Abstract
Mild to moderate traumatic brain injury (mTBI) leads to secondary neuronal loss via excitotoxic mechanisms, including mitochondrial Ca2+ overload. However, in the surviving cellular population, mitochondrial Ca2+ influx, and oxidative metabolism are diminished leading to suboptimal neuronal circuit activity and poor prognosis. Hence we tested the impact of boosting neuronal electrical activity and oxidative metabolism by facilitating mitochondrial Ca2+ uptake in a rat model of mTBI. In developing rats (P25-P26) sustaining an mTBI, we demonstrate post-traumatic changes in cerebral blood flow (CBF) in the sensorimotor cortex in response to whisker stimulation compared to sham using functional Laser Doppler Imaging (fLDI) at adulthood (P67-P73). Compared to sham, whisker stimulation-evoked positive CBF responses decreased while negative CBF responses increased in the mTBI animals. The spatiotemporal CBF changes representing underlying neuronal activity suggested profound changes to neurovascular activity after mTBI. Behavioral assessment of the same cohort of animals prior to fLDI showed that mTBI resulted in persistent contralateral sensorimotor behavioral deficit along with ipsilateral neuronal loss compared to sham. Treating mTBI rats with Kaempferol, a dietary flavonol compound that enhanced mitochondrial Ca2+ uptake, eliminated the inter-hemispheric asymmetry in the whisker stimulation-induced positive CBF responses and the ipsilateral negative CBF responses otherwise observed in the untreated and vehicle-treated mTBI animals in adulthood. Kaempferol also improved somatosensory behavioral measures compared to untreated and vehicle treated mTBI animals without augmenting post-injury neuronal loss. The results indicate that reduced mitochondrial Ca2+ uptake in the surviving populations affect post-traumatic neural activation leading to persistent behavioral deficits. Improvement in sensorimotor behavior and spatiotemporal neurovascular activity following kaempferol treatment suggests that facilitation of mitochondrial Ca2+ uptake in the early window after injury may sustain optimal neural activity and metabolism and contribute to improved function of the surviving cellular populations after mTBI.
Highlights
Preclinical systems level studies of TBI during development can be approached using neuroimaging combined with behavioral assessment from the same subjects as currently done in younger TBI patients
As brain activity related to behavioral tasks such as cognition, sleep, sensory processing, and motor responses result from spatially segregated neuronal assemblies (Harris, 2005), spatiotemporal mapping of stimulus-induced hemodynamic representatives of neural activity are significant for systems-level evaluation of neural plasticity (Logothetis et al, 2001)
The results indicate that facilitation of mitochondrial Ca2+ influx, known to boost ongoing neuronal electrical activity, and metabolism, may be a primary mechanism sustaining normal neural circuit functions in the surviving neuronal population leading to improved outcomes after moderate traumatic brain injury (mTBI)
Summary
Preclinical systems level studies of TBI during development can be approached using neuroimaging combined with behavioral assessment from the same subjects as currently done in younger TBI patients. Functional Laser Doppler Imaging (fLDI) is a preclinical neuroimaging method enabling high spatial resolution (100 μm) mapping of stimulus inducedneural activity represented by changes in microvascular CBF (Kannurpatti and Biswal, 2004, 2006). Accurate spatiotemporal mapping of neural events is limited by the sensitivity to microvascular signals compared to the contribution from large vessels This ability to selectively discriminate signal change from arterioles and capillary compartments (closest in range to neural activity) is defined as functional resolution (Truong and Song, 2009). Neural activity change in response to whisker stimulation between sham and mTBI animals was evaluated by assessing the spatiotemporal change in microvascular CBF in the somatosensory barrel field (S1BF), a region well characterized by electrophysiological and optical mapping studies of neuroplasticity (Welker, 1976; Diamond et al, 1993; Dowling et al, 1996; Kannurpatti and Biswal, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
