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An L, Hong S, Turon T, Pavletic A, Johnson CS, Derbyshire JA, Shen J. Enhanced detection of glutamate via transverse relaxation encoding with narrowband decoupling in the human brain. Magn Reson Med 2025; 93:2278-2286. [PMID: 39834120 PMCID: PMC11971497 DOI: 10.1002/mrm.30431] [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: 07/18/2024] [Revised: 11/23/2024] [Accepted: 12/30/2024] [Indexed: 01/22/2025]
Abstract
PURPOSE This study aims to improve the detection of glutamate (Glu) concentration and T2 using an enhanced transverse relaxation encoding with narrowband decoupling (TREND) technique. METHODS A new editing pulse was designed to simultaneously invert both Glu H3 spins (2.12 ppm and 2.05 ppm) while minimizing the excitation of Glu H4. Additionally, a frequency band was created to invert the lactate (Lac) H2 spin (4.10 ppm) while saturating the NAA aspartyl H2 spin (4.38 ppm). Numerical simulations compared Glu and Lac signals using the original and new editing pulses. In vivo experiments were conducted on healthy participants at 7 T to validate this enhanced TREND technique. RESULTS Numerical simulations showed prominently enhanced Glu and Lac resonance signals with the new editing pulse. In vivo spectra showed a 47% ± 14% increase in Glu/Cr peak amplitude ratios with the new editing pulse. Using the enhanced TREND sequence, Glu/Cr concentration ratios in the anterior cingulate cortex were 1.03 ± 0.07 with Cramer-Rao lower bounds (CRLBs) of 1.1% ± 0.1%, and Glu T2 values were 179 ± 18 ms with CRLBs of 1.2% ± 0.1%. The Lac/Cr concentration ratios in the same voxels were 0.05 ± 0.01 with CRLBs of 26% ± 14%, and Lac T2 values were 196 ± 23 ms with CRLBs of 22% ± 15%. CONCLUSION The new editing pulse significantly enhanced the detection of Glu and enabled the detection of Lac using TREND for measuring both the concentration and T2 of the markers of oxidative metabolism and glycolysis.
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Affiliation(s)
- Li An
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
| | - Sungtak Hong
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
| | - Tara Turon
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
| | - Adriana Pavletic
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
| | | | - John A. Derbyshire
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
| | - Jun Shen
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National Institute of Mental Health, National Institutes of HealthBethesdaMarylandUSA
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2
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Sun WX, Chen TY, Song MM, Gao YJ, Xu SY. Energy metabolism disorders in migraine: triggers, pathways, and therapeutic repurposing. Front Neurol 2025; 16:1561000. [PMID: 40242623 PMCID: PMC12002086 DOI: 10.3389/fneur.2025.1561000] [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: 01/15/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Many migraine triggers, such as stress, sleep deprivation, fatigue, strenuous exercise, and fasting, are potentially linked to disturbances in brain energy metabolism, mitochondrial function, and oxidative stress. Alongside efforts to avoid modifiable factors, prophylactic migraine treatments that target brain energy metabolism have garnered increasing attention. However, the current evidence supporting the use of energy-modulating drugs in migraine treatment guidelines remains weak. This narrative review explores the relationship between energy metabolism and cortical spreading depression susceptibility, metabolic alterations in migraine (including glucose and insulin metabolism, insulin resistance, lipid metabolism, and energy metabolism imaging markers), oxidative stress and antioxidant defenses, mitochondrial dysfunction, and the role of energy metabolism-targeted medications in migraine management. Nutrients may help improve mitochondrial function, thereby alleviating brain energy metabolism deficits and oxidative stress in migraine.
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Affiliation(s)
- Wen-xiu Sun
- Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ting-yan Chen
- Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Mao-mei Song
- Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ying-jie Gao
- Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sui-yi Xu
- Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Neurology, Headache Center, Tianjin First Central Hospital, Tianjin, China
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3
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Tiryaki İ, Kadak KS, Karakulak EZ, Korkmaz OE, Sever O, Esin İS. Effects of exercise on response inhibition performance in adolescent males with attention deficit hyperactivity disorder: A fNIRS Study. Psychiatry Res Neuroimaging 2025; 348:111963. [PMID: 39985961 DOI: 10.1016/j.pscychresns.2025.111963] [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: 12/05/2024] [Revised: 01/23/2025] [Accepted: 02/11/2025] [Indexed: 02/24/2025]
Abstract
This study aimed to examine the impact of exercise on Go/No-Go task behavioral performance, variations in average oxyhemoglobin concentration in the dorsolateral prefrontal cortex (DLPFC), and capillary lactate levels in adolescent males with Attention Deficit Hyperactivity Disorder (ADHD) compared to their healthy peers. This study also aimed to examine the relationships between exercise-induced changes in capillary lactate levels, Go/No-Go task performance, and average oxyhemoglobin concentration in the DLPFC. The study included 20 male adolescents diagnosed with ADHD as the case group and 20 healthy male adolescents as the control group. In the pre-exercise assessment, the case group showed significantly lower oxyhemoglobin concentration in the DLPFC and fewer correct responses on the Go/No-Go task. However, the difference in oxyhemoglobin concentration during the 'Go' blocks remained significant after exercise, whereas the difference in the 'No-Go' blocks lost significance post-exercise. No significant difference in capillary lactate levels was observed between the groups, either pre- or post-exercise. No direct relationship was observed between changes in capillary lactate levels from pre- to post-exercise and changes in behavioral performance or brain activation. Consistent with the literature, we observed positive changes in certain behavioral performance data following exercise. Further studies are needed with larger sample sizes, including both genders and a wider age range of children and adolescents.
