Harnessing the Cholinergic Inflammatory Reflex to Alter Neuroinflammation and Neuropsychiatric Consequences Following Traumatic Brain Injury

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Worldwide, traumatic brain injury (TBI) contributes to more death and disability than other trauma-related injuries. Recent statistics indicate that 69 million people are affected by this “silent epidemic,” with 4.6 million affected persons residing in the United States and Canada. Military personnel are especially vulnerable to TBI, considered a signature injury of recent wars. These closed-head, shockwave-induced blast TBIs (bTBI), caused by proximity to explosive devices, lead to neuropsychiatric impairment that significantly affects the quality of life after injury. Neuroinflammation is linked to neuropsychiatric illness in the general population and thus, may mediate these impairments. There is a critical need for effective anti-inflammatory treatments for blast TBI, an area of active investigation. Extensive research shows that select neuromodulatory and pharmacotherapy tools can be used to activate the cholinergic inflammatory reflex to modulate neuroinflammation, but it is unknown whether either approach can be used after bTBI. The current application will address these gaps in knowledge by determining the utility of vagus nerve stimulation, a neuromodulation tool, and anatabine, a full-cholinergic agonist, using a rodent model of bTBI. Vagus nerve stimulation (VNS), an FDA-approved neuromodulation treatment for select neuropsychiatric disorders, is currently being explored for various inflammatory conditions and neurorehabilitation. Anatabine is similarly being examined for neurorehabilitation, but neither treatment has been used for blast-related, closed-head injuries. The current study aims to address this knowledge gap by completing the following short-term goals in a pre-clinical (mouse) model of bTBI: 1) understand whether the cholinergic pathway can be targeted to alter the inflammatory response to bTBI, and 2) understand whether targeting this pathway can reduce neuropsychiatric deficits that substantially affect the quality of life after injury. These goals will be achieved by completing three specific aims: 1) Characterize the neuroinflammatory response to bTBI as it relates to the neuropsychiatric consequences of injury, 2) Determine the effectiveness of VNS to alter the immune response to improve neuropsychiatric consequences of bTBI, and 3) Determine the effectiveness of a cholinergic agonist to alter the immune response to improve neuropsychiatric consequences of bTBI. Our preliminary data and recent VISN1CDA support our hypotheses and the feasibility of carrying out the proposed research. The current project is designed to extend our proof-of-principle work to clearly define the utility of these novel treatments. If successful, this promising neuromodulation treatment could advance the standard of care for military personnel and improve the quality of life for Veterans and their families. The current Career Development Award-2 will be performed at the White River Junction VA Medical Center and incorporates existing infrastructure and equipment, including a blast tube apparatus, unique equipment that recapitulates battlefield injuries. The candidate has scientific experience with pre-clinical models evaluating dysfunction in the autonomic nervous system and immune system. She has over ten years of research experience, including animal models of disease and neurotrauma, microsurgery, neuromodulation, immunohistochemistry, histology, and microscopy. Dr. Noller has assembled a mentoring team consisting of leading VA scientists and physicians with extensive experience mentoring early career investigators towards independence. The scientific team also includes local experts for consultation on specific aspects of the work. The immediate research activities will support Dr. Noller’s long-term career goal of becoming a translational VA scientist. Specifically, the CDA-2 will provide protected time while she receives mentored training in neuroinflammation, neuroanatomy, quantitative neuropathology, and neurobehavioral assessment of rodents. Collectively completing the research activities and mentored and specialized training will establish her expertise in the field and culminate in full research independence as a VA Research Scientist.