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Knudsen LV, Michel TM, Sheldrick-Michel AJ, Vafaee MS. Does exercise truly affect brain-wide glucose metabolism? J Physiol 2025. [PMID: 39832197 DOI: 10.1113/jp288329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/22/2025] Open
Affiliation(s)
- Laust Vind Knudsen
- Department of Psychiatry, University of Southern Denmark, Odense C, Denmark
| | - Tanja Maria Michel
- Department of Psychiatry, University of Southern Denmark, Odense C, Denmark
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Sala A, Gosseries O, Laureys S, Annen J. Advances in neuroimaging in disorders of consciousness. HANDBOOK OF CLINICAL NEUROLOGY 2025; 207:97-127. [PMID: 39986730 DOI: 10.1016/b978-0-443-13408-1.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2025]
Abstract
Disorders of consciousness (DoC) are a heterogeneous spectrum of clinical conditions, including coma, unresponsive wakefulness syndrome, and minimally conscious state. DoC are clinically defined on the basis of behavioral cues expressed by the patients, on the assumption that such behavioral responses of the patient are representative of the patient's degree of consciousness impairment. However, many studies have highlighted the issues arising from formulating a DoC diagnosis merely on behavioral assessment. Overcoming the limitations of behavioral assessment, neuroimaging provides a direct window on the cerebral activity of the patient, bypassing the motor, perceptual, or cognitive deficits that might hamper the patient's ability to produce an appropriate behavioral response. This chapter provides an overview of available molecular, functional, and structural neuroimaging evidence in patients with DoC. This chapter introduces the neuroimaging tools available in the clinical settings of nuclear medicine and neuroradiology and presents the evidence on the role of neuroimaging tools to improve the clinical management of DoC patients, from the standpoint of differential diagnosis and prognosis. Last, we outline the open questions in the field, and point at actions that are urgently needed to fully exploit neuroimaging tools to advance scientific understanding and clinical management of DoC.
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Affiliation(s)
- Arianna Sala
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Olivia Gosseries
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Steven Laureys
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Jitka Annen
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium; Department of Data Analysis, University of Ghent, Ghent, Belgium
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Kaewchur T, Thientunyakit T, Chamroonrat W, Khiewvan B, Kiatkittikul P, Wongsurawat N, Chotipanich C, Likitjaroen Y, Senanarong V, Pasawang P, Sontrapornpol T, Poon-iad N, Amnuaywattakorn S, Tepmongkol S. Thai Guideline for Nuclear Medicine Investigations of Neurocognitive Disorders: Nuclear Medicine Society of Thailand, the Neurological Society of Thailand, and Thai Medical Physicist Society Collaboration. Diagnostics (Basel) 2024; 14:2474. [PMID: 39594140 PMCID: PMC11592784 DOI: 10.3390/diagnostics14222474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Nuclear medicine investigations play a significant role in diagnosing dementia, mainly using imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). By providing functional and molecular data via brain imaging, nuclear medicine investigations offer valuable insights that complement clinical evaluations and structural imaging in the early detection, diagnosis, and differentiation of various types of dementia, leading to more accurate diagnosis and personalized treatment planning. Therefore, the Nuclear Medicine Society of Thailand, the Neurological Society of Thailand, and the Thai Medical Physicist Society have collaborated to establish these practical nuclear medicine investigation guidelines aiming to (1) identify the role of nuclear medicine studies in patients with neurocognitive disorders; (2) assist referrers in requesting the most appropriate procedure for diagnosis of each type of neurocognitive disorders; and (3) identify scientific evidence that is useful to assisting nuclear medicine professionals in recommending, performing, interpreting, and reporting the results of nuclear medicine investigations in patients with neurocognitive disorders.
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Affiliation(s)
- Tawika Kaewchur
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (T.K.)
- PET/CT and Cyclotron Center, Center for Medicine Excellence, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Tanyaluck Thientunyakit
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (T.T.); (B.K.); (N.P.-i.)
| | - Wichana Chamroonrat
- Division of Nuclear Medicine, Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (W.C.); (S.A.)
| | - Benjapa Khiewvan
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (T.T.); (B.K.); (N.P.-i.)
| | - Peerapon Kiatkittikul
- National Cyclotron and PET Centre, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok 10210, Thailand; (P.K.); (C.C.)
| | - Nantaporn Wongsurawat
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Chanisa Chotipanich
- National Cyclotron and PET Centre, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok 10210, Thailand; (P.K.); (C.C.)
| | - Yuttachai Likitjaroen
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand;
| | - Vorapun Senanarong
- Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
| | - Panya Pasawang
- Division of Nuclear Medicine, Department of Radiology, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand; (P.P.); (T.S.)
| | - Tanawat Sontrapornpol
- Division of Nuclear Medicine, Department of Radiology, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand; (P.P.); (T.S.)
| | - Nucharee Poon-iad
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (T.T.); (B.K.); (N.P.-i.)
| | - Sasithorn Amnuaywattakorn
- Division of Nuclear Medicine, Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (W.C.); (S.A.)
| | - Supatporn Tepmongkol
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Chulalongkorn University Biomedical Imaging Group (CUBIG), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Chula Neuroscience Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
- Center of Excellence in Cognitive Impairment and Dementia, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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4
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Esquea EM, Young RG, Ciraku L, Merzy J, Ahmed NN, Talarico AN, Karuppiah M, Gocal W, Simone NL, Dick A, Reginato MJ. ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.18.619082. [PMID: 39484430 PMCID: PMC11526985 DOI: 10.1101/2024.10.18.619082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo. These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.
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Affiliation(s)
- Emily M. Esquea
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
- These authors contributed equally
| | - Riley G. Young
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
- These authors contributed equally
| | - Lorela Ciraku
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
- These authors contributed equally
| | - Jessica Merzy
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Nusaiba N. Ahmed
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Alexandra N. Talarico
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Mangalam Karuppiah
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Wiktoria Gocal
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Nicole L. Simone
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
- Cancer Risk and Control Program
| | - Alexej Dick
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
| | - Mauricio J. Reginato
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
- Translational and Cellular Oncology Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Karl MT, Kim YD, Rajendran K, Manger PR, Sherwood CC. Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function. J Comp Neurol 2024; 532:e25669. [PMID: 39291629 PMCID: PMC11412485 DOI: 10.1002/cne.25669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.
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Affiliation(s)
- Molly T Karl
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Young Do Kim
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
| | - Kavita Rajendran
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
| | - Paul R Manger
- Faculty of Health Sciences, School of Anatomical Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Chet C Sherwood
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
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Calì C, Cantando I, Veloz Castillo MF, Gonzalez L, Bezzi P. Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases. Int J Mol Sci 2024; 25:8922. [PMID: 39201607 PMCID: PMC11354244 DOI: 10.3390/ijms25168922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes in both physiological and pathological conditions, highlighting their adaptive plasticity and diverse functions. Under normal conditions, astrocytes modulate synaptic activity, recycle neurotransmitters, and maintain the blood-brain barrier, ensuring a balanced energy supply and protection against oxidative stress. However, in response to central nervous system pathologies such as neurotrauma, stroke, infections, and neurodegenerative diseases like Alzheimer's and Huntington's disease, astrocytes undergo significant morphological, molecular, and metabolic changes. Reactive astrocytes upregulate glycolysis and fatty acid oxidation to meet increased energy demands, which can be protective in acute settings but may exacerbate chronic inflammation and disease progression. This review emphasizes the need for advanced molecular, genetic, and physiological tools to further understand astrocyte heterogeneity and their metabolic reprogramming in disease states.
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Affiliation(s)
- Corrado Calì
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10124 Turin, Italy;
- Neuroscience Institute Cavalieri Ottolenghi, 10143 Orbassano, Italy
| | - Iva Cantando
- Department of Fundamental Neurosciences (DNF), University of Lausanne (UNIL), 1005 Lausanne, Switzerland; (I.C.); (L.G.)
| | - Maria Fernanda Veloz Castillo
- Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10124 Turin, Italy;
- Neuroscience Institute Cavalieri Ottolenghi, 10143 Orbassano, Italy
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
| | - Laurine Gonzalez
- Department of Fundamental Neurosciences (DNF), University of Lausanne (UNIL), 1005 Lausanne, Switzerland; (I.C.); (L.G.)
| | - Paola Bezzi
- Department of Fundamental Neurosciences (DNF), University of Lausanne (UNIL), 1005 Lausanne, Switzerland; (I.C.); (L.G.)
- Department of Physiology and Pharmacology, University of Rome Sapienza, 00185 Rome, Italy
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7
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Godbersen GM, Falb P, Klug S, Silberbauer LR, Reed MB, Nics L, Hacker M, Lanzenberger R, Hahn A. Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET. Eur J Nucl Med Mol Imaging 2024; 51:2283-2292. [PMID: 38491215 PMCID: PMC11178598 DOI: 10.1007/s00259-024-06675-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 03/02/2024] [Indexed: 03/18/2024]
Abstract
PURPOSE Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. METHODS We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. RESULTS We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. CONCLUSION The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.
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Affiliation(s)
- Godber Mathis Godbersen
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
| | - Pia Falb
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
| | - Sebastian Klug
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
| | - Leo R Silberbauer
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
| | - Murray Bruce Reed
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
| | - Lukas Nics
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Marcus Hacker
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Rupert Lanzenberger
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria.
| | - Andreas Hahn
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria.
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Maraslioglu-Sperber A, Pizzi E, Fisch JO, Kattler K, Ritter T, Friauf E. Molecular and functional profiling of cell diversity and identity in the lateral superior olive, an auditory brainstem center with ascending and descending projections. Front Cell Neurosci 2024; 18:1354520. [PMID: 38846638 PMCID: PMC11153811 DOI: 10.3389/fncel.2024.1354520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/15/2024] [Indexed: 06/09/2024] Open
Abstract
The lateral superior olive (LSO), a prominent integration center in the auditory brainstem, contains a remarkably heterogeneous population of neurons. Ascending neurons, predominantly principal neurons (pLSOs), process interaural level differences for sound localization. Descending neurons (lateral olivocochlear neurons, LOCs) provide feedback into the cochlea and are thought to protect against acoustic overload. The molecular determinants of the neuronal diversity in the LSO are largely unknown. Here, we used patch-seq analysis in mice at postnatal days P10-12 to classify developing LSO neurons according to their functional and molecular profiles. Across the entire sample (n = 86 neurons), genes involved in ATP synthesis were particularly highly expressed, confirming the energy expenditure of auditory neurons. Two clusters were identified, pLSOs and LOCs. They were distinguished by 353 differentially expressed genes (DEGs), most of which were novel for the LSO. Electrophysiological analysis confirmed the transcriptomic clustering. We focused on genes affecting neuronal input-output properties and validated some of them by immunohistochemistry, electrophysiology, and pharmacology. These genes encode proteins such as osteopontin, Kv11.3, and Kvβ3 (pLSO-specific), calcitonin-gene-related peptide (LOC-specific), or Kv7.2 and Kv7.3 (no DEGs). We identified 12 "Super DEGs" and 12 genes showing "Cluster similarity." Collectively, we provide fundamental and comprehensive insights into the molecular composition of individual ascending and descending neurons in the juvenile auditory brainstem and how this may relate to their specific functions, including developmental aspects.