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Affiliation(s)
| | - Kübra Soğukkanlı Kadak
- The Dream, Sleep and Hypnosis Research Centre (RUHMER), Medipol University, Istanbul, Turkey
| | - Ece Zeynep Karakulak
- The Dream, Sleep and Hypnosis Research Centre (RUHMER), Medipol University, Istanbul, Turkey; Istanbul Atlas University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, İstanbul, Turkey
| | - Onur Erdem Korkmaz
- Department of Electrical and Electronic Engineering, Engineering Faculty, Ataturk University, Erzurum, Turkey
| | - Ozan Sever
- Department of Recreation, Faculty of Sport Sciences, Ataturk University, Erzurum, Turkey
| | - İbrahim Selçuk Esin
- Department of Child and Adolescent Psychiatry, Faculty of Medicine, Health Sciences University, Trabzon, Turkey.
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4
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Li M, Liu T, Zhang Y, Yang M, Li Z, He J, Li J. Fructose-Driven glycolysis supports synaptic function in subterranean rodent - Gansu Zokor (Eospalax cansus). Neuroscience 2025; 568:139-153. [PMID: 39824341 DOI: 10.1016/j.neuroscience.2025.01.025] [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: 07/17/2024] [Revised: 12/15/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
Several studies indicate that fructose can be used as an energy source for subterranean rodents. However, how subterranean rodents utilize fructose metabolism with no apparent physiological drawbacks remains poorly understood. In the present study, we measured field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from Gansu zokor and SD rats hippocampi before and 60 min after replacement of 10 mM glucose in the artificial cerebrospinal fluid (ACSF) with 10 mM fructose (gassed with 95 % O2 and 5 % CO2). Subsequently, we performed transcriptome analysis on Gansu zokor brains incubated with ACSF containing 10 mM fructose and determined the contents of fructose, lactate, ATP, and UA. Whole brain RNA and proteins were extracted to detect the transcriptional levels of Glut5, Khk, Aldoc, and Cs and the translational levels of GLUT5, CS, NRF2, and c-FOS. The results showed that Gansu zokor brains exhibit higher levels of GLUT5 protein and Khk mRNA levels than SD rats to facilitate fructose uptake and metabolism, resulting in increased fructose, ATP, and lactate content in the brain during fructose incubation. Stable UA levels during fructose metabolism reduce the risk of oxidative stress and neuroinflammation, and activation of the Nrf2 pathway increases downstream antioxidant capacity, thereby reducing brain damage. Persistent fEPSP signaling suggests that fructose supports excitatory synaptic transmission in the CA1 region of the hippocampus of the Gansu zokor but leads to hippocampal dysfunction in SD rats. The unique insights about fructose metabolism in the brain of Gansu zokor obtained in our study will be useful for further studies on the evolution of subterranean rodents.
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Affiliation(s)
- Meng Li
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, China; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, China; College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Tianyi Liu
- College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Yingying Zhang
- College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Maohong Yang
- College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Zhuohang Li
- College of Life Science, Shaanxi Normal University, Xi'an, China
| | - Jianping He
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, China; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, China; College of Life Science, Shaanxi Normal University, Xi'an, China.
| | - Jingang Li
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, China; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, China; College of Life Science, Shaanxi Normal University, Xi'an, China.
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5
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Li X, Zhao Z, Ke Y, Jiang Y, Liu Y, Liu Z. Links Between Cellular Energy Metabolism and Pain Sensation. Anesth Analg 2025; 140:616-627. [PMID: 39110636 PMCID: PMC11805490 DOI: 10.1213/ane.0000000000007096] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 02/09/2025]
Abstract
One of the functions of organism cells is to maintain energy homeostasis to promote metabolism and adapt to the environment. The 3 major pathways of cellular energy metabolism are glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Neurons, astrocytes, and microglia are crucial in allodynia, hyperalgesia, and sensitization in nociceptive pathways. This review focused on these 3 major cellular energy metabolism pathways, aiming to elucidate the relationship between neurocyte and pain sensation and present the reprogramming of energy metabolism on pain, as well as the cellular and molecular mechanism underlying various forms of pain. The clinical and preclinical drugs involved in pain treatment and molecular mechanisms via cellular energy metabolism were also discussed.
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Affiliation(s)
- Xiongjuan Li
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Zhao Zhao
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yuwen Ke
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yonghan Jiang
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yuqiang Liu
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Zhiheng Liu
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
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6
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Guedj E, Cionca A, Péron JA, Ayubcha C, Assal F, Horowitz T, Alavi A. Long Coronavirus Disease and the Brain: Molecular Neuroimaging Insights into Neurologic and Psychiatric Sequelae. PET Clin 2025; 20:39-55. [PMID: 39482218 DOI: 10.1016/j.cpet.2024.09.013] [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] [Indexed: 11/03/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has led to a variety of health challenges, with "long COVID" emerging as a widespread and debilitating post-acute syndrome among a considerable number of infected patients. This PET review synthesizes current evidence of the neurologic and psychiatric sequelae of COVID. This review also explores the pathophysiological mechanisms of these results, including astrocyte dysfunction and glutamate dysregulation, as well as the multimodal comparison to MR imaging findings. The findings underscore the potential for long-term brain injury. Additionally, the authors discuss the role of advanced imaging multimodal techniques in diagnosing, monitoring, and guiding treatment strategies for long COVID.
