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Research ArticleNeuroscience
Open Access | 
10.1172/jci.insight.172286
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Liu, H. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
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1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
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1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Liu, C. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
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1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
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1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Ouyang, Y. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Rutledge, C. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Anderson, J. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Wei, Z. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Zhang, Z. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Lu, H. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by van Zijl, P. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Iliff, J. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
Find articles by Xu, J. in: JCI | PubMed | Google Scholar
1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2F.M. Kirby Research Center, Kennedy Krieger Research Institute, Baltimore, USA.
3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
5Veterans Integrated Service Network (VISN) 20 Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, Washington, USA.
6Department of Psychiatry and Behavioral Sciences and
7Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
8Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Wenzhen Duan, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. Phone: 410.502.2866; Email: wduan2@jhmi.edu. Or to: Jiadi Xu, Kennedy Krieger Institute, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, Maryland 21205, USA. Phone: 443.923.9572; Email: xuj@kennedykrieger.org.
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Published September 3, 2024 - More info
Published in Volume 9, Issue 20 on October 22, 2024
AbstractThe accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington’s disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure d-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice before phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further verified with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.
Graphical Abstract
Introduction
Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in exon 1 of the Huntingtin (HTT) gene, which leads to the production of a toxic mutant huntingtin protein (mHTT) (1). A fundamental pathological hallmark of HD is abnormal mHTT accumulation in the brain, where the misfolded and aggregated disease-causative protein propagates and spreads in a prion-like fashion (2).
The principle of brain homeostasis asserts that the elimination of proteins must be in equilibrium with their synthesis, utilization, metabolism, and localized degradation. Interstitial solutes, including proteins, can be cleared across the blood-brain barrier and undergo local cellular uptake and degradation. When not subject to these cellular processes, it was generally believed that they were cleared through exchange with the surrounding cerebrospinal fluid (CSF) in a process that was considered slow and diffuse. Beginning in 2012, the glymphatic (glial-lymphatic) model of fluid and solute exchange was described (3), in which CSF and interstitial fluid (ISF) and solute exchange were observed to be rapid, anatomically organized along perivascular spaces surrounding the cerebral vasculature, and regulated by the sleep-wake cycle (4). More recently, meningeal lymphatic vessels associated with dural sinuses have been characterized that contribute to the clearance of solutes, including those arising from the brain interstitium and from the CSF compartment (5–7). The combined activity of perivascular glymphatic exchange and meningeal lymphatic clearance appears to function together to subserve brain interstitial solute and waste clearance. Importantly, key features of these processes, including perivascular CSF-ISF solute exchange, sleep-active brain solute clearance, and parasagittal solute uptake, have been confirmed in the human brain (8).
The glymphatic system is composed of meningeal lymphatic vessels that drain CSF and ISF toward cervical lymph nodes (4). The function of the glymphatic system is supported by the aquaporin-4 (AQP4) water channel, which presents with high density in perivascular astrocytic endfoot membranes (4). Glymphatic function is a highly regulated process, with changes in its activity accompanying aging as well as disease conditions (9–11). The efficiency of glymphatic clearance is lowered when AQP4 perivascular localization is reduced (12, 13). There is a growing awareness that such reduced AQP4 perivascular localization occurs in neurological disorders (14–17), which in turn is associated with the expression of a protein complex including α-syntrophin (SNTA1) (18, 19).
Evidence has begun to emerge that failure of the glymphatic system leads to an increase of local mHTT concentrations to levels that favor aggregation. One recent study suggested that a dysfunctional glymphatic system may contribute to HD manifestation and interrupt antisense oligonucleotide (ASO) distribution throughout the entire brain (20). Another study reports that secretion of mHTT from cells in the brain, followed by glymphatic clearance from the extracellular space, contributes to mHTT in the CSF (21). Whether the glymphatic system is disturbed in the HD brain, particularly in the premanifest stage, remains unclear.
In this study, we combined an in vivo measure of CSF clearance capacity by dynamic glucose-enhanced (DGE) MRI (22) with fluorescence-based imaging of glymphatic CSF tracer influx in a widely used zQ175-knockin HD mouse model. We observed that CSF clearance efficiency and glymphatic function were impaired in the zQ175 HD mice, before the manifestation of motor deficits and MRI detection of striatal atrophy. The impairment of CSF clearance worsened along with HD progression. Further mechanistic study indicated that AQP4 perivascular localization, a key contributor to glymphatic function, was significantly reduced in both HD mice and HD human brains. These findings set the premise to further investigate the role of glymphatic function in HD pathogenesis as a potential therapeutic target as well as an early biomarker for this devastating disease.