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Affiliation(s)
- Ayse Maraslioglu-Sperber
- Animal Physiology Group, Department of Biology, University of Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Erika Pizzi
- Animal Physiology Group, Department of Biology, University of Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Jonas O. Fisch
- Animal Physiology Group, Department of Biology, University of Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Kathrin Kattler
- Genetics/Epigenetics Group, Department of Biological Sciences, Saarland University, Saarbrücken, Germany
| | - Tamara Ritter
- Animal Physiology Group, Department of Biology, University of Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Eckhard Friauf
- Animal Physiology Group, Department of Biology, University of Kaiserslautern-Landau, Kaiserslautern, Germany
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9
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Dienel GA, Rothman DL. In vivo calibration of genetically encoded metabolite biosensors must account for metabolite metabolism during calibration and cellular volume. J Neurochem 2024; 168:506-532. [PMID: 36726217 DOI: 10.1111/jnc.15775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/21/2023] [Accepted: 01/28/2023] [Indexed: 02/03/2023]
Abstract
Isotopic assays of brain glucose utilization rates have been used for more than four decades to establish relationships between energetics, functional activity, and neurotransmitter cycling. Limitations of these methods include the relatively long time (1-60 min) for the determination of labeled metabolite levels and the lack of cellular resolution. Identification and quantification of fuels for neurons and astrocytes that support activation and higher brain functions are a major, unresolved issues. Glycolysis is preferentially up-regulated during activation even though oxygen level and supply are adequate, causing lactate concentrations to quickly rise during alerting, sensory processing, cognitive tasks, and memory consolidation. However, the fate of lactate (rapid release from brain or cell-cell shuttling coupled with local oxidation) is long disputed. Genetically encoded biosensors can determine intracellular metabolite concentrations and report real-time lactate level responses to sensory, behavioral, and biochemical challenges at the cellular level. Kinetics and time courses of cellular lactate concentration changes are informative, but accurate biosensor calibration is required for quantitative comparisons of lactate levels in astrocytes and neurons. An in vivo calibration procedure for the Laconic lactate biosensor involves intracellular lactate depletion by intravenous pyruvate-mediated trans-acceleration of lactate efflux followed by sensor saturation by intravenous infusion of high doses of lactate plus ammonium chloride. In the present paper, the validity of this procedure is questioned because rapid lactate-pyruvate interconversion in blood, preferential neuronal oxidation of both monocarboxylates, on-going glycolytic metabolism, and cellular volumes were not taken into account. Calibration pitfalls for the Laconic lactate biosensor also apply to other metabolite biosensors that are standardized in vivo by infusion of substrates that can be metabolized in peripheral tissues. We discuss how technical shortcomings negate the conclusion that Laconic sensor calibrations support the existence of an in vivo astrocyte-neuron lactate concentration gradient linked to lactate shuttling from astrocytes to neurons to fuel neuronal activity.
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Affiliation(s)
- Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
| | - Douglas L Rothman
- Magnetic Resonance Research Center and Departments of Radiology and Biomedical Engineering, Yale University, New Haven, Connecticut, USA
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10
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Palandt N, Resch C, Unterlechner P, Voshagen L, Winhart VR, Kunz L. Metabolic response of auditory brainstem neurons to their broad physiological activity range. J Neurochem 2024; 168:663-676. [PMID: 38439211 DOI: 10.1111/jnc.16091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/06/2024]
Abstract
Neurons exhibit a high energetic need, and the question arises as how they metabolically adapt to changing activity states. This is relevant for interpreting functional neuroimaging in different brain areas. Particularly, neurons with a broad firing range might exhibit metabolic adaptations. Therefore, we studied MNTB (medial nucleus of the trapezoid body) principal neurons, which generate action potentials (APs) at frequencies up to several hundred hertz. We performed the experiments in acute brainstem slices of the Mongolian gerbil (Meriones unguiculatus) at 22.5-24.5°C. Upon electrical stimulation of afferent MNTB fibres with 400 stimuli at varying frequencies, we monitored autofluorescence levels of NAD(P)H and FAD and determined the extremum amplitudes of their biphasic response. Additionally, we compared these data with alterations in O2 concentrations measured with an electrochemical sensor. These O2 changes are prominent since MNTB neurons rely on oxidative phosphorylation as shown by our pharmacological experiments. We calculated the O2 consumption rate as change in O2 concentration divided by stimulus durations, because these periods varied inversely with stimulus frequency as a result of the constant number of 400 stimuli applied. The O2 consumption rate increased with stimulation frequency up to a constant value at 600 Hz; that is, energy demand depends on temporal characteristics of activity despite the same number of stimuli. The rates showed no correlation with peak amplitudes of NAD(P)H or FAD, whilst the values of the two molecules were linearly correlated. This points at the complexity of analysing autofluorescence imaging for quantitative metabolic studies, because these values report only relative net changes of many superimposed oxidative and reductive processes. Monitoring O2 concentration rates is, thus, an important tool to improve the interpretation of NAD(P)H/FAD autofluorescence data, as they do not under all conditions and in all systems appropriately reflect the metabolic activity or energy demand.
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Affiliation(s)
- Nicola Palandt
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
- Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximillians-Universität (LMU), Munich, Germany
| | - Cibell Resch
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
| | - Patricia Unterlechner
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
| | - Lukas Voshagen
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
| | - Valentin R Winhart
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
- Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximillians-Universität (LMU), Munich, Germany
| | - Lars Kunz
- Division of Neurobiology, Faculty of Biology, Ludwig-Maximillians-Universität (LMU), Munich, Germany
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11
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Yu ACL, McAllister R, Mularoni N, To CKS. Brief Report: Atypical Temporal Sensitivity in Coarticulation in Autism: Evidence from Sibilant-Vowel Interaction in Cantonese. J Autism Dev Disord 2024:10.1007/s10803-024-06258-w. [PMID: 38431693 DOI: 10.1007/s10803-024-06258-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2024] [Indexed: 03/05/2024]
Abstract
PURPOSE Atypicalities in the prosodic aspects of speech are commonly considered in clinical assessments of autism. While there is an increasing number of studies using objective measures to assess prosodic deficits, such studies have primarily focused on the intonational and rhythmic aspects of prosody. Little is known about prosodic deficits that are reflected at the segmental level, despite the strong connection between prosody and segmental realization. This study examines the nature of sibilant-vowel coarticulation among male adult native speakers of Cantonese with autism and those without. METHODS Fifteen Cantonese-speaking autistic (ASD) adults (mean age = 25 years) and 23 neuro-typical (NT) adults (mean age = 20 years) participated. Each participant read aloud 42 syllables with a sibilant onset in carrier phrase. Spectral means and variance, skewness and kurtosis were measured, and regressed by vocalic rounding (rounded vs. unrounded), cohort (ASD vs. NT), sibilant duration, and articulation rate. RESULTS While neurotypical participants exhibit sibilant-vowel coarticulation that are sensitive to variation in sibilant duration, autistic participants show no sensitivity to segmental temporal changes. CONCLUSION These findings point to the potential for atypicalities in prosody-segment interaction as an important characteristic of autistic speech.
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Affiliation(s)
| | | | | | - Carol K S To
- The University of Hong Kong, Hong Kong SAR, China.
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12
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Ramasubbu R, Brown EC, Mouches P, Moore JA, Clark DL, Molnar CP, Kiss ZHT, Forkert ND. Multimodal imaging measures in the prediction of clinical response to deep brain stimulation for refractory depression: A machine learning approach. World J Biol Psychiatry 2024; 25:175-187. [PMID: 38185882 DOI: 10.1080/15622975.2023.2300795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024]
Abstract
OBJECTIVES This study compared machine learning models using unimodal imaging measures and combined multi-modal imaging measures for deep brain stimulation (DBS) outcome prediction in treatment resistant depression (TRD). METHODS Regional brain glucose metabolism (CMRGlu), cerebral blood flow (CBF), and grey matter volume (GMV) were measured at baseline using 18F-fluorodeoxy glucose (18F-FDG) positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance imaging (MRI), and T1-weighted MRI, respectively, in 19 patients with TRD receiving subcallosal cingulate (SCC)-DBS. Responders (n = 9) were defined by a 50% reduction in HAMD-17 at 6 months from the baseline. Using an atlas-based approach, values of each measure were determined for pre-selected brain regions. OneR feature selection algorithm and the naïve Bayes model was used for classification. Leave-out-one cross validation was used for classifier evaluation. RESULTS The performance accuracy of the CMRGlu classification model (84%) was greater than CBF (74%) or GMV (74%) models. The classification model using the three image modalities together led to a similar accuracy (84%0 compared to the CMRGlu classification model. CONCLUSIONS CMRGlu imaging measures may be useful for the development of multivariate prediction models for SCC-DBS studies for TRD. The future of multivariate methods for multimodal imaging may rest on the selection of complementing features and the developing better models.Clinical Trial Registration: ClinicalTrials.gov (#NCT01983904).
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Affiliation(s)
- Rajamannar Ramasubbu
- Department of Psychiatry, Clinical Neurosciences, Mathison Centre for Mental Health Research & Education, Calgary, Alberta, Canada
- Hotchkiss Brain Institute Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elliot C Brown
- School of Health and Care Management, Arden University, Berlin, Germany
| | - Pauline Mouches
- Department of Radiology, Clinical Neurosciences, Hotchkiss Brain Institute, Cumming school of medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jasmine A Moore
- Department of Radiology, Clinical Neurosciences, Hotchkiss Brain Institute, Cumming school of medicine, University of Calgary, Calgary, Alberta, Canada
| | - Darren L Clark
- Department of Psychiatry, Clinical Neurosciences, Mathison Centre for Mental Health Research & Education, Calgary, Alberta, Canada
- Hotchkiss Brain Institute Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Christine P Molnar
- Department of Radiology, Cumming school of medicine, University of Calgary, Calgary, Alberta, Canada
| | - Zelma H T Kiss
- Department of Psychiatry, Clinical Neurosciences, Mathison Centre for Mental Health Research & Education, Calgary, Alberta, Canada
- Hotchkiss Brain Institute Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Nils D Forkert
- Department of Radiology, Clinical Neurosciences, Hotchkiss Brain Institute, Cumming school of medicine, University of Calgary, Calgary, Alberta, Canada
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13
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Wulaer B, Holtz MA, Nagai J. Homeostasis to Allostasis: Prefrontal Astrocyte Roles in Cognitive Flexibility and Stress Biology. ADVANCES IN NEUROBIOLOGY 2024; 39:137-163. [PMID: 39190074 DOI: 10.1007/978-3-031-64839-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.
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Affiliation(s)
- Bolati Wulaer
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Mika A Holtz
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Jun Nagai
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan.