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Affiliation(s)
- Eric Guedj
- Biophysics and Nuclear Medicine, Aix Marseille University, Marseille, France; APHM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, Marseille, France; Nuclear Medicine Department, CERIMED, Marseille, France.
| | - Alexandre Cionca
- Neuro-X Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Julie A Péron
- Clinical and Experimental Neuropsychology Laboratory, Faculty of Psychology, University of Geneva, Geneva, Switzerland; Neurology Division, Geneva University Hospitals, Geneva, Switzerland
| | - Cyrus Ayubcha
- Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Frédéric Assal
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Tatiana Horowitz
- Biophysics and Nuclear Medicine, Aix Marseille University, Marseille, France; APHM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, Marseille, France; Nuclear Medicine Department, CERIMED, Marseille, France
| | - Abass Alavi
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
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7
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Sámano C, Mazzone GL. The role of astrocytes response triggered by hyperglycaemia during spinal cord injury. Arch Physiol Biochem 2024; 130:724-741. [PMID: 37798949 DOI: 10.1080/13813455.2023.2264538] [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: 03/24/2023] [Accepted: 09/22/2023] [Indexed: 10/07/2023]
Abstract
OBJECTIVE This manuscript aimed to provide a comprehensive overview of the physiological, molecular, and cellular mechanisms triggered by reactive astrocytes (RA) in the context of spinal cord injury (SCI), with a particular focus on cases involving hyperglycaemia. METHODS The compilation of articles related to astrocyte responses in neuropathological conditions, with a specific emphasis on those related to SCI and hyperglycaemia, was conducted by searching through databases including Science Direct, Web of Science, and PubMed. RESULTS AND CONCLUSIONS This article explores the dual role of astrocytes in both neurophysiological and neurodegenerative conditions within the central nervous system (CNS). In the aftermath of SCI and hyperglycaemia, astrocytes undergo a transformation into RA, adopting a distinct phenotype. While there are currently no approved therapies for SCI, various therapeutic strategies have been proposed to alleviate the detrimental effects of RAs following SCI and hyperglycemia. These strategies show promising potential in the treatment of SCI and its likely comorbidities.
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Affiliation(s)
- C Sámano
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa (UAM-C), Ciudad de México, México
| | - G L Mazzone
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Pilar, Buenos Aires, Argentina
- Facultad de Ciencias Biomédicas, Universidad Austral, Pilar, Buenos Aires, Argentina
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8
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Schmidt T, Nagy Z. SAD: semi-supervised automatic detection of BOLD activations in high temporal resolution fMRI data. MAGMA (NEW YORK, N.Y.) 2024; 37:1031-1046. [PMID: 39207582 PMCID: PMC11582144 DOI: 10.1007/s10334-024-01197-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE Despite the prevalent use of the general linear model (GLM) in fMRI data analysis, assuming a pre-defined hemodynamic response function (HRF) for all voxels can lead to reduced reliability and may distort the inferences derived from it. To overcome the necessity of presuming a specific model for the hemodynamic response, we introduce a semi-supervised automatic detection (SAD) method. MATERIALS AND METHODS The proposed SAD method employs a Bi-LSTM neural network to classify high temporal resolution fMRI data. Network training utilized an fMRI dataset with 75-ms temporal resolution in an iterative scheme. Classification performance was evaluated on a second fMRI dataset from the same participant, collected on a different day. Comparative analysis with the standard GLM approach was conducted to evaluate the cooperative effectiveness of the SAD method. RESULTS The SAD method performed well based on the classification scores: true-positive rate = 0.961, area under the receiver operating curve = 0.998, true-negative rate = 0.99, F1-score = 0.979, False-negative rate = 0.038, false-discovery rate = 0.002, false-positive rate = 0.002 at 75-ms temporal resolution. CONCLUSION SAD can detect hemodynamic responses at 75-ms temporal resolution without relying on a specific shape of an HRF. Future work could expand the use cases to include more participants and different fMRI paradigms.
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Affiliation(s)
- Tim Schmidt
- Laboratory for Social and Neural Systems Research, SNS-Lab, University of Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland.
- Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Zurich, Switzerland.
| | - Zoltán Nagy
- Laboratory for Social and Neural Systems Research, SNS-Lab, University of Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland
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9
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Bosco P, Akcan U, Williams D, Buchanan HM, Agalliu D, Sproul AA. Generating iAstrocytes From Human Induced Pluripotent Stem Cells by Combining Low-Density Passaging of Neural Progenitor Cells and Transcription Factor NFIA Transdifferentiation. Curr Protoc 2024; 4:e70049. [PMID: 39546395 DOI: 10.1002/cpz1.70049] [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] [Indexed: 11/17/2024]
Abstract
Astrocytes are key regulators of central nervous system (CNS) homeostasis, and their dysfunction is implicated in neurological and neurodegenerative disorders. Here, we describe a two-step protocol to generate astrocytes from human induced pluripotent stem cells (hiPSCs) using a bankable neural progenitor cell (NPC) intermediate, followed by low-density passaging and overexpression of the gliogenic transcription factor NFIA. A bankable NPC intermediate allows for facile differentiation into both purified neuronal and astrocyte cell types in parallel from the same genetic background, depending on the experimental needs. This article presents a protocol to generate NPCs from hiPSCs, which are then differentiated into hiPSC-derived astrocytes, termed iAstrocytes. The resulting iAstrocytes express key markers of astrocyte identity at transcript and protein levels by bulk RNA-Seq and immunocytochemistry, respectively. Additionally, they respond to the inflammatory stimuli poly(I:C) and generate waves of calcium activity in response to either physical activity or the addition of ATP. Our approach offers a simple and robust method to generate and characterize human astrocytes, which can be used to model human disease affecting this cell type. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Differentiation of hiPSCs to NPCs Basic Protocol 2: Differentiation of NPCs into iAstrocytes Support Protocol 1: Molecular validation of iAstrocytes Support Protocol 2: Calcium imaging-based validation of iAstrocyte function Support Protocol 3: Differentiation of NPCs into neurons.
