Abstract
Inflammation is associated with most brain diseases and is thought to contribute to disease pathology.
Unregulated inflammation can contribute to secondary brain damage and neurodegeneration following traumatic
brain injury (TBI). While the majority of TBI research has focused on the role of central inflammation in TBI
pathophysiology, the contribution of peripheral inflammation is under investigated. A detrimental role for
peripheral inflammation was first demonstrated by Helen Bramlett and colleagues, who reported that
intraperitoneal administration of pro-inflammatory cytokines to TBI animals can result in poor outcome. Previous
studies have shown that vagus nerve stimulation can reduce both peripheral inflammation and mortality following
bacterial lipopolysaccharide (LPS) injection, a widely used model to study inflammation, sepsis and organ failure.
Subsequent studies have shown that release of acetylcholine from vagus efferents stimulates a7 nicotinic
acetylcholine receptors (a7nAChR) on inflammatory cells, leading to reduced release of pro-inflammatory
cytokines into the circulation. As acetylcholine is rapidly degraded after release, and a7nAChR undergo rapid
desensitization, additional mechanisms may be involved in regulating peripheral inflammation. We examined
the vagus efferents and their cell bodies located in the dorsal motor nucleus of vagus (DMN) for the expression
of neuropeptides, which are often co-released with neurotransmitters and have a relatively longer half-lives. We
have found that cocaine- and amphetamine-regulated transcript (CART) peptide (CARTp) is expressed at high
levels in DMN neurons. We propose to test the hypothesis that that CARTp acts to regulate peripheral
inflammation and can be used to improve TBI outcome. We will first test this hypothesis by examining the role
of vagus CARTp in TBI-associated inflammation using neutralizing CARTp antibodies and administration of
exogenous CARTp targeted to the spleen. Using CRISPR-Cas, we will delete the Cartpt gene in the DMN, and
will measure the levels of circulating pro-inflammatory cytokines following TBI. We will then test the therapeutic
potential of CARTp as a treatment for TBI by examining its effect on inflammation, blood brain barrier (BBB)
permeability, and inflammatory cell infiltration into the injured brain. Finally, we will examine if post-TBI CARTp
administration can reduce neuronal loss and improve cognitive outcome. Sex as a biological variable will be
assessed. The results from these studies will have implications not only for TBI, as well as for the numerous
other diseases in which inflammation is a contributor.