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14
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Stoll EA. A thermodynamical model of non-deterministic computation in cortical neural networks. Phys Biol 2023; 21:016003. [PMID: 38078366 DOI: 10.1088/1478-3975/ad0f2d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023]
Abstract
Neuronal populations in the cerebral cortex engage in probabilistic coding, effectively encoding the state of the surrounding environment with high accuracy and extraordinary energy efficiency. A new approach models the inherently probabilistic nature of cortical neuron signaling outcomes as a thermodynamic process of non-deterministic computation. A mean field approach is used, with the trial Hamiltonian maximizing available free energy and minimizing the net quantity of entropy, compared with a reference Hamiltonian. Thermodynamic quantities are always conserved during the computation; free energy must be expended to produce information, and free energy is released during information compression, as correlations are identified between the encoding system and its surrounding environment. Due to the relationship between the Gibbs free energy equation and the Nernst equation, any increase in free energy is paired with a local decrease in membrane potential. As a result, this process of thermodynamic computation adjusts the likelihood of each neuron firing an action potential. This model shows that non-deterministic signaling outcomes can be achieved by noisy cortical neurons, through an energy-efficient computational process that involves optimally redistributing a Hamiltonian over some time evolution. Calculations demonstrate that the energy efficiency of the human brain is consistent with this model of non-deterministic computation, with net entropy production far too low to retain the assumptions of a classical system.
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Affiliation(s)
- Elizabeth A Stoll
- Western Institute for Advanced Study, Denver, Colorado, United States of America
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15
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Ibrahim BA, Louie JJ, Shinagawa Y, Xiao G, Asilador AR, Sable HJK, Schantz SL, Llano DA. Developmental Exposure to Polychlorinated Biphenyls Prevents Recovery from Noise-Induced Hearing Loss and Disrupts the Functional Organization of the Inferior Colliculus. J Neurosci 2023; 43:4580-4597. [PMID: 37147134 PMCID: PMC10286948 DOI: 10.1523/jneurosci.0030-23.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/07/2023] Open
Abstract
Exposure to combinations of environmental toxins is growing in prevalence; and therefore, understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins, polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise, interact to produce dysfunction in central auditory processing. PCBs are well established to impose negative developmental impacts on hearing. However, it is not known whether developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 min of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus (IC) revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.SIGNIFICANCE STATEMENT Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the prenatal and postnatal developmental changes induced by polychlorinated biphenyls (PCBs) could negatively impact the resilience of the brain to noise-induced hearing loss (NIHL) later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.
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Affiliation(s)
- Baher A Ibrahim
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Jeremy J Louie
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Yoshitaka Shinagawa
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Gang Xiao
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Alexander R Asilador
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Helen J K Sable
- The Department of Psychology, The University of Memphis, Memphis, Tennessee 38152
| | - Susan L Schantz
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
| | - Daniel A Llano
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
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16
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Gibbons TD, Cotter JD, Ainslie PN, Abraham WC, Mockett BG, Campbell HA, Jones EMW, Jenkins EJ, Thomas KN. Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans. J Physiol 2023; 601:2121-2137. [PMID: 36631068 DOI: 10.1113/jp283582] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 11/18/2022] [Indexed: 01/13/2023] Open
Abstract
Intermittent fasting and exercise provide neuroprotection from age-related cognitive decline. A link between these two seemingly distinct stressors is their capability to steer the brain away from exclusively glucose metabolism. This cerebral substrate switch has been implicated in upregulating brain-derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, learning and memory, and may underlie some of these neuroprotective effects. We examined the isolated and interactive effects of (1) 20-h fasting, (2) 90-min light exercise, and (3) high-intensity exercise on peripheral venous BDNF in 12 human volunteers. A follow-up study isolated the influence of cerebrovascular shear stress on circulating BDNF. Fasting for 20 h decreased glucose and increased ketones (P ≤ 0.0157) but had no effect on BDNF (P ≥ 0.4637). Light cycling at 25% of peak oxygen uptake (V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ) increased serum BDNF by 6 ± 8% (independent of being fed or fasted) and was mediated by a 7 ± 6% increase in platelets (P < 0.0001). Plasma BDNF was increased from 336 pg l-1 [46,626] to 390 pg l-1 [127,653] by 90-min of light cycling (P = 0.0128). Six 40-s intervals at 100% ofV ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ increased plasma and serum BDNF, as well as the BDNF-per-platelet ratio 4- to 5-fold more than light exercise did (P ≤ 0.0044). Plasma BDNF was correlated with circulating lactate during the high-intensity intervals (r = 0.47, P = 0.0057), but not during light exercise (P = 0.7407). Changes in cerebral shear stress - whether occurring naturally during exercise or induced experimentally with inspired CO2 - did not correspond with changes in BDNF (P ≥ 0.2730). BDNF responses to low-intensity exercise are mediated by increased circulating platelets, and increasing either exercise duration or particularly intensity is required to liberate free BDNF. KEY POINTS: Intermittent fasting and exercise both have potent neuroprotective effects and an acute upregulation of brain-derived neurotrophic factor (BDNF) appears to be a common mechanistic link. Switching the brain's fuel source from glucose to either ketone bodies or lactate, i.e. a cerebral substrate switch, has been shown to promote BDNF production in the rodent brain. Fasting for 20 h caused a 9-fold increase in ketone body delivery to the brain but had no effect on any metric of BDNF in peripheral circulation at rest. Prolonged (90 min) light cycling exercise increased plasma- and serum-derived BDNF irrespective of being fed or fasted and seemed to be independent of changes in cerebral shear stress. Six minutes of high-intensity cycling intervals increased every metric of circulating BDNF by 4 to 5 times more than prolonged low-intensity cycling; the increase in plasma-derived BDNF was correlated with a 6-fold increase in circulating lactate irrespective of feeding or fasting. Compared to 1 day of fasting with or without prolonged light exercise, high-intensity exercise is a much more efficient means to increase BDNF in circulation.
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Affiliation(s)
- Travis D Gibbons
- School of Physical Education, Sport & Exercise Sciences, University of Otago, Dunedin, New Zealand
- Centre for Heart, Lung and Vascular Health, University of British Columbia - Okanagan, School of Health and Exercise Science, Kelowna, British Columbia, Canada
| | - James D Cotter
- School of Physical Education, Sport & Exercise Sciences, University of Otago, Dunedin, New Zealand
| | - Philip N Ainslie
- Centre for Heart, Lung and Vascular Health, University of British Columbia - Okanagan, School of Health and Exercise Science, Kelowna, British Columbia, Canada
| | - Wickliffe C Abraham
- Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Bruce G Mockett
- Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Holly A Campbell
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
| | - Emma M W Jones
- School of Physical Education, Sport & Exercise Sciences, University of Otago, Dunedin, New Zealand
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
| | - Elliott J Jenkins
- School of Physical Education, Sport & Exercise Sciences, University of Otago, Dunedin, New Zealand
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Kate N Thomas
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
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17
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Ibrahim BA, Louie J, Shinagawa Y, Xiao G, Asilador AR, Sable HJK, Schantz SL, Llano DA. Developmental exposure to polychlorinated biphenyls prevents recovery from noise-induced hearing loss and disrupts the functional organization of the inferior colliculus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.23.534008. [PMID: 36993666 PMCID: PMC10055398 DOI: 10.1101/2023.03.23.534008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
Exposure to combinations of environmental toxins is growing in prevalence, and therefore understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins - polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise - interact to produce dysfunction in central auditory processing. PCBs are well-established to impose negative developmental impacts on hearing. However, it is not known if developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 minutes of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins. Significance statement Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.
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Affiliation(s)
- Baher A. Ibrahim
- Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Jeremy Louie
- Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Yoshitaka Shinagawa
- Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Gang Xiao
- Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Alexander R. Asilador
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Helen J. K. Sable
- The Department of Psychology, The University of Memphis, Memphis, TN 38152, USA
| | - Susan L. Schantz
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Department of Comparative Biosciences, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Daniel A. Llano
- Department of Molecular & Integrative Physiology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science & Technology, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Carle Illinois College of Medicine, the University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
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18
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Bharathi SS, Zhang BB, Paul E, Zhang Y, Schmidt AV, Fowler B, Wu Y, Tiemeyer M, Inamori KI, Inokuchi JI, Goetzman ES. GM3 synthase deficiency increases brain glucose metabolism in mice. Mol Genet Metab 2022; 137:342-348. [PMID: 36335793 PMCID: PMC11061803 DOI: 10.1016/j.ymgme.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
GM3 synthase (GM3S) deficiency is a rare neurodevelopmental disorder caused by an inability to synthesize gangliosides, for which there is currently no treatment. Gangliosides are brain-enriched, plasma membrane glycosphingolipids with poorly understood biological functions related to cell adhesion, growth, and receptor-mediated signal transduction. Here, we investigated the effects of GM3S deficiency on metabolism and mitochondrial function in a mouse model. By indirect calorimetry, GM3S knockout mice exhibited increased whole-body respiration and an increased reliance upon carbohydrate as an energy source. 18F-FDG PET confirmed higher brain glucose uptake in knockout mice, and GM3S deficient N41 neuronal cells showed higher glucose utilization in vitro. Brain mitochondria from knockout mice respired at a higher rate on Complex I substrates including pyruvate. This appeared to be due to higher expression of pyruvate dehydrogenase (PDH) and lower phosphorylation of PDH, which would favor pyruvate entry into the mitochondrial TCA cycle. Finally, it was observed that blocking glucose metabolism with the glycolysis inhibitor 2-deoxyglucose reduced seizure intensity in GM3S knockout mice following administration of kainate. In conclusion, GM3S deficiency may be associated with a hypermetabolic phenotype that could promote seizure activity.
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Affiliation(s)
- Sivakama S Bharathi
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Bob B Zhang
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Eli Paul
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Yuxun Zhang
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Alexandra V Schmidt
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Benjamin Fowler
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Yijen Wu
- Department of Developmental Biology, University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America
| | - Michael Tiemeyer
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States of America
| | - Kei-Ichiro Inamori
- Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan
| | - Jin-Ichi Inokuchi
- Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan
| | - Eric S Goetzman
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America..
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19
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Needham BD, Funabashi M, Adame MD, Wang Z, Boktor JC, Haney J, Wu WL, Rabut C, Ladinsky MS, Hwang SJ, Guo Y, Zhu Q, Griffiths JA, Knight R, Bjorkman PJ, Shapiro MG, Geschwind DH, Holschneider DP, Fischbach MA, Mazmanian SK. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature 2022; 602:647-653. [PMID: 35165440 PMCID: PMC9170029 DOI: 10.1038/s41586-022-04396-8] [Citation(s) in RCA: 227] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 01/02/2022] [Indexed: 12/14/2022]
Abstract
Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
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Affiliation(s)
- Brittany D Needham
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
| | - Masanori Funabashi
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, USA
- Translational Research Department, Daiichi Sankyo RD Novare Co Ltd, Tokyo, Japan
| | - Mark D Adame
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Zhuo Wang
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joseph C Boktor
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Jillian Haney
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Wei-Li Wu
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Claire Rabut
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Mark S Ladinsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Son-Jong Hwang
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Yumei Guo
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Qiyun Zhu
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Jessica A Griffiths
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Pamela J Bjorkman
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Mikhail G Shapiro
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Daniel H Geschwind
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Daniel P Holschneider
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Viterbi School of Engineering, Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Michael A Fischbach
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, USA
| | - Sarkis K Mazmanian
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
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20
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Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology. Metabolites 2022; 12:metabo12010072. [PMID: 35050194 PMCID: PMC8780167 DOI: 10.3390/metabo12010072] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 11/17/2022] Open
Abstract
The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well.
