Mild repetitive head impacts alter perivascular flow in the midbrain dopaminergic system in awake rats

Xuezhu Cai; Ian C Harding; Aymen H Sadaka; Bradley Colarusso; Praveen Kulkarni; Eno Ebong; Ju Qiao; Nick R O'Hare; Craig F Ferris

doi:10.1093/braincomms/fcab265

Mild repetitive head impacts alter perivascular flow in the midbrain dopaminergic system in awake rats

Brain Commun. 2021 Nov 3;3(4):fcab265. doi: 10.1093/braincomms/fcab265. eCollection 2021.

Authors

Xuezhu Cai¹, Ian C Harding², Aymen H Sadaka¹, Bradley Colarusso¹, Praveen Kulkarni¹, Eno Ebong^{2

3

4}, Ju Qiao¹, Nick R O'Hare², Craig F Ferris^{1

5

6}

Affiliations

¹ Department of Psychology, Center for Translational NeuroImaging, Northeastern University, Boston, MA 02115, USA.
² Department of Bioengineering, Northeastern University, Boston, MA 02115, USA.
³ Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA.
⁴ Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
⁵ Department of Psychology, Northeastern University, Boston, MA 02115, USA.
⁶ Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.

Abstract

Head injury is a known risk factor for Parkinson's disease. Disruption in the perivascular clearance of metabolic waste and unwanted proteins is thought to be a contributing factor to disease progression. We hypothesized that repetitive mild head impacts, without evidence of structural brain damage, would increase microgliosis and AQP4 expression and depolarization and alter perivascular flow in the midbrain dopaminergic system. Adult male rats were subjected to sham, or two mild head impacts separated by 48 h. Three weeks later, fully awake rats were imaged using dynamic, contrast-enhanced MRI to follow the distribution of intraventricular gadobenate dimeglumine contrast agent. Images were registered to and analysed using a 3D MRI rat atlas providing site-specific data on 171 different brain areas. Following imaging, rats were tested for cognitive function using the Barnes maze assay. Histological analyses of tyrosine hydroxylase, microglia activation and AQP4 expression and polarization were performed on a parallel cohort of head impacted rats at 20 days post insult to coordinate with the time of imaging. There was no change in the global flux of contrast agent between sham and head impacted rats. The midbrain dopaminergic system showed a significant decrease in the influx of contrast agent as compared to sham controls together with a significant increase in microgliosis, AQP4 expression and depolarization. There were no deficits in cognitive function. The histology showed a significant level of neuroinflammation in the midbrain dopaminergic system 3 weeks post mild repetitive head impact but no loss in tyrosine hydroxylase. MRI revealed no structural brain damage emphasizing the potential serious consequences of mild head impacts on sustained brain neuroinflammation in this area critical to the pathophysiology of Parkinson's.

Keywords: end-feet; microglia; neuroinflammation; substantia nigra; ventral tegmental area.

Grants and funding

K01 HL125499/HL/NHLBI NIH HHS/United States