Distributed feature representations of natural stimuli across parallel retinal pathways
(2024) Nature Communications, 15 (1), art. no. 1920, .
Hsiang, J.-C.a , Shen, N.a , Soto, F.a , Kerschensteiner, D.a b c
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, they differ in sensitivity to coherent motion in naturalistic movies. Motion information is distributed across ON bipolar cells in the upper and the lower blocks, multiplexed with temporal and spatial contrast, independent features of natural scenes. Comparing the responses of different boutons within the same arbor, we find that axons of all ON bipolar cell types function as computational units. Thus, our results provide insights into the visual feature extraction from naturalistic stimuli and reveal how structural and functional organization cooperate to generate parallel ON pathways for temporal and spatial information in the mammalian retina. © The Author(s) 2024.
Funding details
National Institutes of HealthNIHEY026978, EY027411, EY034001
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy
(2024) The Journal of Experimental Medicine, 221 (4), .
Toral-Rios, D.a , Long, J.M.b c d , Ulrich, J.D.b c , Yu, J.e , Strickland, M.R.b , Han, X.f , Holtzman, D.M.b c d , Cashikar, A.G.a b c g , Paul, S.M.a b c g
a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
e Department of Genetics, Genome Technology Access Center at the McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, United States
f Department of Medicine, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
g Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO, United States
Abstract
Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a “disease-associated microglia” signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases. © 2024 Toral-Rios et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (11), pp. e2316118121.
Kolesnikov, A.V.a , Murphy, D.P.b , Corbo, J.C.b , Kefalov, V.J.a
a Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA 92697
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.
Author Keywords
photoreceptors; retina; retinitis pigmentosa
Document Type: Article
Publication Stage: Final
Source: Scopus
Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation
(2024) Journal of Neurophysiology, 131 (3), pp. 529-540.
Salvatore, S.V.a , Lambert, P.M.a c , Benz, A.a , Rensing, N.R.b , Wong, M.b , Zorumski, C.F.a d , Mennerick, S.a d
a Department of Psychiatry, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
c Medical Scientist Training Program, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Cortical electroencephalograms (EEGs) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of excitation/inhibition ratio, we analyzed video-EEG during active exploration in mice of both sexes during various pharmacological manipulations with the fitting oscillations and one over f (FOOOF) algorithm. We found that GABAA receptor (GABAAR)-positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at subconvulsive doses) did not follow the prediction. To tilt excitation/inhibition ratio more selectively toward excitation, we suppressed the activity of parvalbumin-positive interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of cortical excitation/inhibition ratio. © 2024 the American Physiological Society.
Author Keywords
cortical; electroencephalogram; gamma aminobutyric acid; inhibition
Document Type: Article
Publication Stage: Final
Source: Scopus
Reduction of cell surface attachment in experimental hydrocephalus using a novel ventricular catheter with modified tethered liquid perfluorocarbon
(2024) Journal of Neurosurgery, 140 (3), pp. 627-638.