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Affiliation(s)
- Patrick Bosco
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York
| | - Ugur Akcan
- Department of Neurology, Columbia University Irving Medical Center, New York, New York
| | - Damian Williams
- Department of Neurology, Columbia University Irving Medical Center, New York, New York
- Center for Translational Research in Neurodevelopmental Disease, Columbia University Irving Medical Center, New York, New York
| | - Heather M Buchanan
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Dritan Agalliu
- Department of Neurology, Columbia University Irving Medical Center, New York, New York
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Andrew A Sproul
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
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10
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Sarnyai Z, Ben-Shachar D. Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework. Psychiatry Res 2024; 342:116220. [PMID: 39369460 DOI: 10.1016/j.psychres.2024.116220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/21/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024]
Abstract
Schizophrenia is a chronic, neurodevelopmental disorder with unknown aetiology and pathophysiology that emphasises the role of neurotransmitter imbalance and abnormalities in synaptic plasticity. The currently used pharmacological approach, the antipsychotic drugs, which have limited efficacy and an array of side-effects, have been developed based on the neurotransmitter hypothesis. Recent research has uncovered systemic and brain abnormalities in glucose and energy metabolism, focusing on altered glycolysis and mitochondrial oxidative phosphorylation. These findings call for a re-conceptualisation of schizophrenia pathophysiology as a progressing bioenergetics failure. In this review, we provide an overview of the fundamentals of brain bioenergetics and the changes identified in schizophrenia. We then propose a new explanatory framework positing that schizophrenia is a disease of impaired dynamic metabolic flexibility, which also reconciles findings of abnormal glucose and energy metabolism in the periphery and in the brain along the course of the disease. This evidence-based framework and testable hypothesis has the potential to transform the way we conceptualise this debilitating condition and to develop novel treatment approaches.
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Affiliation(s)
- Zoltán Sarnyai
- Laboratory of Psychobiology, Department of Neuroscience, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Department of Psychiatry, Rambam Health Campus, Haifa, Israel; Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia.
| | - Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Neuroscience, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Department of Psychiatry, Rambam Health Campus, Haifa, Israel.
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11
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Longhitano C, Finlay S, Peachey I, Swift JL, Fayet-Moore F, Bartle T, Vos G, Rudd D, Shareef O, Gordon S, Azghadi MR, Campbell I, Sethi S, Palmer C, Sarnyai Z. The effects of ketogenic metabolic therapy on mental health and metabolic outcomes in schizophrenia and bipolar disorder: a randomized controlled clinical trial protocol. Front Nutr 2024; 11:1444483. [PMID: 39234289 PMCID: PMC11371693 DOI: 10.3389/fnut.2024.1444483] [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: 06/05/2024] [Accepted: 07/23/2024] [Indexed: 09/06/2024] Open
Abstract
Background Schizophrenia, schizoaffective disorder, and bipolar affective disorder are debilitating psychiatric conditions characterized by a chronic pattern of emotional, behavioral, and cognitive disturbances. Shared psychopathology includes the pre-eminence of altered affective states, disorders of thoughts, and behavioral control. Additionally, those conditions share epidemiological traits, including significant cardiovascular, metabolic, infectious, and respiratory co-morbidities, resulting in reduced life expectancy of up to 25 years. Nutritional ketosis has been successfully used to treat a range of neurological disorders and preclinical data have convincingly shown potential for its use in animal models of psychotic disorders. More recent data from open clinical trials have pointed toward a dramatic reduction in psychotic, affective, and metabolic symptoms in both schizophrenia and bipolar affective disorder. Objectives to investigate the effects of nutritional ketosis via a modified ketogenic diet (MKD) over 14 weeks in stable community patients with bipolar disorder, schizoaffective disorder, or schizophrenia. Design A randomized placebo-controlled clinical trial of 100 non-hospitalized adult participants with a diagnosis of bipolar disorder, schizoaffective disorder, or schizophrenia who are capable of consenting and willing to change their diets. Intervention Dietitian-led and medically supervised ketogenic diet compared to a diet following the Australian Guide to Healthy Eating for 14 weeks. Outcomes The primary outcomes include psychiatric and cognitive measures, reported as symptom improvement and functional changes in the Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMS), Beck Depression Inventory (BDI), WHO Disability Schedule, Affect Lability Scale and the Cambridge Cognitive Battery. The secondary metabolic outcomes include changes in body weight, blood pressure, liver and kidney function tests, lipid profiles, and markers of insulin resistance. Ketone and glucose levels will be used to study the correlation between primary and secondary outcomes. Optional hair cortisol analysis will assess long-term stress and variations in fecal microbiome composition. Autonomic nervous system activity will be measured via wearable devices (OURA ring and EMBRACE wristband) in the form of skin conductance, oximetry, continuous pulse monitoring, respiratory rate, movement tracking, and sleep quality. Based on the encouraging results from established preclinical research, clinical data from other neurodevelopment disorders, and open trials in bipolar disorder and schizophrenia, we predict that the ketogenic metabolic therapy will be well tolerated and result in improved psychiatric and metabolic outcomes as well as global measures of social and community functioning. We additionally predict that a correlation may exist between the level of ketosis achieved and the metabolic, cognitive, and psychiatric outcomes in the intervention group.
