Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain's mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces surrounding pial arteries, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the cisterna magna using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows that are consistent in all respects with the flows observed in earlier experiments with single-syringe injection.
All data generated or analyzed for this study are included in the manuscript. Source data files have been provided for Figures 4a, 4d, 4e, and 5i.The particle-tracking Matlab code used in this study is available in the public domain GitLab repository found here: https://gitlab-public.circ.rochester.edu/araghuna/bulk-flow-is-not-an-artifact_raghunandan_et_al_2021.git
- Maiken Nedergaard
- John H Thomas
- Douglas H Kelley
- Antonio Ladron-de-Guevara
- Humberto Mestre
- Maiken Nedergaard
- John H Thomas
- Douglas H Kelley
- Jeffrey Tithof
The funding agencies did not influence study design, data collection, and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments were approved and conducted in accordance with the relevant guidelines and regulations stipulated by theUniversity Committee on Animal Resources of the University of Rochester Medical Center (Protocol No. 2011-023), certiﬁedby Association for Assessment and Accreditation of Laboratory Animal Care.
- Claire Wyart, Institut du Cerveau et la Moelle épinière, Hôpital Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, France
© 2021, Raghunandan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson’s disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.
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