Garcia-Bonilla, M.a , Harris, C.A.b , Bandyopadhyay, S.c , Moore, J.a , Horbatiuk, J.b , Limbrick, D.D.a , Swarup, R.a , Crouthamel, J.a , Jones, A.c , Khasawneh, A.b , Petroj, A.b , Hehar, S.b , Sierra, M.b , Anderson, J.c , Murray, R.c , Talcott, M.R.a d , McAllister, J.P.a
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, United States
c 3FreeFlow Medical Devices LLC, Lancaster, Pennsylvania; and
d Chicago, IL, United States
Abstract
OBJECTIVE: Ventriculoperitoneal shunting, the most common treatment for the neurological disorder hydrocephalus, has a failure rate of up to 98% within 10 years of placement, mainly because of proximal obstruction of the ventricular catheter (VC). The authors developed a new VC design modified with tethered liquid perfluorocarbon (TLP) and tested it in a porcine model of hydrocephalus. In this study, they aimed to determine if their TLP VC design reduced cell surface attachment and consequent shunt obstruction in the pig model. METHODS: TLP VCs were designed to reduce drainage hole obstruction using modified TLP and slightly enlarged draining holes, but their number and placement remained very similar to standard VCs. First, the authors tested the device in nonhydrocephalic rats to assess biocompatibility. After confirming safety, they implanted the VCs in hydrocephalic pigs. Hydrocephalus was induced by intracisternal kaolin injections in 30-day-old domestic juvenile pigs. Surgical implantation of the ventriculoperitoneal shunt (clinical control or TLP) was performed 10-14 days postinduction and maintained up to 30 days posttreatment. MRI was performed to measure ventricular volume before treatment and 10 and 30 days after treatment. Histological and immunohistochemical analyses of brain tissue and explanted VCs, intracranial pressure measurement, and clinical scoring were performed when the animals were euthanized. RESULTS: TLP VCs showed a similar surgical feel, kink resistance, and stiffness to control VCs. In rats (biocompatibility assessment), TLP VCs did not show brain inflammatory reactions after 30 or 60 days of implantation. In pigs, TLP VCs demonstrated increased survival time, improved clinical outcome scores, and significantly reduced total attached cells on the VCs compared with standard clinical control VCs. TLP VCs exhibited similar, but not worse, results related to ventriculomegaly, intracranial pressure, and the local tissue response around the cortical shunt track in pigs. CONCLUSIONS: TLP VCs may be a strong candidate to reduce proximal VC obstruction and improve hydrocephalus treatment.
Author Keywords
hydrocephalus; modified tethered liquid perfluorocarbon; pig model; shunt obstruction; ventricular catheter
Document Type: Article
Publication Stage: Final
Source: Scopus
The brain’s “dark energy” puzzle: How strongly is glucose metabolism linked to resting-state brain activity?
(2024) Journal of Cerebral Blood Flow and Metabolism, .
Volpi, T.a b , Silvestri, E.c , Aiello, M.d , Lee, J.J.e , Vlassenko, A.G.e , Goyal, M.S.e , Corbetta, M.a f , Bertoldo, A.a c
a Padova Neuroscience Center, University of Padova, Padova, Italy
b Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
c Department of Information Engineering, University of Padova, Padova, Italy
d IRCCS SDN, Naples, 80143, Italy
e Neuroimaging Laboratories, the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
f Department of Neuroscience, University of Padova, Padova, Italy
Abstract
Brain glucose metabolism, which can be investigated at the macroscale level with [18F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain’s spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain’s metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain’s ‘dark energy’. © The Author(s) 2024.
Author Keywords
Brain glucose metabolism; functional-metabolic model; multilevel modeling; spontaneous activity; [18F]FDG PET
Funding details
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience
National Institute on AgingNIAR01AG053503, R01AG057536
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Redox-dependent Cd2+ inhibition of BK-type Ca2+-activated K+ channels
(2024) Biophysical Journal, .
Zhang, G.a , Yang, H.a b , Wang, Y.a , Liang, H.a , Shi, J.a , Cui, J.a
a Department of Biomedical Engineering, Washington University, St. Louis, Missouri, United States
b Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States
Abstract
Large-conductance Ca2+-activated K+ channels (BK channels) are formed by Slo1 subunits as a homotetramer. Besides Ca2+, other divalent cations, such as Cd2+, also activate BK channels when applied intracellularly by shifting the conductance-voltage relation to more negative voltages. However, we found that if the inside-out patch containing BK channels was treated with solution containing reducing agents such as dithiothreitol (DTT), then subsequent Cd2+ application completely inhibited BK currents. The DTT-dependent Cd2+ inhibition could be reversed by treating the patch with solutions containing H2O2, suggesting that a redox reaction regulates the Cd2+ inhibition of BK channels. Similar DTT-dependent Cd2+ inhibition was also observed in a mutant BK channel, Core-MT, in which the cytosolic domain of the channel is deleted, and in the proton-activated Slo3 channels but not observed in the voltage-gated Shaker K+ channels. A possible mechanism for the DTT-dependent Cd2+ inhibition is that DTT treatment breaks one or more disulfide bonds between cysteine pairs in the BK channel protein and the freed thiol groups coordinate with Cd2+ to form an ion bridge that blocks the channel or locks the channel at the closed state. However, surprisingly, none of the mutations of all cysteine residues in Slo1 affect the DTT-dependent Cd2+ inhibition. These results are puzzling, with an apparent contradiction: on one hand, a redox reaction seems to regulate Cd2+ inhibition of the channel, but on the other hand, no cysteine residue in the Slo1 subunit seems to be involved in such inhibition. © 2024 Biophysical Society
Funding details
National Institutes of HealthNIHGM149998, RO1 GM114694
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests
(2024) Nature Medicine, .