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Affiliation(s)
- Calogero Longhitano
- Townsville University Hospital and Health Service, Mental Health Service Group, Queensland Health, Townsville, QLD, Australia
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
| | - Sabine Finlay
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia
| | - Isabella Peachey
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
| | - Jaymee-Leigh Swift
- Mater Hospital, Aurora Healthcare and James Cook University, Townsville, QLD, Australia
| | - Flavia Fayet-Moore
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW, Australia
- FoodiQ Global, Sydney, NSW, Australia
| | - Toby Bartle
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia
| | - Gideon Vos
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- Electrical and Electronics Engineering, College of Science and Engineering, James Cook University, Townsville, QLD, Australia
| | - Donna Rudd
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia
| | - Omer Shareef
- Townsville University Hospital and Health Service, Mental Health Service Group, Queensland Health, Townsville, QLD, Australia
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
| | - Shaileigh Gordon
- Townsville University Hospital and Health Service, Mental Health Service Group, Queensland Health, Townsville, QLD, Australia
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
| | - Mostafa Rahimi Azghadi
- Electrical and Electronics Engineering, College of Science and Engineering, James Cook University, Townsville, QLD, Australia
| | - Iain Campbell
- Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
| | - Shebani Sethi
- Metabolic Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, United States
| | | | - Zoltan Sarnyai
- Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia
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12
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Srichawla BS. Future of neurocritical care: Integrating neurophysics, multimodal monitoring, and machine learning. World J Crit Care Med 2024; 13:91397. [PMID: 38855276 PMCID: PMC11155497 DOI: 10.5492/wjccm.v13.i2.91397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/27/2024] [Accepted: 03/06/2024] [Indexed: 06/03/2024] Open
Abstract
Multimodal monitoring (MMM) in the intensive care unit (ICU) has become increasingly sophisticated with the integration of neurophysical principles. However, the challenge remains to select and interpret the most appropriate combination of neuromonitoring modalities to optimize patient outcomes. This manuscript reviewed current neuromonitoring tools, focusing on intracranial pressure, cerebral electrical activity, metabolism, and invasive and noninvasive autoregulation monitoring. In addition, the integration of advanced machine learning and data science tools within the ICU were discussed. Invasive monitoring includes analysis of intracranial pressure waveforms, jugular venous oximetry, monitoring of brain tissue oxygenation, thermal diffusion flowmetry, electrocorticography, depth electroencephalography, and cerebral microdialysis. Noninvasive measures include transcranial Doppler, tympanic membrane displacement, near-infrared spectroscopy, optic nerve sheath diameter, positron emission tomography, and systemic hemodynamic monitoring including heart rate variability analysis. The neurophysical basis and clinical relevance of each method within the ICU setting were examined. Machine learning algorithms have shown promise by helping to analyze and interpret data in real time from continuous MMM tools, helping clinicians make more accurate and timely decisions. These algorithms can integrate diverse data streams to generate predictive models for patient outcomes and optimize treatment strategies. MMM, grounded in neurophysics, offers a more nuanced understanding of cerebral physiology and disease in the ICU. Although each modality has its strengths and limitations, its integrated use, especially in combination with machine learning algorithms, can offer invaluable information for individualized patient care.
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Affiliation(s)
- Bahadar S Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
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13
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Bansal Y, Codeluppi SA, Banasr M. Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target. Int J Mol Sci 2024; 25:6357. [PMID: 38928062 PMCID: PMC11204179 DOI: 10.3390/ijms25126357] [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: 05/04/2024] [Revised: 05/30/2024] [Accepted: 06/02/2024] [Indexed: 06/28/2024] Open
Abstract
Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.
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Affiliation(s)
- Yashika Bansal
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
| | - Sierra A. Codeluppi
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2C8, Canada
| | - Mounira Banasr
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2C8, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON M2J 4A6, Canada
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14
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Benarroch E. What Is the Role of Lactate in Brain Metabolism, Plasticity, and Neurodegeneration? Neurology 2024; 102:e209378. [PMID: 38574305 DOI: 10.1212/wnl.0000000000209378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 02/27/2024] [Indexed: 04/06/2024] Open
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15
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Kann O. Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations. J Neurochem 2024; 168:608-631. [PMID: 37309602 DOI: 10.1111/jnc.15867] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 06/14/2023]
Abstract
Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30-70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation-inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5'-triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.