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21
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Evaluation of Age and Sex-Related Metabolic Changes in Healthy Subjects: An Italian Brain 18F-FDG PET Study. J Clin Med 2021; 10:jcm10214932. [PMID: 34768454 PMCID: PMC8584846 DOI: 10.3390/jcm10214932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 11/26/2022] Open
Abstract
Background: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection of cerebral metabolic alterations in neurological diseases vs. normal aging. We assess age- and sex-related brain metabolic changes in healthy subjects, exploring impact of activity normalization methods. Methods: brain scans of Italian Association of Nuclear Medicine normative database (151 subjects, 67 Males, 84 Females, aged 20–84) were selected. Global mean, white matter, and pons activity were explored as normalization reference. We performed voxel-based and ROI analyses using SPM12 and IBM-SPSS software. Results: SPM proved a negative correlation between age and brain glucose metabolism involving frontal lobes, anterior-cingulate and insular cortices bilaterally. Narrower clusters were detected in lateral parietal lobes, precuneus, temporal pole and medial areas bilaterally. Normalizing on pons activity, we found a more significant negative correlation and no positive one. ROIs analysis confirmed SPM results. Moreover, a significant age × sex interaction effect was revealed, with worse metabolic reduction in posterior-cingulate cortices in females than males, especially in post-menopausal age. Conclusions: this study demonstrated an age-related metabolic reduction in frontal lobes and in some parieto-temporal areas more evident in females. Results suggested pons as the most appropriate normalization reference. Knowledge of age- and sex-related cerebral metabolic changes is critical to correctly interpreting brain 18F-FDG PET imaging.
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22
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Zhou X, Chen H, Wang L, Lenahan C, Lian L, Ou Y, He Y. Mitochondrial Dynamics: A Potential Therapeutic Target for Ischemic Stroke. Front Aging Neurosci 2021; 13:721428. [PMID: 34557086 PMCID: PMC8452989 DOI: 10.3389/fnagi.2021.721428] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/16/2021] [Indexed: 12/13/2022] Open
Abstract
Stroke is one of the leading causes of death and disability worldwide. Brain injury after ischemic stroke involves multiple pathophysiological mechanisms, such as oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium overload, neuroinflammation, neuronal apoptosis, and blood-brain barrier (BBB) disruption. All of these factors are associated with dysfunctional energy metabolism after stroke. Mitochondria are organelles that provide adenosine triphosphate (ATP) to the cell through oxidative phosphorylation. Mitochondrial dynamics means that the mitochondria are constantly changing and that they maintain the normal physiological functions of the cell through continuous division and fusion. Mitochondrial dynamics are closely associated with various pathophysiological mechanisms of post-stroke brain injury. In this review, we will discuss the role of the molecular mechanisms of mitochondrial dynamics in energy metabolism after ischemic stroke, as well as new strategies to restore energy homeostasis and neural function. Through this, we hope to uncover new therapeutic targets for the treatment of ischemic stroke.
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Affiliation(s)
- Xiangyue Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hanmin Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Wang
- Department of Operating Room, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cameron Lenahan
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
| | - Lifei Lian
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yibo Ou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Chang D, Brown Q, Tsui G, He Y, Liu J, Shi L, Rodríguez-Contreras A. Distinct Cellular Profiles of Hif1a and Vegf mRNA Localization in Microglia, Astrocytes and Neurons during a Period of Vascular Maturation in the Auditory Brainstem of Neonate Rats. Brain Sci 2021; 11:brainsci11070944. [PMID: 34356178 PMCID: PMC8304335 DOI: 10.3390/brainsci11070944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/11/2021] [Accepted: 07/15/2021] [Indexed: 01/09/2023] Open
Abstract
Defining the relationship between vascular development and the expression of hypoxia-inducible factors (Hifs) and vascular endothelial growth factor (Vegf) in the auditory brainstem is important to understand how tissue hypoxia caused by oxygen shortage contributes to sensory deficits in neonates. In this study, we used histology, molecular labeling, confocal microscopy and 3D image processing methods to test the hypothesis that significant maturation of the vascular bed in the medial nucleus of the trapezoid body (MNTB) occurs during the postnatal period that precedes hearing onset. Isolectin-B4 histochemistry experiments suggested that the MNTB vasculature becomes more elaborate between P5 and P10. When combined with a cell proliferation marker and immunohistochemistry, we found that vascular growth coincides with a switch in the localization of proliferating cells to perivascular locations, and an increase in the density of microglia within the MNTB. Furthermore, microglia were identified as perivascular cells with proliferative activity during the period of vascular maturation. Lastly, combined in situ hybridization and immunohistochemistry experiments showed distinct profiles of Hif1a and Vegf mRNA localization in microglia, astrocytes and MNTB principal neurons. These results suggest that different cells of the neuro-glio-vascular unit are likely targets of hypoxic insult in the auditory brainstem of neonate rats.
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Affiliation(s)
- Daphne Chang
- Center for Discovery and Innovation, Department of Biology, Institute for Ultrafast Spectroscopy and Lasers, City University of New York, City College, New York, NY 10031, USA; (D.C.); (Q.B.); (G.T.)
| | - Quetanya Brown
- Center for Discovery and Innovation, Department of Biology, Institute for Ultrafast Spectroscopy and Lasers, City University of New York, City College, New York, NY 10031, USA; (D.C.); (Q.B.); (G.T.)
| | - Grace Tsui
- Center for Discovery and Innovation, Department of Biology, Institute for Ultrafast Spectroscopy and Lasers, City University of New York, City College, New York, NY 10031, USA; (D.C.); (Q.B.); (G.T.)
| | - Ye He
- Neuroscience Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, NY 10031, USA; (Y.H.); (J.L.)
| | - Jia Liu
- Neuroscience Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, NY 10031, USA; (Y.H.); (J.L.)
| | - Lingyan Shi
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
- Correspondence: (L.S.); (A.R.-C.)
| | - Adrián Rodríguez-Contreras
- Center for Discovery and Innovation, Department of Biology, Institute for Ultrafast Spectroscopy and Lasers, City University of New York, City College, New York, NY 10031, USA; (D.C.); (Q.B.); (G.T.)
- Correspondence: (L.S.); (A.R.-C.)
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24
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Guo M, Fang Y, Zhu J, Chen C, Zhang Z, Tian X, Xiang H, Manyande A, Ehsanifar M, Jafari AJ, Xu F, Wang J, Peng M. Investigation of metabolic kinetics in different brain regions of awake rats using the [ 1H- 13C]-NMR technique. J Pharm Biomed Anal 2021; 204:114240. [PMID: 34246879 DOI: 10.1016/j.jpba.2021.114240] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022]
Abstract
Energy metabolism and neurotransmission are necessary for sustaining normal life activities. Hence, neurological or psychiatric disorders are always associated with changes in neurotransmitters and energy metabolic states in the brain. Most studies have only focused on the most important neurotransmitters, particularly GABA and Glu, however, other metabolites such as NAA and aspartate which are also very important for cerebral function are rarely investigated. In this study, most of the metabolic kinetics information of different brain regions was investigated in awake rats using the [1H-13C]-NMR technique. Briefly, rats (n = 8) were infused [1-13C] glucose through the tail vein for two minutes. After 20 min of glucose metabolism, the animals were sacrificed and the brain tissue was extracted and treated. Utilizing the 1H observed/13C-edited nuclear magnetic resonance (POCE-NMR), the enrichment of neurochemicals was detected which reflected the metabolic changes in different brain regions and the metabolic connections between neurons and glial cells in the brain. The results suggest that the distribution of every metabolite differed from every brain region and the metabolic rate of NAA was relatively low at 8.64 ± 2.37 μmol/g/h. In addition, there were some correlations between several 13C enriched metabolites, such as Glu4-Gln4 (p = 0.062), Glu4-GABA2 (p < 0.01), Glx2-Glx3 (p < 0.001), Asp3-NAA3 (p < 0.001). This correlativity reflects the signal transmission between astrocytes and neurons, as well as the potential interaction between energy metabolism and neurotransmission. In conclusion, the current study systematically demonstrated the metabolic kinetics in the brain which shed light on brain functions and the mechanisms of various pathophysiological states.
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Affiliation(s)
- Meimei Guo
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China; Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR China
| | - Yuanyuan Fang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China; Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR China
| | - Jinpiao Zhu
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China; Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR China
| | - Chang Chen
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China
| | - Zongze Zhang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China
| | - Xuebi Tian
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, PR China
| | - Hongbing Xiang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, PR China
| | - Anne Manyande
- School of Human and Social Sciences, University of West London, London, UK
| | - Mojtaba Ehsanifar
- Department of Environmental Health Engineering, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ahmad Jonidi Jafari
- Department of Environmental Health Engineering, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Fuqiang Xu
- Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Jie Wang
- Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, 2nd Hospital of Shijiazhuang, Shijiazhuang, Hebei, 050051, PR China.
| | - Mian Peng
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, PR China.
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25
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Resting-state brain metabolic fingerprinting clusters (biomarkers) and predictive models for major depression in multiple myeloma patients. PLoS One 2021; 16:e0251026. [PMID: 33956824 PMCID: PMC8101966 DOI: 10.1371/journal.pone.0251026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 04/17/2021] [Indexed: 01/18/2023] Open
Abstract
Background Major depression is a common comorbidity in cancer patients. Oncology clinics lack practical, objective tools for simultaneous evaluation of cancer and major depression. Fludeoxyglucose F-18 positron emission tomography–computed tomography (FDG PET/CT) is universally applied in modern medicine. Methods We used a retrospective analysis of whole-body FDG PET/CT images to identify brain regional metabolic patterns of major depression in multiple myeloma patients. The study included 134 multiple myeloma (MM) patients, 38 with major depression (group 1) and 96 without major depression (group 2). Results In the current study, Statistic Parameter Mapping (SPM) demonstrated that the major depression patient group (n = 38) had significant regional metabolic differences (clusters of continuous voxels) as compared to the non-major depression group (n = 96) with the criteria of height threshold T = 4.38 and extent threshold > 100 voxels. The five significant hypo- and three hyper-metabolic clusters from the computed T contrast maps were localized on the glass-brain view, consistent with published brain metabolic changes in major depression patients. Subsequently, using these clusters as features for classification learner, the fine tree and medium tree algorithms from 25 classification algorithms best fitted our data (accuracy 0.85%; AUC 0.88; sensitivity 79%; and specificity 88%). Conclusion This study demonstrated that whole-body FDG PET/CT scans could provide added value for screening for major depression in cancer patients in addition to staging and evaluating response to chemoradiation therapies.
