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Pericyte ablation causes hypoactivity and reactive gliosis in adult mice
Jake M Cashion1, Lachlan S Brown1, Gary P Morris1
1Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Insights
Loss of brain pericytes in adult mice impairs motor function and causes behavioral changes. This pericyte dysfunction leads to increased neuronal hypoxia, blood-brain barrier disruption, and glial reactivity, highlighting their critical role in brain health.
Area of Science:
- Neuroscience
- Vascular Biology
- Cell Biology
Background:
- Capillary pericytes regulate crucial brain functions including blood flow, blood-brain barrier (BBB) integrity, and neuroinflammation.
- Pericyte loss or dysfunction is a feature of many neurological diseases, but its direct impact is hard to isolate.
- Understanding the specific consequences of pericyte loss is vital for developing targeted therapies.
Purpose of the Study:
- To directly evaluate the effects of adult pericyte loss on mouse behavior and physiological brain responses.
- To establish a dose-dependent relationship between pericyte ablation levels and observed outcomes.
- To investigate the impact of pericyte loss on motor function, BBB integrity, neuronal hypoxia, and glial activation.
Main Methods:
- Utilized Pdgfrβ-CreERT2:: Rosa26-DTA transgenic mice for inducible and dose-dependent pericyte ablation via tamoxifen administration.
- Administered varying doses of tamoxifen (100mg/kg or 2x300mg/kg) to achieve differential pericyte loss (∼50% or >80%).
- Assessed behavioral changes using the open field test and beam walk task. Conducted histopathological analyses to evaluate BBB integrity, neuronal hypoxia, and glial reactivity (astrogliosis, microgliosis/macrophage infiltration).
Main Results:
- Dose-dependent pericyte ablation was confirmed, with >80% loss achieved at higher tamoxifen doses.
- Mice with significant pericyte loss exhibited impaired motor function, including reduced distance traveled, increased immobility, and more frequent slips on a beam walk.
- Histological analysis revealed increased vessel lumen width, mild BBB disruption, neuronal hypoxia, astrogliosis, and increased IBA1+ immunoreactivity in pericyte-ablated brains.
Conclusions:
- Adult pericyte loss directly compromises brain health and function.
- Pericyte deficiency leads to significant behavioral alterations and motor deficits in mice.
- These findings underscore the critical role of pericytes in maintaining brain homeostasis and suggest their dysfunction as a direct contributor to neurological impairment.
Abstract:
Capillary pericytes are important regulators of cerebral blood flow, blood-brain barrier integrity and neuroinflammation, but can become lost or dysfunctional in disease. The consequences of pericyte loss or dysfunction is extremely difficult to discern when it forms one component of a complex disease process. To evaluate this directly, we examined the effect of adult pericyte loss on mouse voluntary movement and motor function, and physiological responses such as hypoxia, blood-brain barrier (BBB) integrity and glial reactivity. Tamoxifen delivery to Pdgfrβ-CreERT2:: Rosa26-DTA transgenic mice was titrated to produce a dose-dependent ablation of pericytes in vivo. 100mg/kg of tamoxifen ablated approximately half of all brain pericytes, while two consecutive daily doses of 300mg/kg tamoxifen ablated >80% of brain pericytes. In the open field test, mice with ∼50% pericyte loss spent more time immobile and travelled half the distance of control mice. Mice with >80% pericyte ablation also slipped more frequently while performing the beam walk task. Our histopathological analyses of the brain revealed that blood vessel density was unchanged, but vessel lumen width was increased. Pericyte-ablated mice also exhibited: mild BBB disruption; increased neuronal hypoxia; astrogliosis and increased IBA1+ immunoreactivity, suggestive of microgliosis and/or macrophage infiltration. Our results highlight the importance of pericytes in the brain, as pericyte loss can directly compromise brain health and induce behavioural alterations in mice.
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