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Affiliation(s)
- Oliver Kann
- Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany
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16
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Orr TJ, Lesha E, Kramer AH, Cecia A, Dugan JE, Schwartz B, Einhaus SL. Traumatic Brain Injury: A Comprehensive Review of Biomechanics and Molecular Pathophysiology. World Neurosurg 2024; 185:74-88. [PMID: 38272305 DOI: 10.1016/j.wneu.2024.01.084] [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: 09/25/2023] [Revised: 01/14/2024] [Accepted: 01/16/2024] [Indexed: 01/27/2024]
Abstract
Traumatic brain injury (TBI) is a critical public health concern with profound consequences for affected individuals. This comprehensive literature review delves into TBI intricacies, encompassing primary injury biomechanics and the molecular pathophysiology of the secondary injury cascade. Primary TBI involves a complex interplay of forces, including impact loading, blast overpressure, and impulsive loading, leading to diverse injury patterns. These forces can be categorized into inertial (e.g., rotational acceleration causing focal and diffuse injuries) and contact forces (primarily causing focal injuries like skull fractures). Understanding their interactions is crucial for effective injury management. The secondary injury cascade in TBI comprises multifaceted molecular and cellular responses, including altered ion concentrations, dysfunctional neurotransmitter networks, oxidative stress, and cellular energy disturbances. These disruptions impair synaptic function, neurotransmission, and neuroplasticity, resulting in cognitive and behavioral deficits. Moreover, neuroinflammatory responses play a pivotal role in exacerbating damage. As we endeavor to bridge the knowledge gap between biomechanics and molecular pathophysiology, further research is imperative to unravel the nuanced interplay between mechanical forces and their consequences at the molecular and cellular levels, ultimately guiding the development of targeted therapeutic strategies to mitigate the debilitating effects of TBI. In this study, we aim to provide a concise review of the bridge between biomechanical processes causing primary injury and the ensuing molecular pathophysiology of secondary injury, while detailing the subsequent clinical course for this patient population. This knowledge is crucial for advancing our understanding of TBI and developing effective interventions to improve outcomes for those affected.
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Affiliation(s)
- Taylor J Orr
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
| | - Emal Lesha
- Department of Neurological Surgery, University of Tennessee Health Science Center, Memphis, Tennessee; Semmes Murphey Clinic, Memphis, Tennessee
| | - Alexandra H Kramer
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Arba Cecia
- School of Medicine, Loyola University Chicago, Chicago, Illinois
| | - John E Dugan
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Barrett Schwartz
- Department of Neurological Surgery, University of Tennessee Health Science Center, Memphis, Tennessee; Semmes Murphey Clinic, Memphis, Tennessee
| | - Stephanie L Einhaus
- Department of Neurological Surgery, University of Tennessee Health Science Center, Memphis, Tennessee; Semmes Murphey Clinic, Memphis, Tennessee
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17
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Paška J, Wang B, Chen AM, Madelin G, Brown R. Triple-tuned birdcage and single-tuned dipole array for quadri-nuclear head MRI at 7 T. Magn Reson Med 2024; 91:2188-2199. [PMID: 38116692 PMCID: PMC10950522 DOI: 10.1002/mrm.29977] [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: 06/02/2023] [Revised: 10/31/2023] [Accepted: 11/28/2023] [Indexed: 12/21/2023]
Abstract
PURPOSE The purpose of this work was to design and build a coil for quadri-nuclear MRI of the human brain at 7 T. METHODS We built a transmit/receive triple-tuned (45.6 MHz for 2 $$ {}^2 $$ H, 78.6 MHz for 23 $$ {}^{23} $$ Na, and 120.3 MHz for 31 $$ {}^{31} $$ P) quadrature four-rod birdcage that was geometrically interleaved with a transmit/receive four-channel dipole array (297.2 MHz for 1 $$ {}^1 $$ H). The birdcage rods contained passive, two-pole resonant circuits that emulated capacitors required for single-tuning at three frequencies. The birdcage assembly also included triple-tuned matching networks, baluns, and transmit/receive switches. We assessed the performance of the coil with quality factor (Q) and signal-to-noise ratio (SNR) measurements, and performed in vivo multinuclear MRI and MR spectroscopic imaging (MRSI). RESULTS Q measurements showed that the triple-tuned birdcage efficiency was within 33% of that of single-tuned baseline birdcages at all three frequencies. The quadri-tuned coil SNR was 78%, 59%, 44%, and 48% lower than that of single or dual-tuned reference coils for 1 $$ {}^1 $$ H, 2 $$ {}^2 $$ H, 23 $$ {}^{23} $$ Na, and 31 $$ {}^{31} $$ P, respectively. Quadri-nuclear MRI and MRSI was demonstrated in brain in vivo in about 30 min. CONCLUSION While the SNR of the quadruple tuned coil was significantly lower than dual- and single-tuned reference coils, it represents a step toward truly simultaneous quadri-nuclear measurements.
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Affiliation(s)
- Jan Paška
- Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Bili Wang
- Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Anna M. Chen
- Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Guillaume Madelin
- Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Ryan Brown
- Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
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18
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Chamaa F, Magistretti PJ, Fiumelli H. Astrocyte-derived lactate in stress disorders. Neurobiol Dis 2024; 192:106417. [PMID: 38296112 DOI: 10.1016/j.nbd.2024.106417] [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: 08/27/2023] [Revised: 12/04/2023] [Accepted: 01/23/2024] [Indexed: 02/05/2024] Open
Abstract
Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders.
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Affiliation(s)
- Farah Chamaa
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia
| | - Pierre J Magistretti
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia
| | - Hubert Fiumelli
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.
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19
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Catalano M, Limatola C, Trettel F. Non-neoplastic astrocytes: key players for brain tumor progression. Front Cell Neurosci 2024; 17:1352130. [PMID: 38293652 PMCID: PMC10825036 DOI: 10.3389/fncel.2023.1352130] [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: 12/07/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024] Open
Abstract
Astrocytes are highly plastic cells whose activity is essential to maintain the cerebral homeostasis, regulating synaptogenesis and synaptic transmission, vascular and metabolic functions, ions, neuro- and gliotransmitters concentrations. In pathological conditions, astrocytes may undergo transient or long-lasting molecular and functional changes that contribute to disease resolution or exacerbation. In recent years, many studies demonstrated that non-neoplastic astrocytes are key cells of the tumor microenvironment that contribute to the pathogenesis of glioblastoma, the most common primary malignant brain tumor and of secondary metastatic brain tumors. This Mini Review covers the recent development of research on non-neoplastic astrocytes as tumor-modulators. Their double-edged capability to promote cancer progression or to represent potential tools to counteract brain tumors will be discussed.