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26
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Zhao Q, Pohl KM, Sullivan EV, Pfefferbaum A, Zahr NM. Jacobian Mapping Reveals Converging Brain Substrates of Disruption and Repair in Response to Ethanol Exposure and Abstinence in 2 Strains of Rats. Alcohol Clin Exp Res 2021; 45:92-104. [PMID: 33119896 PMCID: PMC8138868 DOI: 10.1111/acer.14496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/22/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND In a previous study using Jacobian mapping to evaluate the morphological effects on the brain of binge (4-day) intragastric ethanol (EtOH) on wild-type Wistar rats, we reported reversible thalamic shrinkage and lateral ventricular enlargement, but persistent superior and inferior colliculi shrinkage in response to binge EtOH treatment. METHODS Herein, we used similar voxel-based comparisons of Magnetic Resonance Images collected in EtOH-exposed relative to control animals to test the hypothesis that regardless of the intoxication protocol or the rat strain, the hippocampi, thalami, and colliculi would be affected. RESULTS Two experiments [binge (4-day) intragastric EtOH in Fisher 344 rats and chronic (1-month) vaporized EtOH in Wistar rats] showed similarly affected brain regions including retrosplenial and cingulate cortices, dorsal hippocampi, central and ventroposterior thalami, superior and inferior colliculi, periaqueductal gray, and corpus callosum. While most of these regions showed significant recovery, volumes of the colliculi and periaqueductal gray continued to show response to each proximal EtOH exposure but at diminished levels with repeated cycles. CONCLUSIONS Given the high metabolic rate of these enduringly affected regions, the current findings suggest that EtOH per se may affect cellular respiration leading to brain volume deficits. Further, responsivity greatly diminished likely reflecting neuroadaptation to repeated alcohol exposure. In summary, this unbiased, in vivo-based approach demonstrating convergent brain systems responsive to 2 EtOH exposure protocols in 2 rat strains highlights regions that warrant further investigation in both animal models of alcoholism and in humans with alcohol use disorder.
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Affiliation(s)
- Qingyu Zhao
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA 94305
| | - Kilian M. Pohl
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA 94305
- Neuroscience Program, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025
| | - Edith V. Sullivan
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA 94305
| | - Adolf Pfefferbaum
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA 94305
- Neuroscience Program, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025
| | - Natalie M. Zahr
- Neuroscience Program, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025
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27
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Davis KM, Ryan JL, Aaron VD, Sims JB. PET and SPECT Imaging of the Brain: History, Technical Considerations, Applications, and Radiotracers. Semin Ultrasound CT MR 2020; 41:521-529. [PMID: 33308491 DOI: 10.1053/j.sult.2020.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Advances in nuclear medicine have revolutionized our ability to accurately diagnose patients with a wide array of neurologic pathologies and provide appropriate therapy. The development of new radiopharmaceuticals has made possible the identification of regional differences in brain tissue composition and metabolism. In addition, the evolution of 3-dimensional molecular imaging followed by fusion with computed tomography and magnetic resonance imaging have allowed for more precise localization of pathologies. This review will introduce single photon emission computed tomography and positron emission tomographic imaging of the brain, including the history of their development, technical considerations, and a brief overview of pertinent radiopharmaceuticals and their applications.
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Affiliation(s)
- Korbin M Davis
- Indiana University School of Medicine, Department of Radiology and Imaging Sciences, Indianapolis, IN.
| | - Joshua L Ryan
- Indiana University School of Medicine, Department of Radiology and Imaging Sciences, Indianapolis, IN
| | - Vasantha D Aaron
- Indiana University School of Medicine, Department of Radiology and Imaging Sciences, Indianapolis, IN
| | - Justin B Sims
- Indiana University School of Medicine, Department of Radiology and Imaging Sciences, Indianapolis, IN
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28
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Bordia T, Zahr NM. The Inferior Colliculus in Alcoholism and Beyond. Front Syst Neurosci 2020; 14:606345. [PMID: 33362482 PMCID: PMC7759542 DOI: 10.3389/fnsys.2020.606345] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/02/2020] [Indexed: 12/28/2022] Open
Abstract
Post-mortem neuropathological and in vivo neuroimaging methods have demonstrated the vulnerability of the inferior colliculus to the sequelae of thiamine deficiency as occurs in Wernicke-Korsakoff Syndrome (WKS). A rich literature in animal models ranging from mice to monkeys-including our neuroimaging studies in rats-has shown involvement of the inferior colliculi in the neural response to thiamine depletion, frequently accomplished with pyrithiamine, an inhibitor of thiamine metabolism. In uncomplicated alcoholism (i.e., absent diagnosable neurological concomitants), the literature citing involvement of the inferior colliculus is scarce, has nearly all been accomplished in preclinical models, and is predominately discussed in the context of ethanol withdrawal. Our recent work using novel, voxel-based analysis of structural Magnetic Resonance Imaging (MRI) has demonstrated significant, persistent shrinkage of the inferior colliculus using acute and chronic ethanol exposure paradigms in two strains of rats. We speculate that these consistent findings should be considered from the perspective of the inferior colliculi having a relatively high CNS metabolic rate. As such, they are especially vulnerable to hypoxic injury and may be provide a common anatomical link among a variety of disparate insults. An argument will be made that the inferior colliculi have functions, possibly related to auditory gating, necessary for awareness of the external environment. Multimodal imaging including diffusion methods to provide more accurate in vivo visualization and quantification of the inferior colliculi may clarify the roles of brain stem nuclei such as the inferior colliculi in alcoholism and other neuropathologies marked by altered metabolism.
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Affiliation(s)
- Tanuja Bordia
- Neuroscience Program, SRI International, Menlo Park, CA, United States
| | - Natalie M. Zahr
- Neuroscience Program, SRI International, Menlo Park, CA, United States
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
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29
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Kilonzo VW, Sweet RA, Glausier JR, Pitts MW. Deficits in Glutamic Acid Decarboxylase 67 Immunoreactivity, Parvalbumin Interneurons, and Perineuronal Nets in the Inferior Colliculus of Subjects With Schizophrenia. Schizophr Bull 2020; 46:1053-1059. [PMID: 32681171 PMCID: PMC7505180 DOI: 10.1093/schbul/sbaa082] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aberrant processing of auditory stimuli is a prominent feature of schizophrenia (SZ). Prior studies have chronicled histological abnormalities in the auditory cortex of SZ subjects, but whether deficits exist at upstream, subcortical levels has yet to be established. En route to the auditory cortex, ascending information is integrated in the inferior colliculus (IC), a highly gamma amino butyric acid (GABA) ergic midbrain structure that is critically involved in auditory processing. The IC contains a dense population of parvalbumin-immunoreactive interneurons (PVIs), a cell type characterized by increased metabolic demands and enhanced vulnerability to oxidative stress. During development, PVIs are preferentially surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures that promote redox homeostasis and excitatory/inhibitory balance. Moreover, in SZ, deficits in PVIs, PNNs, and the GABA synthesizing enzyme, glutamic acid decarboxylase (Gad67), have been extensively documented in cortical regions. Yet, whether similar impairments exist in the IC is currently unknown. Thus, we compared IC samples of age- and sex-matched pairs of SZ and unaffected control subjects. SZ subjects exhibited lower levels of Gad67 immunoreactivity and a decreased density of PVIs and PNNs within the IC. These findings provide the first histological evidence of IC GABAergic abnormalities in SZ and suggest that SZ-related auditory dysfunction may stem, in part, from altered IC inhibitory tone.
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Affiliation(s)
- Victor W Kilonzo
- Department of Cell and Molecular Biology, University of Hawaii, Honolulu, HI
| | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Jill R Glausier
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Matthew W Pitts
- Department of Cell and Molecular Biology, University of Hawaii, Honolulu, HI
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30
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Reevaluation of Astrocyte-Neuron Energy Metabolism with Astrocyte Volume Fraction Correction: Impact on Cellular Glucose Oxidation Rates, Glutamate-Glutamine Cycle Energetics, Glycogen Levels and Utilization Rates vs. Exercising Muscle, and Na +/K + Pumping Rates. Neurochem Res 2020; 45:2607-2630. [PMID: 32948935 DOI: 10.1007/s11064-020-03125-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 12/22/2022]
Abstract
Accurate quantification of cellular contributions to rates of substrate utilization in resting, activated, and diseased brain is essential for interpretation of data from studies using [18F]fluorodeoxyglucose-positron-emission tomography (FDG-PET) and [13C]glucose/magnetic resonance spectroscopy (MRS). A generally-accepted dogma is that neurons have the highest energy demands of all brain cells, and calculated neuronal rates of glucose oxidation in awake, resting brain accounts for 70-80%, with astrocytes 20-30%. However, these proportions do not take cell type volume fractions into account. To evaluate the conclusion that neuron-astrocyte glucose oxidation rates are similar when adjusted for astrocytic volume fraction (Hertz, Magn Reson Imaging 2011; 29, 1319), the present study analyzed data from 31 studies. On average, astrocytes occupy 6.1, 9.6, and 15% of tissue volume in hippocampus, cerebral cortex, and cerebellum, respectively, and regional astrocytic metabolic rates are adjusted for volume fraction by multiplying by 17.6, 11.4, and 6.8, respectively. After adjustment, astrocytic glucose oxidation rates in resting awake rat brain are 4-10 fold higher than neuronal oxidation rates. Volume-fraction adjustment also increases brain glycogen concentrations and utilization rates to be similar to or exceed exercising muscle. Ion flux calculations to evaluate sodium/potassium homeostasis during neurotransmission are not correct if astrocyte-neuron volume fractions are assumed to be equal. High rates of glucose and glycogen utilization after adjustment for volume fraction indicate that astrocytic energy demands are much greater than recognized, with most of the ATP being used for functions other than glutamate processing in the glutamate-glutamine cycle, challenging the notion that astrocytes 'feed hungry neurons'.
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Dienel GA. Hypothesis: A Novel Neuroprotective Role for Glucose-6-phosphatase (G6PC3) in Brain-To Maintain Energy-Dependent Functions Including Cognitive Processes. Neurochem Res 2020; 45:2529-2552. [PMID: 32815045 DOI: 10.1007/s11064-020-03113-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022]
Abstract
The isoform of glucose-6-phosphatase in liver, G6PC1, has a major role in whole-body glucose homeostasis, whereas G6PC3 is widely distributed among organs but has poorly-understood functions. A recent, elegant analysis of neutrophil dysfunction in G6PC3-deficient patients revealed G6PC3 is a neutrophil metabolite repair enzyme that hydrolyzes 1,5-anhydroglucitol-6-phosphate, a toxic metabolite derived from a glucose analog present in food. These patients exhibit a spectrum of phenotypic characteristics and some have learning disabilities, revealing a potential linkage between cognitive processes and G6PC3 activity. Previously-debated and discounted functions for brain G6PC3 include causing an ATP-consuming futile cycle that interferes with metabolic brain imaging assays and a nutritional role involving astrocyte-neuron glucose-lactate trafficking. Detailed analysis of the anhydroglucitol literature reveals that it competes with glucose for transport into brain, is present in human cerebrospinal fluid, and is phosphorylated by hexokinase. Anhydroglucitol-6-phosphate is present in rodent brain and other organs where its accumulation can inhibit hexokinase by competition with ATP. Calculated hexokinase inhibition indicates that energetics of brain and erythrocytes would be more adversely affected by anhydroglucitol-6-phosphate accumulation than heart. These findings strongly support the paradigm-shifting hypothesis that brain G6PC3 removes a toxic metabolite, thereby maintaining brain glucose metabolism- and ATP-dependent functions, including cognitive processes.