Barthélemy, N.R.a b , Salvadó, G.c , Schindler, S.E.a d , He, Y.a b , Janelidze, S.c , Collij, L.E.c e f , Saef, B.a , Henson, R.L.a , Chen, C.D.g , Gordon, B.A.g , Li, Y.a h , La Joie, R.i , Benzinger, T.L.S.g , Morris, J.C.a d , Mattsson-Carlgren, N.c j k , Palmqvist, S.c l , Ossenkoppele, R.c f m , Rabinovici, G.D.i n , Stomrud, E.c l , Bateman, R.J.a b d , Hansson, O.c l
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center, Washington University School of Medicine, St. Louis, MO, United States
c Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
d Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), Washington University School of Medicine, St. Louis, MO, United States
e Department of Radiology and Nuclear Medicine, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
f Amsterdam Neuroscience, Brain Imaging, Amsterdam, Netherlands
g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
h Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
i Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
j Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
k Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
l Memory Clinic, Skåne University Hospital, Malmö, Sweden
m Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
n Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
Abstract
With the emergence of Alzheimer’s disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95–0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89–90% for Aβ PET and 87–88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments. © The Author(s) 2024.
Funding details
1412/22
2022-1259
2022-Projekt0080
National Institutes of HealthNIHR01AG070941
National Institute on AgingNIAR01AG083740
Alzheimer’s AssociationAASG-23-1061717, ZEN24-1069572
Siemens USA
GE Healthcare
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
American College of RadiologyACR
Horizon 2020 Framework ProgrammeH2020101061836, AARF-22-972612, AF-980942
Coins for Alzheimer’s Research TrustCART
GHR FoundationGHR
Rainwater Charitable FoundationRCF
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGADP01AG003991, P01AG026276, P30-AG062422, P30AG066444, R35 AG072362, R56AG061900, RF1AG061900, U01 AG057195, ZEN-21-848216
European Research CouncilERCADG-101096455
Lunds UniversitetLU
HjärnfondenFO2021-0293
Knut och Alice Wallenbergs Stiftelse2022-0231
VetenskapsrådetVR2022-00775, ERAPERMED2021-184
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
AlzheimerfondenAF-980907
University Hospital FoundationUHF2020-O000028
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls
(2024) Journal of Cerebral Blood Flow and Metabolism, .
Fellah, S.a , Ying, C.b , Wang, Y.a , Guilliams, K.P.a c , Fields, M.E.a c , Chen, Y.a , Lewis, J.a , Mirro, A.c , Cohen, R.a , Igwe, N.a , Eldeniz, C.b , Jiang, D.d , Lu, H.d , Powers, W.J.e , Lee, J.-M.a b , Ford, A.L.a b , An, H.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Department of Neurology, Duke University School of Medicine, Durham, NC, United States
Abstract
Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD. © The Author(s) 2024.
Author Keywords
Asymmetric spin echo; magnetic resonance imaging; oxygen extraction fraction; sickle cell disease; T2-relaxation-under-spin-tagging
Funding details
National Institutes of HealthNIHR01HL129241, RF1NS116565
National Institute of Neurological Disorders and StrokeNINDSR01NS121065
National Center for Advancing Translational SciencesNCATSKL2TR002346, R01HL157188, R01NS082561, R21NS127425
Document Type: Article
Publication Stage: Article in Press
Source: Scopus