Theranostics 2021; 11(16):7685-7699. doi:10.7150/thno.60190 This issue Cite

Research Paper

Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury

James R Mester1,2✉, Paolo Bazzigaluppi2,3, Adrienne Dorr2, Tina Beckett2,3, Matthew Burke5,6, JoAnne McLaurin3,7, John G Sled1,4, Bojana Stefanovic1,2

1. University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada.
2. Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
3. Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
4. Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
5. Neuropsychiatry Program, Department of Psychiatry and Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
6. Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
7. University of Toronto, Department of Laboratory Medicine and Pathology, Toronto, Ontario, Canada.

Citation:
Mester JR, Bazzigaluppi P, Dorr A, Beckett T, Burke M, McLaurin J, Sled JG, Stefanovic B. Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury. Theranostics 2021; 11(16):7685-7699. doi:10.7150/thno.60190. https://www.thno.org/v11p7685.htm
Other styles

File import instruction

Abstract

Graphic abstract

Rationale: Mild traumatic brain injury (mTBI), the most common type of brain trauma, frequently leads to chronic cognitive and neurobehavioral deficits. Intervening effectively is impeded by our poor understanding of its pathophysiological sequelae.

Methods: To elucidate the long-term neurovascular sequelae of mTBI, we combined optogenetics, two-photon fluorescence microscopy, and intracortical electrophysiological recordings in mice to selectively stimulate peri-contusional neurons weeks following repeated closed-head injury and probe individual vessel's function and local neuronal reactivity.

Results: Compared to sham-operated animals, mTBI mice showed doubled cortical venular speeds (115 ± 25%) and strongly elevated cortical venular reactivity (53 ± 17%). Concomitantly, the pericontusional neurons exhibited attenuated spontaneous activity (-57 ± 79%) and decreased reactivity (-47 ± 28%). Post-mortem immunofluorescence revealed signs of peri-contusional senescence and DNA damage, in the absence of neuronal loss or gliosis. Alteration of neuronal and vascular functioning was largely prevented by chronic, low dose, systemic administration of a GABA-A receptor inverse agonist (L-655,708), commencing 3 days following the third impact.

Conclusions: Our findings indicate that repeated mTBI leads to dramatic changes in the neurovascular unit function and that attenuation of tonic inhibition can prevent these alterations. The sustained disruption of the neurovascular function may underlie the concussed brain's long-term susceptibility to injury, and calls for development of better functional assays as well as of neurovascularly targeted interventions.

Keywords: Traumatic brain injury, Two-photon fluorescence microscopy, Optogenetics, Neurovascular coupling, L-655, 708


Citation styles

APA
Mester, J.R., Bazzigaluppi, P., Dorr, A., Beckett, T., Burke, M., McLaurin, J., Sled, J.G., Stefanovic, B. (2021). Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury. Theranostics, 11(16), 7685-7699. https://doi.org/10.7150/thno.60190.

ACS
Mester, J.R.; Bazzigaluppi, P.; Dorr, A.; Beckett, T.; Burke, M.; McLaurin, J.; Sled, J.G.; Stefanovic, B. Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury. Theranostics 2021, 11 (16), 7685-7699. DOI: 10.7150/thno.60190.

NLM
Mester JR, Bazzigaluppi P, Dorr A, Beckett T, Burke M, McLaurin J, Sled JG, Stefanovic B. Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury. Theranostics 2021; 11(16):7685-7699. doi:10.7150/thno.60190. https://www.thno.org/v11p7685.htm

CSE
Mester JR, Bazzigaluppi P, Dorr A, Beckett T, Burke M, McLaurin J, Sled JG, Stefanovic B. 2021. Attenuation of tonic inhibition prevents chronic neurovascular impairments in a Thy1-ChR2 mouse model of repeated, mild traumatic brain injury. Theranostics. 11(16):7685-7699.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image