Mild traumatic brain injury (mTBI) affects hundreds of millions of young people world-wide each year.
Epidemiological studies link repetitive mTBI to dementia and neurodegenerative disease later in life, however
causative mechanisms remain undefined. Disruption of circadian rhythms is a prominent manifestation of the
post-concussive syndrome and has been associated with Alzheimer’s-like neurodegeneration but the
mechanisms linking mTBI, neurodegeneration, and circadian rhythms is unknown, highlighting a key unmet need
in mTBI and an unexplored therapeutic opportunity. We previously reported that IL-1 receptor-1 signaling is
required for post-injury cognitive deficits in mTBI models, implicating inflammatory pathways as key pathogenic
mechanisms. We hypothesized that there would be direct molecular connections between the circadian clock
and neuroimmune signaling through the IL-1 receptor pathway. Our preliminary data show that repetitive mTBI
induces phosphorylation of the key circadian clock protein BMAL1 in wild type but not IL-1R1-deficient mouse
brain. Our ongoing work has identified a critical function for BMAL1 phosphorylation in the organization of
presynaptic function and long-term memory. Our results lead to our hypothesis that repetitive mTBI induces
synaptic dysfunction and cognitive deficits via IL-1R1-mediated hyperphosphorylation of BMAL1. In Aim 1, we
will define how ILR1-mediated pBMAL1 signaling in response to mTBI corrupts the timing of synaptic function
and impairs synaptic plasticity. In Aim 2, we will use combinatorial and complementary transgenic approaches
including mouse models uniquely available to our groups, to define the cell types responsible for IL-1R-mediated
signaling that culminate in cognitive dysfunction after mTBI. Finally, Aim 3 will define a novel signaling pathway
by which IL-1-mediated hyperphosphorylation of pBMAL1 after mTBI results in dysfunctional regulation of key
synaptic and neuronal kinases such as CaMKIIA with subsequent promulgation of tau-related aggregation and
impaired synaptic plasticity. Successful completion of the Aims is expected to provide a cellular and molecular
basis for repetitive mTBI-induced cognitive dysfunction and identify new therapeutic targets to alleviate sequelae
of concussions and other forms of repetitive mTBI.