Abstracts

Traumatic brain injury (TBI) is increasingly recognized as a source of long-term neurological dysfunction in military and civilian populations. In patients with moderate to severe TBI, many experience somatosensory deficits and network hyper-activity that can even lead to prevalent forms of toxic neural excitability, including seizures and spreading depolarizations (SD), both of which are indicative of worse clinical outcomes. We recently found that swelling in neurons at 48-hours post-TBI, a period of maximal edema, is associated with reduced cellular and network excitability. Moreover, cell excitability is increased when we eliminate edema with bumetanide or mannitol, suggesting a causative link between neuronal edema and excitability. We observe no neuronal edema 1-week after TBI; leading us to hypothesize that without the protective effects of edema, like those we observed 48-hours after TBI, network excitability will be enhanced at 1-week post-TBI. In fact, clinical studies from TBI patients show enhanced SD vulnerability and prolonged lesion progression at this delayed excitability window.

Therefore, we assessed cortical synaptic and network activity at 1-week post-controlled cortical impact (CCI) TBI, as well as their underlying mechanisms, using two-photon microscopy with fluorescent indicators of calcium and glutamate, in layer 2/3 barrel cortex of awake female mice.

Our results show increases in the percentage of neurons firing in response to sensory stimulations in female CCI animals, in contrast to sham animals. In addition, we find less adaptation to frequency-dependent evoked responses in CCI mice in contrast to the expected adaptation we see in sham animals. Interestingly, when we induce SD, a known event linked to worse clinical outcomes after TBI, SD-associated calcium transients have a significantly larger amplitude and a greater area under the curve in CCI animals compared to sham animals, further suggesting a network under strain, and these calcium increases can lead to long-term effects on synaptic function and plasticity. This enhanced network excitability may be a result of heightened excitatory neurotransmission, enhanced thalamocortical input, or reduced inhibitory input in cortical neurons. When we examine glutamate transients as a proxy to excitatory signaling, we observe no changes in cortical activity in female mice after CCI.

Together, our data reveal enhanced cortical sensory processing in females after TBI, when edema-associated protection is minimal. Mechanistically, glutamate may not be a key mediator influencing the changes in female cortical processing. Future experiments will reveal whether the intracortical crosstalk and/or thalamocortical inputs underlie excitability changes within sensory circuitry after TBI in females.