either male or female throughout all proposed studies will assure findings are broadly applicable. The team will also jointly explore clinically feasible neuroprotective therapeutics, such as hypothermia, that could be used to minimize the neurologic impairment, poor motor function and cognitive deficits caused by acute brain injury in neonates.
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| Ferreira, Gustavo C; McKenna, Mary C (2017) L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res 42:1661-1675 |
| Shah, Shetal; Wong, Shale; Bearer, Cynthia et al. (2017) Environmental health reform in a synthetic world. Pediatr Res 82:373-375 |