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Affiliation(s)
- Myriam Catalano
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Cristina Limatola
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Flavia Trettel
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
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20
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Pio T, Hill EJ, Kebede N, Andersen J, Sloan SA. Neuron-Astrocyte Interactions: A Human Perspective. ADVANCES IN NEUROBIOLOGY 2024; 39:69-93. [PMID: 39190072 DOI: 10.1007/978-3-031-64839-7_4] [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
This chapter explores the intricate interactions between neurons and astrocytes within the nervous system with a particular emphasis on studies conducted in human tissue or with human cells. We specifically explore how neuron-astrocyte interactions relate to processes of cellular development, morphology, migration, synapse formation, and metabolism. These findings enrich our understanding of basic neurobiology and how disruptions in these processes are relevant to human diseases.The study of human neuron-astrocyte interactions is made possible because of transformative in vitro advancements that have facilitated the generation and sustained culture of human neural cells. In addition, the rise of techniques like sequencing at single-cell resolution has enabled the exploration of numerous human cell atlases and their comparisons to other animal model systems. Thus, the innovations outlined in this chapter illuminate the convergence and divergence of neuron-astrocyte interactions across species. As technologies progress, continually more sophisticated in vitro systems will increasingly reflect in vivo environments and deepen our command of neuron-glial interactions in human biology.
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Affiliation(s)
- Taylor Pio
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Emily J Hill
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Nardos Kebede
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Jimena Andersen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven A Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
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21
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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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22
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Schmidt T, Vannesjo SJ, Sommer S, Nagy Z. fMRI with whole-brain coverage, 75-ms temporal resolution and high SNR by combining HiHi reshuffling and multiband imaging. Magn Reson Imaging 2023; 103:48-53. [PMID: 37385353 DOI: 10.1016/j.mri.2023.06.015] [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: 03/21/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
Increasing the temporal resolution of the blood‑oxygen level-dependent (BOLD) response is usually accompanied by a decrease in repetition time and therefore also a reduction of the magnetic resonance (MR) signal due to incomplete T1 relaxation and thus a loss of signal-to-noise ratio (SNR). A previous data reordering method can achieve higher temporal sampling rate without the loss of SNR but at the cost of increased scan time. In this proof-of-principle work, we show that combining HiHi reshuffling with multiband acceleration allows us to measure the in vivo BOLD response with a 75-ms sampling rate that is decoupled from the acquisition repetition time (here 1.5 s and hence higher SNR) while covering the entire forebrain with 60 2-mm slices in a ~ 35-min scan. We provide single-voxel time-courses of the BOLD responses in the primary visual and primary motor cortices in three fMRI experiments on a 7 T scanner - 1 male (scanned twice on different days for test-retest reproducibility) and 1 female participant.
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Affiliation(s)
- Tim Schmidt
- Laboratory for Social and Neural Systems Research, University of Zurich, Zurich, Switzerland; Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Zurich, Switzerland.
| | - S Johanna Vannesjo
- Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway
| | - Stefan Sommer
- Siemens Healthineers International AG, Zurich, Switzerland; Swiss Center for Musculoskeletal Imaging (SCMI), Balgrist Campus, Zurich, Switzerland; Advanced Clinical Imaging Technology (ACIT), Siemens Healthineers International AG, Lausanne, Switzerland
| | - Zoltán Nagy
- Laboratory for Social and Neural Systems Research, University of Zurich, Zurich, Switzerland
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23
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Ji T, Pang Y, Cheng M, Wang R, Chen X, Zhang C, Liu M, Zhang J, Zhong C. mNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury. iScience 2023; 26:107913. [PMID: 37810220 PMCID: PMC10550729 DOI: 10.1016/j.isci.2023.107913] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/22/2023] [Accepted: 09/12/2023] [Indexed: 10/10/2023] Open
Abstract
N-acetyl aspartyl-glutamate (NAAG) is easily inactivated for the hydrolysis of NAAG peptidase on the surface of glial cells, thereby losing its endogenous neuroprotective effect after traumatic brain injury. In this study, lentiviral vectors were used to over express/knock out NAAG synthetase II (Rimkla) in mouse embryonic neural stem cells (mNSCs) in vitro and these mNSCs were transplanted at the lesion site in a mouse model of controlled cortical impact (CCI). In vivo experiments showed that transplantation of mNSCs overexpressing Rimkla regulated glutamate-glutamine cycling between adjacent astrocytes and neurons in the subacute phase of CCI, thereby enhancing support for neuronal metabolism and promoting neuronal synaptic repair in the hippocampal CA3 region. Taken together, these findings demonstrate that transplantation of neural stem cells overexpressing Rimkla can effectively increase the NAAG concentration in local brain regions, which opens up new ideas for the maintenance of NAAG neuroprotective effects after TBI.
