This application seeks to better understand the pathophysiology of mild traumatic brain injury (mTBI) in a well- characterized and well-controlled mouse model, incorporating multiple transgenic, structural, optogenetic and electrophysiological approaches. While our previously funded efforts focused on mTBI-induced diffuse axonal injury (DAI) occurring within Lamina V neurons, together with the generalized excitation of the non DAI injured axons, the current application turns its attention to multiple forms of cortical circuit disruption, in which the interneurons play a major role. The premise of this application is that the parvalbumin (PV) and somatostatin (SS) expressing interneurons, which are major regulators of cortical inhibitory/excitatory balance, undergo DAI, creating synaptic and network dysfunction. A specific effect of interneuron DAI to be investigated is PV deafferentation of intact pyramidal neurons? perisomatic and axonal initial segments (AIS), which may contribute to network hyperexcitability. These structural and functional studies will be accomplished by multiple transgenic approaches relying upon the use of YFP-H mice in concert with interneuron-specific cre mice crossed with either RFP reporter mice or mice with floxed Channelrhodopsin. Confocal and EM analyses will be used to detect the potential for DAI within the RFP-labeled PV and SS interneuronal populations, while electrophysiological recordings will determine whether these same neurons have altered intrinsic or synaptic input properties. The synaptic terminal distribution from these interneurons onto specific postsynaptic partners will be assessed to determine whether deafferentation in the perisomatic, AIS and pyramidal dendritic domains occurs. Correlate optogenetic electrophysiological studies will be used to assess whether the output from the SS and PV interneurons is functionally altered, while additional electrophysiological measures, including focal GABA uncaging will determine if the AIS and GABAergic receptors at the AIS are affected by the mTBI. All measures will be examined over a time course from 1 to 60 days after injury to determine not only initial dysfunction, but also the potential for recovery over time. We believe that these studies will help to completely reshape our understanding of mTBI, emphasizing the concept of neocortical circuit disruption and highlighting the involvement of cortical interneurons. These findings should move the field away from its current emphasis on mTBI-induced white matter change as the sole contributor to mTBI associated morbidity.
The proposed studies are highly relevant to public health in that they address a national healthcare problem focusing on mild traumatic brain injury, which is an issue receiving increased emphasis in the United States due to its prevalence and unexpected morbidity in both our military and civilian populations. Further benefit will follow from the conduct of the proposed studies in that they will provide unprecedented insight into the issue of neocortical circuit disruption following mild traumatic brain injury and its overall implications for brain circuit dysfunction and potential reorganization and repair.
|Sun, Jianli; Jacobs, Kimberle M (2016) Knockout of Cyclophilin-D Provides Partial Amelioration of Intrinsic and Synaptic Properties Altered by Mild Traumatic Brain Injury. Front Syst Neurosci 10:63|
|Hånell, Anders; Greer, John E; McGinn, Melissa J et al. (2015) Traumatic brain injury-induced axonal phenotypes react differently to treatment. Acta Neuropathol 129:317-32|
|Hånell, Anders; Greer, John E; Jacobs, Kimberle M (2015) Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury. J Neurotrauma 32:1590-8|
|Miyauchi, Takashi; Wei, Enoch P; Povlishock, John T (2014) Evidence for the therapeutic efficacy of either mild hypothermia or oxygen radical scavengers after repetitive mild traumatic brain injury. J Neurotrauma 31:773-81|
|Greer, John E; Hanell, Anders; McGinn, Melissa J et al. (2013) Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment. Acta Neuropathol 126:59-74|
|Miyauchi, Takashi; Wei, Enoch P; Povlishock, John T (2013) Therapeutic targeting of the axonal and microvascular change associated with repetitive mild traumatic brain injury. J Neurotrauma 30:1664-71|
|Greer, John E; Povlishock, John T; Jacobs, Kimberle M (2012) Electrophysiological abnormalities in both axotomized and nonaxotomized pyramidal neurons following mild traumatic brain injury. J Neurosci 32:6682-7|