ResultsCSF clearance capacity measured by DGE MRI is Aqp4 dependent and reflects glymphatic CSF-ISF exchange capacity in mice. We recently developed a DGE MRI (22–25) approach that can sensitively assess d-glucose signal changes in the mouse CSF (26). Because glucose transporters are highly enriched in the brain capillary endothelial cells and choroid plexus epithelial cells (27, 28), d-glucose can rapidly penetrate the blood CSF barrier (BCSFB) and enter CSF. This unique feature provides an opportunity to measure CSF clearance efficiency by monitoring d-glucose levels in CSF following intravenous delivery. Because AQP4 (protein) is essential for functional glymphatic transport (29) and significantly compromised glymphatic function has been reported in Aqp4-KO mice (30), we first evaluated CSF clearance efficiency in an Aqp4-KO mouse model.
The absence of Aqp4 expression in the Aqp4-KO mice was verified (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.172286DS1); we then conducted DGE MRI scans in both 4-month-old Aqp4-KO mice and wild-type (WT) mice. Following d-glucose injection via the tail vein, DGE signal in the CSF rapidly reached a peak in both mouse genotypes. In WT mice, d-glucose signal decayed gradually following the peak, indicating gradual d-glucose clearance from CSF, while DGE signal in the CSF of Aqp4-KO mice was sustained or even slightly elevated during the MRI scan session (40 minutes) (Supplemental Figure 1, B and C). The uptake of d-glucose in CSF was comparable (P > 0.05) in the 2 groups (Supplemental Figure 1D), while d-glucose clearance was significantly lower (P < 0.05) in Aqp4-KO mice than WT mice (Supplemental Figure 1E). Here we used a γ-variate model with 3 unknowns (Smax, μin, and μout) to fit the uptake and get an initial rate estimate (μout) for the clearance by fitting only the first 20 minutes after infusion. This method from our previous studies (26) is summarized in the Supplemental Methods. Taken together, these results suggest that loss of the Aqp4 gene, which suppresses perivascular glymphatic exchange, slows CSF d-glucose clearance in mice. Thus, CSF d-glucose clearance capacity is AQP4 dependent.
In subsequent experiments (detailed below), we evaluated whether altered CSF clearance efficiency paralleled changes in the influx of fluorescent CSF tracers into the brain tissue of HD mice, a validated approach for assessing glymphatic function in rodents. Importantly, similar results were observed. Combined, these results strongly support the notion that CSF d-glucose clearance efficiency reflects glymphatic CSF-ISF exchange capacity.
Impaired glymphatic function is evident in zQ175 HD mice before phenotypic onset from measures of (i) CSF clearance efficiency by DGE MRI and (ii) influx of a fluorescence CSF tracer from cisterna magna to brain parenchyma. The zQ175 knockin model has been well characterized and used in HD preclinical studies. Heterozygous zQ175 HD mice start to show significant striatal atrophy and motor deficits on the balance beam around 6 months of age, with symptoms progressing along with age. Using structural MRI measures and motor function assessment, we verified that there was no significant striatal atrophy (Supplemental Figure 2A), and motor function on the balance beam (Supplemental Figure 2B) was preserved in 4-month-old zQ175 (heterozygous) HD mice, indicating that this age is a premanifest stage of zQ175 HD model.
We then used DGE MRI to assess CSF d-glucose clearance in 4-month-old zQ175 HD mice. After a baseline DGE signal was established, d-glucose was injected via the tail vein into 4-month-old zQ175 mice and WT littermate controls, and DGE MRI scans were conducted over a 40-minute period. We monitored DGE signals in the CSF of the third ventricle (representative images shown in Figure 1A). DGE signals reached a peak in the CSF within 1–2 minutes following i.v. injection of d-glucose. WT mice showed a gradual DGE signal decay, indicating normal d-glucose clearance in the CSF. In contrast, zQ175 HD mice exhibited sustained d-glucose signals in the CSF for the entire scan period (Figure 1, A and B) (P < 0.05 vs. WT). The d-glucose clearance in zQ175 HD mice was significantly slower than that in WT mice (P < 0.05, Figure 1C), while the d-glucose uptake in CSF was comparable between groups (P < 0.05, Figure 1D). These CSF d-glucose uptake results were consistent with the levels of glucose transporters in the brain (Supplemental Figure 2C).