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Affiliation(s)
- Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Mail Slot 500, Little Rock, AR, 72205, USA.
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
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Qiu J, Singh P, Pan G, de Paolis A, Champagne FA, Liu J, Cardoso L, Rodríguez-Contreras A. Defining the relationship between maternal care behavior and sensory development in Wistar rats: Auditory periphery development, eye opening and brain gene expression. PLoS One 2020; 15:e0237933. [PMID: 32822407 PMCID: PMC7442246 DOI: 10.1371/journal.pone.0237933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 08/05/2020] [Indexed: 12/18/2022] Open
Abstract
Defining the relationship between maternal care, sensory development and brain gene expression in neonates is important to understand the impact of environmental challenges during sensitive periods in early life. In this study, we used a selection approach to test the hypothesis that variation in maternal licking and grooming (LG) during the first week of life influences sensory development in Wistar rat pups. We tracked the onset of the auditory brainstem response (ABR), the timing of eye opening (EO), middle ear development with micro-CT X-ray tomography, and used qRT-PCR to monitor changes in gene expression of the hypoxia-sensitive pathway and neurotrophin signaling in pups reared by low-LG or high-LG dams. The results show the first evidence that the transcription of genes involved in the hypoxia-sensitive pathway and neurotrophin signaling is regulated during separate sensitive periods that occur before and after hearing onset, respectively. Although the timing of ABR onset, EO, and the relative mRNA levels of genes involved in the hypoxia-sensitive pathway did not differ between pups from different LG groups, we found statistically significant increases in the relative mRNA levels of four genes involved in neurotrophin signaling in auditory brain regions from pups of different LG backgrounds. These results suggest that sensitivity to hypoxic challenge might be widespread in the auditory system of neonate rats before hearing onset, and that maternal LG may affect the transcription of genes involved in experience-dependent neuroplasticity.
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Affiliation(s)
- Jingyun Qiu
- Department of Biology and Center for Discovery and Innovation, City College, City University of New York, New York, New York, United States of America
| | - Preethi Singh
- Department of Biology and Center for Discovery and Innovation, City College, City University of New York, New York, New York, United States of America
| | - Geng Pan
- Department of Biology and Center for Discovery and Innovation, City College, City University of New York, New York, New York, United States of America
| | - Annalisa de Paolis
- Department of Biomedical Engineering, City College, City University of New York, New York, New York, United States of America
| | - Frances A. Champagne
- Department of Psychology, University of Texas at Austin, Austin, Texas, United States of America
| | - Jia Liu
- Neuroscience Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, New York, United States of America
| | - Luis Cardoso
- Department of Biomedical Engineering, City College, City University of New York, New York, New York, United States of America
| | - Adrián Rodríguez-Contreras
- Department of Biology and Center for Discovery and Innovation, City College, City University of New York, New York, New York, United States of America
- * E-mail:
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33
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McGregor M, Richer K, Ananth M, Thanos PK. The functional networks of a novel environment: Neural activity mapping in awake unrestrained rats using positron emission tomography. Brain Behav 2020; 10:e01646. [PMID: 32562468 PMCID: PMC7428510 DOI: 10.1002/brb3.1646] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 04/01/2020] [Accepted: 04/02/2020] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Novel environment stimulation is thought to have an important role in cognitive development and has been shown to encourage exploratory behavior in rats. However, psychopathology or perceived danger or stress can impede this exploratory drive. The balance between brain circuits controlling the exploratory drive elicited by a novel environment, and the avoidance response to stressors, is not well understood. METHODS Using positron emission tomography (PET) and the glucose analog [18 F]fluorodeoxyglucose (18F-FDG), we assessed awake brain glucose metabolism (BGluM) in rats while in a novel environment (cage of an unfamiliar male rat) and non-novel environment (the animal's home cage). RESULTS Exposure to the novel environment increased BGluM in regions associated with vision (visual cortex), motor function and motivated behavior (striatum and motor cortex), and anxiety (stria terminalis), and decreased BGluM in regions associated with auditory processing (auditory cortex, insular cortex, inferior colliculus), locomotor activity (globus pallidus, striatum, motor cortex, ventral thalamic nucleus), spatial navigation (retrosplenial cortex), and working memory (hippocampus, cingulate cortex, prelimbic cortex, orbitofrontal cortex). CONCLUSION These results suggest that the novel cage is a stressful environment that inhibits activity in brain regions associated with exploratory behavior. Patterns of inhibition in the novel cage also support the proposed rat default mode network, indicating that animals are more cognitively engaged in this environment. Additionally, these data support the unique capability of combining FDG-PET with psychopharmacology experiments to examine novelty seeking and brain activation in the context of decision making, risk taking, and cognitive function more generally, along with response to environmental or stress challenges.
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Affiliation(s)
- Matthew McGregor
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Kaleigh Richer
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA.,Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA
| | - Mala Ananth
- Department of Neurobiology, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Panayotis K Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA.,Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA
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34
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Deme P, Rojas C, Slusher BS, Rais R, Afghah Z, Geiger JD, Haughey NJ. Bioenergetic adaptations to HIV infection. Could modulation of energy substrate utilization improve brain health in people living with HIV-1? Exp Neurol 2020; 327:113181. [PMID: 31930991 PMCID: PMC7233457 DOI: 10.1016/j.expneurol.2020.113181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 12/10/2019] [Accepted: 01/10/2020] [Indexed: 12/18/2022]
Abstract
The human brain consumes more energy than any other organ in the body and it relies on an uninterrupted supply of energy in the form of adenosine triphosphate (ATP) to maintain normal cognitive function. This constant supply of energy is made available through an interdependent system of metabolic pathways in neurons, glia and endothelial cells that each have specialized roles in the delivery and metabolism of multiple energetic substrates. Perturbations in brain energy metabolism is associated with a number of different neurodegenerative conditions including impairments in cognition associated with infection by the Human Immunodeficiency Type 1 Virus (HIV-1). Adaptive changes in brain energy metabolism are apparent early following infection, do not fully normalize with the initiation of antiretroviral therapy (ART), and often worsen with length of infection and duration of anti-retroviral therapeutic use. There is now a considerable amount of cumulative evidence that suggests mild forms of cognitive impairments in people living with HIV-1 (PLWH) may be reversible and are associated with specific modifications in brain energy metabolism. In this review we discuss brain energy metabolism with an emphasis on adaptations that occur in response to HIV-1 infection. The potential for interventions that target brain energy metabolism to preserve or restore cognition in PLWH are also discussed.
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Affiliation(s)
- Pragney Deme
- The Johns Hopkins University School of Medicine, Department of Neurology, United States
| | - Camilo Rojas
- The Johns Hopkins University School of Medicine, Department of Comparative Medicine and Pathobiology, United States
| | - Barbara S Slusher
- The Johns Hopkins University School of Medicine, Department of Neurology, United States; The Johns Hopkins University School of Medicine, Department of The Solomon H. Snyder Department of Neuroscience, United States; The Johns Hopkins University School of Medicine, Department of Comparative Medicine and Pathobiology, United States; The Johns Hopkins University School of Medicine, Department of Psychiatry, United States
| | - Raina Rais
- The Johns Hopkins University School of Medicine, Department of Neurology, United States; The Johns Hopkins University School of Medicine, Department of The Solomon H. Snyder Department of Neuroscience, United States; The Johns Hopkins University School of Medicine, Department of Comparative Medicine and Pathobiology, United States; The Johns Hopkins University School of Medicine, Department of Psychiatry, United States
| | - Zahra Afghah
- The University of North Dakota School of Medicine and Health Sciences, Department of Biomedical Sciences, United States
| | - Jonathan D Geiger
- The University of North Dakota School of Medicine and Health Sciences, Department of Biomedical Sciences, United States
| | - Norman J Haughey
- The Johns Hopkins University School of Medicine, Department of Neurology, United States; The Johns Hopkins University School of Medicine, Department of Psychiatry, United States.
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McNay EC, Pearson-Leary J. GluT4: A central player in hippocampal memory and brain insulin resistance. Exp Neurol 2020; 323:113076. [PMID: 31614121 PMCID: PMC6936336 DOI: 10.1016/j.expneurol.2019.113076] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/19/2019] [Accepted: 10/01/2019] [Indexed: 12/24/2022]
Abstract
Insulin is now well-established as playing multiple roles within the brain, and specifically as regulating hippocampal cognitive processes and metabolism. Impairments to insulin signaling, such as those seen in type 2 diabetes and Alzheimer's disease, are associated with brain hypometabolism and cognitive impairment, but the mechanisms of insulin's central effects are not determined. Several lines of research converge to suggest that the insulin-responsive glucose transporter GluT4 plays a central role in hippocampal memory processes, and that reduced activation of this transporter may underpin the cognitive impairments seen as a consequence of insulin resistance.
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Affiliation(s)
- Ewan C McNay
- Behavioral Neuroscience, University at Albany, Albany, NY, USA.
| | - Jiah Pearson-Leary
- Department of Anesthesiology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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36
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Yu D, Yan H, Zhou J, Yang X, Lu Y, Han Y. A circuit view of deep brain stimulation in Alzheimer's disease and the possible mechanisms. Mol Neurodegener 2019; 14:33. [PMID: 31395077 PMCID: PMC6688355 DOI: 10.1186/s13024-019-0334-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 07/26/2019] [Indexed: 02/08/2023] Open
Abstract
Alzheimer's disease (AD) is characterized by chronic progressive cognitive deterioration frequently accompanied by psychopathological symptoms, including changes in personality and social isolation, which severely reduce quality of life. Currently, no viable therapies or present-day drugs developed for the treatment of AD symptoms are able to slow or reverse AD progression or prevent the advance of neurodegeneration. As such, non-drug alternatives are currently being tested, including deep brain stimulation (DBS). DBS is an established therapy for several neurological and psychiatric indications, such as movement disorders. Studies assessing DBS for other disorders have also found improvements in cognitive function, providing the impetus for clinical trials on DBS for AD. Targets of DBS in AD clinical trials and animal model studies include the fornix, entorhinal cortex (EC), nucleus basalis of Meynert (NBM), and vertical limb of diagonal band (VDB). However, there is still no comprehensive theory explaining the effects of DBS on AD symptoms or a consensus on which targets provide optimal benefits. This article reviews the anatomy of memory circuits related to AD, as well as studies on DBS rescue of AD in these circuits and the possible therapeutic mechanisms.
