Translational Study of Blast mTBI Effects on Locus Ceruleus-Cerebellar Network Structure and Function

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Mild traumatic brain injuries (mTBIs or concussions) caused by blast overpressure from exploding ordnance are the “signature injuries” of the wars in Iraq and Afghanistan. Postconcussive symptoms are common and often persist for years after Veterans have returned from deployment(s); however, the neuropathobiology underlying these symptoms is poorly understood. Our published and preliminary studies demonstrate in a battlefield-relevant mouse model of blast mTBI, in living Veterans with repetitive blast mTBIs, and in postmortem brain tissue from Veterans and Servicemembers with blast mTBIs that the cerebellum is particularly vulnerable. The cerebellum is increasingly implicated in cognitive/behavioral changes characteristic of persistent postconcussive symptoms. Our preliminary studies suggest that these neuropathobiologic changes extend to the noradrenergic locus coeruleus (LC) and its projections to the cerebellar dentate nucleus (CDN) via the superior cerebellar peduncles (SCP). To understand the nature and implications of mTBI damage to the LC-cerebellar dentate nucleus network, the following conceptually integrated translational Specific Aims are proposed: Specific Aim 1.1. To determine whether LC and cerebellar changes on initial DTI scan predict longitudinal impairments in: a) cerebellar regional glucose uptake by FDG-PET, b) working memory, and c) cognitive set-shifting in Iraq/Afghanistan Veterans with repetitive blast mTBI. Specific Aim 1.2. To determine in postmortem brain tissue from repetitive mTBI Veteran/Servicemember and control cases whether mTBI is specifically associated with LC-cerebellar fiber injury and/or loss as compared to LC-cortical and/or LC-hippocampal fibers injury and/or loss. Specific Aim 2. To determine, in our mouse blast model, whether LC-cerebellar projections are specifically vulnerable to degeneration following repetitive blast mTBI. Cerebellum-projecting LC neurons will be labeled using a canine adenovirus (CAV) red fluorescent reporter in mice expressing green fluorescent protein in LC fibers. Single cell RNA sequencing will test whether dual-labeled LC neurons projecting to the cerebellum exhibit a specific neurodegenerative and cell stress phenotype following repetitive blast mTBI. Specific Aim 3.1. To determine in non-blast mice whether working memory and cognitive set shifting deficits are caused by nonspecific SCP WM injury or by specific injury to LC fibers projecting to the cerebellum. SCP WM injury will be induced by bilateral injection of 1% lysolecithin. LC fiber injury will be induced using bilateral viral transduction with CAV-Cre AAV-DO diphtheria toxin. Specific Aim 3.2. To determine in non-blast mice if loss of NA signaling by LC neurons projecting to the posterior cerebellum is sufficient to cause working memory and cognitive set shifting deficits similar to blast mTBI. A viral transgenic approach will be used to knock out TH expression bilaterally in LC neurons passing through the SCP.