Figure 1Impaired glymphatic system as revealed by DGE MRI and fluorescence-based imaging in premanifest zQ175 HD mice. (A) Illustration of DGE MRI scan timeline (upper panel) and representative DGE images for the third ventricle (lower panel) in a WT mouse and a zQ175 mouse at 4 months of age. (B) Average CSF-based DGE signal changes during the entire scan period from male WT and zQ175 mice. n = 5 mice/genotype. (C) Comparison of fitted clearance parameter μout for CSF. *P < 0.05 vs. WT by standard Student’s t test. (D) Comparison of fitted uptake parameter μin for CSF. (E) Representative images of BSA-647 fluorescent dye distribution in the brain parenchyma at 60 minutes after intra-CM injection. Note the wide distribution of fluorescent dye along the glymphatic pathway in WT mice, while very limited fluorescence distribution was seen in the HD mouse brain. Scale bar = 1 cm. The left panel shows the BSA-647 fluorescence images, and the right panel shows BSA-647 fluorescence images merged with DAPI staining images. (F) Quantification of the fluorescent dye distribution at 60 minutes after CSF tracer injection. *P < 0.05 vs. WT by standard Student’s t test. (G) Representative images of BSA-647 fluorescent dye distribution in the brain parenchyma at 180 minutes after intra-CM injection. Scale bar = 1 cm. (H) Quantification of the fluorescent dye distribution at 180 minutes after tracer injection. *P < 0.05 vs. WT by standard Student’s t test.
To determine whether blood d-glucose levels influenced d-glucose uptake/clearance in the CSF, dynamic glucose signals in the sagittal sinus were monitored during the entire scan period. We observed no significant difference in blood DGE signals between the 2 genotypes (Supplemental Figure 2E), including glucose clearance, uptake, and maximal d-glucose signal difference in the vein (Supplemental Figure 2, F–H). These results indicate that the CSF data from Figure 1 suggest a potential impairment of glymphatic function in premanifest zQ175 HD mice.
We further validated these MRI findings with a gold standard, fluorescence-based CSF tracer imaging technique. A fluorescent tracer, Alexa Fluor 647–labeled BSA (BSA-647), was injected into the cisterna magna (CM) in premanifest zQ175 mice to evaluate the glymphatic influx efficiency; 60 minutes and 180 minutes following tracer injection, BSA-647 fluorescent dye distribution in the parenchyma was quantified. We observed significantly reduced fluorescent tracer movement into the brain parenchyma along the glymphatic network in 4-month-old zQ175 HD mice compared with age-matched WT controls at both time points (Figure 1, E–H), verifying the reduced glymphatic influx in premanifest zQ175 HD mice. Furthermore, we injected BSA-647 into the striatum to evaluate glymphatic efflux efficiency in zQ175 mice. At 180 minutes after the tracer injection, we observed a trend of more tracers sustained in the striatum in zQ175 mice compared with those in the littermate control mice (Supplemental Figure 3A) but no statistical difference (Supplemental Figure 3B). Taken together, these data demonstrate the capacity of DGE MRI to detect glymphatic function and that glymphatic function, particularly glymphatic influx, is compromised in zQ175 HD mice before striatal atrophy and motor deficits.
Reduced Aqp4 perivascular localization in premanifest zQ175 HD mouse brain. Glymphatic clearance efficiency is mediated by astrocytic AQP4 water channels that are present at high density in perivascular astrocytic endfoot membranes. Thus, AQP4-dependent convective flow is critical for effective glymphatic clearance, and AQP4 perivascular localization is required for glymphatic function. To determine if Aqp4 perivascular localization was altered in the 4-month-old zQ175 HD mouse brain, we performed coimmunostaining of Aqp4 and vascular marker protein collagen IV to examine Aqp4 perivascular colocalization. As visualized, Aqp4 immunosignals were concentrated on the perivascular domains in both the striatum and cerebral cortex (Figure 2, A–C) of WT mice, indicated by colocalized Aqp4 and collagen IV immunosignals. In contrast, zQ175 HD mice exhibited significantly reduced Aqp4 immunosignals in the perivascular domains in both the striatum (Figure 2, A and B) and cerebral cortex (Figure 2, A and C), suggesting loss of AQP4 perivascular localization in the zQ175 HD mouse brain before phenotypic onset.
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