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Affiliation(s)
- Danfang Yu
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurology, Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan, China
| | - Huanhuan Yan
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Zhou
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaodan Yang
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Youming Lu
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. .,Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
| | - Yunyun Han
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. .,Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
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37
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Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMRO2. Neuroimage 2019; 197:742-760. [DOI: 10.1016/j.neuroimage.2017.07.041] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/10/2017] [Accepted: 07/19/2017] [Indexed: 12/22/2022] Open
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38
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Brill SE, Janz K, Singh A, Friauf E. Considerable differences between auditory medulla, auditory midbrain, and hippocampal synapses during sustained high-frequency stimulation: Exceptional vesicle replenishment restricted to sound localization circuit. Hear Res 2019; 381:107771. [PMID: 31394425 DOI: 10.1016/j.heares.2019.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/11/2019] [Accepted: 07/14/2019] [Indexed: 11/25/2022]
Abstract
Reliable synaptic transmission is essential for interneuronal communication. Synaptic inputs to auditory brainstem neurons, particularly those involved in sound localization, are characterized by resilience during sustained activity and temporal precision in the sub-millisecond range. Both features are obtained by synchronous release of a high number of synaptic vesicles following a single action potential. Here, we compare transmission behavior of three heterogeneous types of inputs in the auditory midbrain and medulla. The first terminate in the central inferior colliculus (ICc) and are glutamatergic (activated from the lateral lemniscus, LL). The medullary inputs terminate in the lateral superior olive (LSO) and are glutamatergic (from the cochlear nuclear complex, CN) or glycinergic (from the medial nucleus of the trapezoid body, MNTB). LSO neurons are the first to integrate binaural information and compute interaural level differences, whereas ICc neurons receive information from almost all auditory brainstem nuclei and construct an initial auditory image used for reflexive behavior. We hypothesized that CN-LSO and MNTB-LSO inputs are more resilient to synaptic fatigue during sustained stimulation than LL-ICc inputs. To test the hypothesis, we performed whole-cell patch-clamp recordings in acute brainstem slices of juvenile mice. We investigated the synaptic performance during prolonged periods of high-frequency stimulation (60 s, up to 200 Hz) and assessed several features, e.g. depression, recovery, latency, temporal precision, quantal size and content, readily releasable pool size, release probability, and replenishment rate. Overall, LL-ICc inputs performed less robustly and temporally precisely than CN-LSO and MNTB-LSO inputs. When stimulated at ≥50 Hz, the former depressed completely within a few seconds. In contrast, CN-LSO and MNTB-LSO inputs transmitted faithfully up to 200 Hz, indicative of very efficient replenishment mechanisms. LSO inputs also displayed considerably lower latency jitter than LL-ICc inputs. The latter behaved similarly to two types of input in the hippocampus for which we performed a meta-analysis. Mechanistically, the high-fidelity behavior of LSO inputs, particularly MNTB-LSO synapses, is based on exceptional release properties not present at auditory midbrain or hippocampal inputs. We conclude that robustness and temporal precision are hallmarks of auditory synapses in the medullary brainstem. These key features are less eminent at higher stations, such as the ICc, and they are also absent outside the central auditory system, namely the hippocampal formation.
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Affiliation(s)
- Sina E Brill
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663, Kaiserslautern, Germany
| | - Katrin Janz
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663, Kaiserslautern, Germany
| | - Abhyudai Singh
- Electrical & Computer Engineering, University of Delaware, Newark, DE, USA
| | - Eckhard Friauf
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663, Kaiserslautern, Germany.
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Viglianti BL, Wale DJ, Ma T, Johnson TD, Bohnen NI, Wong KK, Ky C, Frey KA, Townsend DM, Rubello D, Gross MD. Effects of plasma glucose levels on regional cerebral 18F-fluorodeoxyglucose uptake: Implications for dementia evaluation with brain PET imaging. Biomed Pharmacother 2019; 112:108628. [PMID: 30784923 PMCID: PMC6714976 DOI: 10.1016/j.biopha.2019.108628] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 01/22/2019] [Accepted: 01/24/2019] [Indexed: 11/19/2022] Open
Abstract
Purpose: Hyperglycemia affects FDG uptake in the brain, potentially emulating
Alzheimer’s disease in normal individuals. This study investigates
global and regional cerebral FDG uptake as a function of plasma glucose in a
cohort of patients. Methods: 120 consecutive male patients with FDG PET/CT for initial oncologic
staging (July-Dee 2015) were reviewed. Patients with dementia,
cerebrovascular accident, structural brain lesion, prior oncology treatment
or high metabolic tumor burden (recently shown affecting brain FDG uptake)
were excluded. 53 (24 nondiabetic) eligible patients (age 65.7 ± 2.8
mean ± SE) were analyzed with parametric computer software,
MIMneuro™. Regional Z-scores were evaluated as a function of plasma
glucose and age using multi variable linear mixed effects models with false
discovery analysis adjusting for multiple comparisons. If the regression
slope was significantly (p < 0.05) different than zero, hyperglycemia
effect was present. Results: There was a negative inverse relationship (p < 0.001) between
global brain FDG uptake and hyperglycemia. No regional hyperglycemia effect
on uptake were present when subjects were normalized using pons or
cerebellum. However, regional hyperglycemia effects were seen (p <
0.047–0.001) when normalizing by the whole brain. No obvious pattern
was seen in the regions affected. Age had a significant effect using whole
brain normalization (p < 0.04–0.01). Conclusions: Cortical variation in FDG uptake were identified when subjects were
hyperglycemic. However, these variations didn’t fit a particular
pattern of dementia and the severity of the affect is not likely to alter
clinical interpretation.
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Affiliation(s)
- Benjamin L Viglianti
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI, USA.
| | - Daniel J Wale
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI, USA
| | - Tianwen Ma
- Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Timothy D Johnson
- Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Nicolaas I Bohnen
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI, USA
| | - Ka Kit Wong
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Christy Ky
- University of Michigan School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kirk A Frey
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Danyelle M Townsend
- Department of Physiology, Division of New Drugs Development, University of Southern Carolina, USA
| | - Domenico Rubello
- Department of Nuclear Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy.
| | - Milton D Gross
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI, USA
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40
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Moritz CP, Mühlhaus T, Tenzer S, Schulenborg T, Friauf E. Poor transcript-protein correlation in the brain: negatively correlating gene products reveal neuronal polarity as a potential cause. J Neurochem 2019; 149:582-604. [PMID: 30664243 DOI: 10.1111/jnc.14664] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/15/2018] [Accepted: 01/02/2019] [Indexed: 01/02/2023]
Abstract
Transcription, translation, and turnover of transcripts and proteins are essential for cellular function. The contribution of those factors to protein levels is under debate, as transcript levels and cognate protein levels do not necessarily correlate due to regulation of translation and protein turnover. Here we propose neuronal polarity as a third factor that is particularly evident in the CNS, leading to considerable distances between somata and axon terminals. Consequently, transcript levels may negatively correlate with cognate protein levels in CNS regions, i.e., transcript and protein levels behave reciprocally. To test this hypothesis, we performed an integrative inter-omics study and analyzed three interconnected rat auditory brainstem regions (cochlear nuclear complex, CN; superior olivary complex, SOC; inferior colliculus, IC) and the rest of the brain as a reference. We obtained transcript and protein sets in these regions of interest (ROIs) by DNA microarrays and label-free mass spectrometry, and performed principal component and correlation analyses. We found 508 transcript|protein pairs and detected poor to moderate transcript|protein correlation in all ROIs, as evidenced by coefficients of determination from 0.34 to 0.54. We identified 57-80 negatively correlating gene products in the ROIs and intensively analyzed four of them for which the correlation was poorest. Three cognate proteins (Slc6a11, Syngr1, Tppp) were synaptic and hence candidates for a negative correlation because of protein transport into axon terminals. Thus, we systematically analyzed the negatively correlating gene products. Gene ontology analyses revealed overrepresented transport/synapse-related proteins, supporting our hypothesis. We present 30 synapse/transport-related proteins with poor transcript|protein correlation. In conclusion, our analyses support that protein transport in polar cells is a third factor that influences the protein level and, thereby, the transcript|protein correlation. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* and *Open Data* because it provided all relevant information to reproduce the study in the manuscript and because it made the data publicly available. The data can be accessed at https://osf.io/ha28n/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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Affiliation(s)
- Christian P Moritz
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.,Synaptopathies and Autoantibodies, Institut NeuroMyoGène INSERM U1217/ CNRS, UMR 5310, Faculty of Medicine, University Jean Monnet, Saint-Étienne, France
| | - Timo Mühlhaus
- Computational Systems Biology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
| | - Stefan Tenzer
- Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Thomas Schulenborg
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.,Division of Allergology, Paul-Ehrlich-Institut, Langen, Germany
| | - Eckhard Friauf
- Animal Physiology Group, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
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Abstract
Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components. Neuronal glucose oxidation exceeds that in astrocytes, but both rates increase in direct proportion to excitatory neurotransmission; signaling and metabolism are closely coupled at the local level. Exact details of neuron-astrocyte glutamate-glutamine cycling remain to be established, and the specific roles of glucose and lactate in the cellular energetics of these processes are debated. Glycolysis is preferentially upregulated during brain activation even though oxygen availability is sufficient (aerobic glycolysis). Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in excess of oxygen, and adrenergic regulation of aerobic glycolysis draws attention to astrocytic metabolism, particularly glycogen turnover, which has a high impact on the oxygen-carbohydrate mismatch. Aerobic glycolysis is proposed to be predominant in young children and specific brain regions, but re-evaluation of data is necessary. Shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation, neurotransmission, and memory consolidation are controversial topics for which alternative mechanisms are proposed. Nutritional therapy and vagus nerve stimulation are translational bridges from metabolism to clinical treatment of diverse brain disorders.
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Affiliation(s)
- Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences , Little Rock, Arkansas ; and Department of Cell Biology and Physiology, University of New Mexico , Albuquerque, New Mexico
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Rothman DL, Dienel GA. Development of a Model to Test Whether Glycogenolysis Can Support Astrocytic Energy Demands of Na +, K +-ATPase and Glutamate-Glutamine Cycling, Sparing an Equivalent Amount of Glucose for Neurons. ADVANCES IN NEUROBIOLOGY 2019; 23:385-433. [PMID: 31667817 DOI: 10.1007/978-3-030-27480-1_14] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recent studies of glycogen in brain have suggested a much more important role in brain energy metabolism and function than previously recognized, including findings of much higher than previously recognized concentrations, consumption at substantial rates compared with utilization of blood-borne glucose, and involvement in ion pumping and in neurotransmission and memory. However, it remains unclear how glycogenolysis is coupled to neuronal activity and provides support for neuronal as well as astroglial function. At present, quantitative aspects of glycogenolysis in brain functions are very difficult to assess due to its metabolic lability, heterogeneous distributions within and among cells, and extreme sensitivity to physiological stimuli. To begin to address this problem, the present study develops a model based on pathway fluxes, mass balance, and literature relevant to functions and turnover of pathways that intersect with glycogen mobilization. A series of equations is developed to describe the stoichiometric relationships between net glycogen consumption that is predominantly in astrocytes with the rate of the glutamate-glutamine cycle, rates of astrocytic and neuronal glycolytic and oxidative metabolism, and the energetics of sodium/potassium pumping in astrocytes and neurons during brain activation. Literature supporting the assumptions of the model is discussed in detail. The overall conclusion is that astrocyte glycogen metabolism is primarily coupled to neuronal function via fueling glycolytically pumping of Na+ and K+ and sparing glucose for neuronal oxidation, as opposed to previous proposals of coupling neurotransmission via glutamate transport, lactate shuttling, and neuronal oxidation of lactate.
