Cellular responses of neurons and oligodendrocytes to mechanical injury

Jennifer Alexandra Creed

doi:10.17918/00000636

Traumatic brain injury (TBI) results in dynamic pressure gradients which cause high rate deformation of the underlying brain parenchyma (mechanical injury) and incite a series of subsequent extracellular signaling phenomena that activate intracellular cascades, generating a complex disease that has been challenging to treat. The neurochemical sequelae are complicated by the diversity of cell types found within the brain, including neurons and oligodendrocytes, which may demonstrate discrete temporal responses to brain trauma as well as react differentially to varying levels of insult. Moreover, specific cellular compartments, including the cell body and cellular extensions (dendrite, axon, myelin sheath), may show selective vulnerability following TBI. In this thesis, I address the responses of neurons and oligodendrocytes following traumatic brain injury in vivo or dynamic stretch in vitro. We show that in both the mammalian brain and in dissociated mammalian cultures, mechanical trauma causes structural cellular abnormalities, aberrant enzymatic activity and ultimately cell death in a temporal- and severity-dependent manner. Following trauma, neuronal dendrites become fragmented while axons are marked by dysfunction as demonstrated by impaired transport and reduced compound action potential amplitude. Similarly, oligodendrocytes show disrupted myelin processes after mechanical insult. Both neurons and oligodendrocytes undergo cell death following mechanical insult, which is accompanied by post-injury elevations in protease activation, namely mediated by calpains and caspase-3, as well as activation of the c-Jun N-terminal Kinase (JNK) signaling pathway. Administration of antagonists targeting the ionotropic glutamate receptors, N-Methyl-D-Aspartate receptor (NMDAR) and [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), reduce protease activation and subsequent cell demise following mechanical insult in vitro but are not protective after TBI. JNK inhibitors reduced kinase activation but do not improve trauma-induced axonal injury. Collectively, these data suggest a role for glutamate receptor-mediated enzyme activation and subsequent neuronal and oligodendrocyte damage following mechanical injury in vivo and in vitro . Importantly, results from this thesis underline the complex nature of traumatic brain injury and open the door to addressing in-depth mechanistic questions concerning cellular and molecular responses to mechanical insult.

Cellular responses of neurons and oligodendrocytes to mechanical injury

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Cellular responses of neurons and oligodendrocytes to mechanical injury

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