Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

Perinatal nutritional iron deficiency impairs noradrenergic-mediated synaptic efficacy in the CA1 area of rat hippocampus.

Many studies have shown that perinatal nutritional iron deficiency (ID) produces learning impairments in children. Research has also shown that catecholamines like epinephrine and norepinephrine play a pivotal role in the consolidation of memories. In this study, we sought to determine if perinatal ID impairs the following: 1) noradrenergic synaptic function in the hippocampus; and 2) several forms of hippocampus-dependent fear learning. Electrophysiological brain slice methods were used to examine noradrenergic-mediated synaptic efficacy in the CA1-hippocampus of rats that were subjected to perinatal ID or control (CN) diets. Rats were fed ID (3 mg Fe/kg) or CN (45 mg Fe/kg) diets on gestational d 14. These diets were maintained until postnatal d (P) 12 after which all rats were switched to the CN diet. Hippocampal slices were prepared between P26 and P30. The noradrenergic agonist isoproterenol (ISO) (1, 2, or 4 micromol) was used to induce modulatory increases in synaptic efficacy in the hippocampal slices. CN slices showed a long-lasting increase in synaptic efficacy as the result of ISO perfusion in the slice bath, whereas ID slices did not show increases in synaptic efficacy as the result of ISO perfusion. ID and CN groups did not differ when ISO was perfused through slices from adult rats (P61). Both young and adult ID rats showed reduced levels of hippocampus-dependent fear learning compared with the young and adult CN rats. Together, these findings suggest that ID may impair early forms of noradrenergic-mediated synaptic plasticity, which may in turn play a role in adult learning deficits.