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Affiliation(s)
- Douglas L Rothman
- Magnetic Resonance Research Center and Department of Radiology, Yale University, New Haven, CT, USA.
| | - Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.,Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, USA
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Yerys BE, Herrington JD, Bartley GK, Liu HS, Detre JA, Schultz RT. Arterial spin labeling provides a reliable neurobiological marker of autism spectrum disorder. J Neurodev Disord 2018; 10:32. [PMID: 30541425 PMCID: PMC6292037 DOI: 10.1186/s11689-018-9250-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 11/14/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Research on neurobiological markers of autism spectrum disorder (ASD) has been elusive. However, radionuclide studies of cerebral blood flow (CBF) have shown decreased blood flow (hypoperfusion) in the temporal lobes of individuals with ASD across ages and intelligence. This observation fits with current neuroscientific models that implicate temporal regions in social perception and social cognition. Arterial spin labeled perfusion MRI allows noninvasive quantification of regional CBF as part of a multimodal MRI protocol. This method is almost entirely absent from ASD research to date. Our a priori hypothesis was that children with ASD would present with hypoperfusion in the temporal lobes-most notably the fusiform gyrus (given its prominent role in ASD social perception deficits). We also sought to examine the reproducibility of CBF measures, and their relationship to individual differences in facial recognition and ASD symptoms. METHODS A total of 58 males (33 with ASD) between the ages of 12 and 17 years participated in the study. All children completed two arterial spin labeling and structural (T1) scans using a 3 T Siemens Verio scanner approximately 8 weeks apart, as well as behavioral testing at time 1 that included diagnostic measures and the Benton Facial Recognition Test. CBF was the key dependent variable, as was facial recognition performance, and ASD symptoms. The two scans were used for reliability analyses. RESULTS The ASD group showed hypoperfusion in the bilateral fusiform gyrus and in right inferior temporal gyrus. Intra-class correlations showed moderate to good reliability across time within both groups, and no diagnostic group × time interactions. CBF in the left fusiform gyrus was significantly positively correlated with facial recognition. No significant correlations were observed with core ASD symptoms. CONCLUSIONS Arterial spin labeling revealed hypoperfusion in children with ASD in regions critical to social perception and cognition. The left fusiform gyrus plays an important role in facial recognition, and greater CBF in this region was correlated with more normative facial recognition performance in children with ASD. This study takes an important first step in establishing CBF of the temporal lobes as a reliable marker of ASD.
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Affiliation(s)
- Benjamin E. Yerys
- Center for Autism Research, The Children’s Hospital of Philadelphia, Roberts Center for Pediatric Research, 2716 South Street, 5th floor, Philadelphia, PA 19146-2305 USA
- Department of Psychiatry, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
| | - John D. Herrington
- Center for Autism Research, The Children’s Hospital of Philadelphia, Roberts Center for Pediatric Research, 2716 South Street, 5th floor, Philadelphia, PA 19146-2305 USA
- Department of Psychiatry, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
| | - Gregory K. Bartley
- Center for Autism Research, The Children’s Hospital of Philadelphia, Roberts Center for Pediatric Research, 2716 South Street, 5th floor, Philadelphia, PA 19146-2305 USA
| | - Hua-Shan Liu
- Department of Neurology, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
| | - John A. Detre
- Department of Neurology, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
| | - Robert T. Schultz
- Center for Autism Research, The Children’s Hospital of Philadelphia, Roberts Center for Pediatric Research, 2716 South Street, 5th floor, Philadelphia, PA 19146-2305 USA
- Department of Psychiatry, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
- Department of Pediatrics, Perelman School Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
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Remme MWH, Rinzel J, Schreiber S. Function and energy consumption constrain neuronal biophysics in a canonical computation: Coincidence detection. PLoS Comput Biol 2018; 14:e1006612. [PMID: 30521528 PMCID: PMC6312336 DOI: 10.1371/journal.pcbi.1006612] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 12/31/2018] [Accepted: 10/29/2018] [Indexed: 12/19/2022] Open
Abstract
Neural morphology and membrane properties vary greatly between cell types in the nervous system. The computations and local circuit connectivity that neurons support are thought to be the key factors constraining the cells' biophysical properties. Nevertheless, additional constraints can be expected to further shape neuronal design. Here, we focus on a particularly energy-intense system (as indicated by metabolic markers): principal neurons in the medial superior olive (MSO) nucleus of the auditory brainstem. Based on a modeling approach, we show that a trade-off between the level of performance of a functionally relevant computation and energy consumption predicts optimal ranges for cell morphology and membrane properties. The biophysical parameters appear most strongly constrained by functional needs, while energy use is minimized as long as function can be maintained. The key factors that determine model performance and energy consumption are 1) the saturation of the synaptic conductance input and 2) the temporal resolution of the postsynaptic signals as they reach the soma, which is largely determined by active membrane properties. MSO cells seem to operate close to pareto optimality, i.e., the trade-off boundary between performance and energy consumption that is formed by the set of optimal models. Good performance for drastically lower costs could in theory be achieved by small neurons without dendrites, as seen in the avian auditory system, pointing to additional constraints for mammalian MSO cells, including their circuit connectivity.
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Affiliation(s)
- Michiel W. H. Remme
- Institute for Theoretical Biology, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
- * E-mail: (MWHR); (SS)
| | - John Rinzel
- Center for Neural Science, New York University, New York, New York, United States of America
- Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America
| | - Susanne Schreiber
- Institute for Theoretical Biology, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
- * E-mail: (MWHR); (SS)
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Molecular Imaging in Huntington's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 142:289-333. [PMID: 30409256 DOI: 10.1016/bs.irn.2018.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non-invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD.
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Dienel GA. Metabolomic Assays of Postmortem Brain Extracts: Pitfalls in Extrapolation of Concentrations of Glucose and Amino Acids to Metabolic Dysregulation In Vivo in Neurological Diseases. Neurochem Res 2018; 44:2239-2260. [DOI: 10.1007/s11064-018-2611-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/05/2018] [Accepted: 08/06/2018] [Indexed: 01/03/2023]
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McGarrity S, Mason R, Fone KC, Pezze M, Bast T. Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits. Cereb Cortex 2018; 27:4447-4462. [PMID: 27550864 DOI: 10.1093/cercor/bhw247] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 07/18/2016] [Indexed: 12/18/2022] Open
Abstract
Subconvulsive hippocampal neural disinhibition, that is reduced GABAergic inhibition, has been implicated in neuropsychiatric disorders characterized by attentional and memory deficits, including schizophrenia and age-related cognitive decline. Considering that neural disinhibition may disrupt both intra-hippocampal processing and processing in hippocampal projection sites, we hypothesized that hippocampal disinhibition disrupts hippocampus-dependent memory performance and, based on strong hippocampo-prefrontal connectivity, also prefrontal-dependent attention. In support of this hypothesis, we report that acute hippocampal disinhibition by microinfusion of the GABA-A receptor antagonist picrotoxin in rats impaired hippocampus-dependent everyday-type rapid place learning performance on the watermaze delayed-matching-to-place test and prefrontal-dependent attentional performance on the 5-choice-serial-reaction-time test, which does not normally require the hippocampus. For comparison, we also examined psychosis-related sensorimotor effects, using startle/prepulse inhibition (PPI) and locomotor testing. Hippocampal picrotoxin moderately increased locomotion and slightly reduced startle reactivity, without affecting PPI. In vivo electrophysiological recordings in the vicinity of the infusion site showed that picrotoxin mainly enhanced burst firing of hippocampal neurons. In conclusion, hippocampal neural disinhibition disrupts hippocampus-dependent memory performance and also manifests through deficits in not normally hippocampus-dependent attentional performance. These behavioral deficits may reflect a disrupted control of burst firing, which may disrupt hippocampal processing and cause aberrant drive to hippocampal projection sites.
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Affiliation(s)
- Stephanie McGarrity
- School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK.,Neuroscience@Nottingham, University of Nottingham, Nottingham NG7 2RD, UK
| | - Rob Mason
- Neuroscience@Nottingham, University of Nottingham, Nottingham NG7 2RD, UK.,School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
| | - Kevin C Fone
- Neuroscience@Nottingham, University of Nottingham, Nottingham NG7 2RD, UK.,School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
| | - Marie Pezze
- School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK.,Neuroscience@Nottingham, University of Nottingham, Nottingham NG7 2RD, UK
| | - Tobias Bast
- School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK.,Neuroscience@Nottingham, University of Nottingham, Nottingham NG7 2RD, UK
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Measurement of pediatric regional cerebral blood flow from 6 months to 15 years of age in a clinical population. Eur J Radiol 2018; 101:38-44. [DOI: 10.1016/j.ejrad.2018.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/17/2017] [Accepted: 02/05/2018] [Indexed: 12/16/2022]
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Abstract
Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.
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50
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Brosel S, Grothe B, Kunz L. An auditory brainstem nucleus as a model system for neuronal metabolic demands. Eur J Neurosci 2018; 47:222-235. [PMID: 29205598 DOI: 10.1111/ejn.13789] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 02/03/2023]
Abstract
The correlation between neuronal activity and metabolism is essential for coding, plasticity, neurological disorders and the interpretation of functional neuroimaging data. Most likely, metabolic requirements depend upon neuron type, and macroscopic energy demands vary with brain region. However, specific needs of individual neuron types are enigmatic. Therefore, we monitored metabolic activity in the lateral superior olive (LSO), an auditory brainstem nucleus containing only one neuron type. LSO neurons exhibit extreme but well-described biophysics with firing rates of several hundred hertz and low input resistances of a few megaohms. We recorded changes in NADH and flavin adenine dinucleotide (FAD) autofluorescence and O2 concentration in acute brainstem slices of Mongolian gerbils (Meriones unguiculatus) following electrical stimulation. The LSO shows the typical biphasic NADH/FAD response up to a physiologically relevant frequency of 400 Hz. In the same animal, we compared the LSO with the hippocampal CA1 region and the cerebral cortex. The rate of NADH/FADH2 consumption and regeneration was slowest in LSO. However, frequency dependence was only similar during the consumption phase but varied during regeneration within the three brain regions. Changes in NADH, FAD and O2 levels and blocking metabolic reactions indicate a pronounced contribution of mitochondrial oxidative phosphorylation in the LSO which is known for the other brain regions as well. Lactate transport and interconversion are involved in LSO metabolism as we found in immunohistochemical and pharmacological experiments. Our findings show that the LSO represents an apt, biophysically distinct model for brain metabolism and that neuronal properties determine metabolic needs.
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Affiliation(s)
- Sonja Brosel
- Department Biology II, Division of Neurobiology, LMU Munich, Großhaderner Str. 2, 82152, Planegg-Martinsried, Germany
| | - Benedikt Grothe
- Department Biology II, Division of Neurobiology, LMU Munich, Großhaderner Str. 2, 82152, Planegg-Martinsried, Germany
| | - Lars Kunz
- Department Biology II, Division of Neurobiology, LMU Munich, Großhaderner Str. 2, 82152, Planegg-Martinsried, Germany
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