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Affiliation(s)
- Tongjie Ji
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ying Pang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Meng Cheng
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Rui Wang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xu Chen
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chunyu Zhang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Min Liu
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Zhang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Institute for Advanced Study, Tongji University, Shanghai, China
| | - Chunlong Zhong
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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24
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Theriault JE, Shaffer C, Dienel GA, Sander CY, Hooker JM, Dickerson BC, Barrett LF, Quigley KS. A functional account of stimulation-based aerobic glycolysis and its role in interpreting BOLD signal intensity increases in neuroimaging experiments. Neurosci Biobehav Rev 2023; 153:105373. [PMID: 37634556 PMCID: PMC10591873 DOI: 10.1016/j.neubiorev.2023.105373] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/28/2023] [Accepted: 08/23/2023] [Indexed: 08/29/2023]
Abstract
In aerobic glycolysis, oxygen is abundant, and yet cells metabolize glucose without using it, decreasing their ATP per glucose yield by 15-fold. During task-based stimulation, aerobic glycolysis occurs in localized brain regions, presenting a puzzle: why produce ATP inefficiently when, all else being equal, evolution should favor the efficient use of metabolic resources? The answer is that all else is not equal. We propose that a tradeoff exists between efficient ATP production and the efficiency with which ATP is spent to transmit information. Aerobic glycolysis, despite yielding little ATP per glucose, may support neuronal signaling in thin (< 0.5 µm), information-efficient axons. We call this the efficiency tradeoff hypothesis. This tradeoff has potential implications for interpretations of task-related BOLD "activation" observed in fMRI. We hypothesize that BOLD "activation" may index local increases in aerobic glycolysis, which support signaling in thin axons carrying "bottom-up" information, or "prediction error"-i.e., the BIAPEM (BOLD increases approximate prediction error metabolism) hypothesis. Finally, we explore implications of our hypotheses for human brain evolution, social behavior, and mental disorders.
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Affiliation(s)
- Jordan E Theriault
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
| | - Clare Shaffer
- Northeastern University, Department of Psychology, Boston, MA, 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
| | - Christin Y Sander
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Jacob M Hooker
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Bradford C Dickerson
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Lisa Feldman Barrett
- Northeastern University, Department of Psychology, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Karen S Quigley
- Northeastern University, Department of Psychology, Boston, MA, USA; VA Bedford Healthcare System, Bedford, MA, USA
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25
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Kanaya T, Ito R, Morizawa YM, Sasaki D, Yamao H, Ishikane H, Hiraoka Y, Tanaka K, Matsui K. Glial modulation of the parallel memory formation. Glia 2023. [PMID: 37364894 DOI: 10.1002/glia.24431] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 06/04/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023]
Abstract
Actions from glial cells could affect the readiness and efficacy of learning and memory. Using a mouse cerebellar-dependent horizontal optokinetic response motor learning paradigm, short-term memory (STM) formation during the online training period and long-term memory (LTM) formation during the offline rest period were studied. A large variability of online and offline learning efficacies was found. The early bloomers with booming STM often had a suppressed LTM formation and late bloomers with no apparent acute training effect often exhibited boosted offline learning performance. Anion channels containing LRRC8A are known to release glutamate. Conditional knockout of LRRC8A specifically in astrocytes including cerebellar Bergmann glia resulted in a complete loss of STM formation while the LTM formation during the rest period remained. Optogenetic manipulation of glial activity by channelrhodopsin-2 or archaerhodopsin-T (ArchT) during the online training resulted in enhancement or suppression of STM formation, respectively. STM and LTM are likely to be triggered simultaneously during online training, but LTM is expressed later during the offline period. STM appears to be volatile and the achievement during the online training is not handed over to LTM. In addition, we found that glial ArchT photoactivation during the rest period resulted in the augmentation of LTM formation. These data suggest that STM formation and LTM formation are parallel separate processes. Strategies to weigh more on the STM or the LTM could depend on the actions of the glial cells.
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Affiliation(s)
- Teppei Kanaya
- Super-Network Brain Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Ryo Ito
- Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Yosuke M Morizawa
- Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Daichi Sasaki
- Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Hiroki Yamao
- Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Hiroshi Ishikane
- Department of Psychology, Graduate School of Humanities, Senshu University, Kawasaki, Japan
| | - Yuichi Hiraoka
- Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ko Matsui
- Super-Network Brain Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
- Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
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26
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Bavato F, Esposito F, Dornbierer DA, Zölch N, Quednow BB, Staempfli P, Landolt HP, Seifritz E, Bosch OG. Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA. Cereb Cortex 2023:7086058. [DOI: 10.1093/cercor/bhad097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/29/2023] Open
Abstract
AbstractSodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABAB receptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate in the anterior cingulate cortex (ACC). In sum, 16 healthy male volunteers received 50 mg/kg GHB p.o. or placebo at 02:30 a.m. to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00 a.m. of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared with placebo. This SN-rCEN coupling was significantly associated with changes in GABA levels in the ACC (pall < 0.05). The observed neural pattern is compatible with a functional switch to a more extrinsic brain state, which may serve as a neurobiological signature of the wake-promoting effects of GHB.
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27
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Szrejder M, Typiak M, Pikul P, Audzeyenka I, Rachubik P, Rogacka D, Narajczyk M, Piwkowska A. Role of L-lactate as an energy substrate in primary rat podocytes under physiological and glucose deprivation conditions. Eur J Cell Biol 2023; 102:151298. [PMID: 36805821 DOI: 10.1016/j.ejcb.2023.151298] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/09/2023] [Accepted: 02/09/2023] [Indexed: 02/12/2023] Open
Abstract
Lactate has long been acknowledged to be a metabolic waste product, but it has more recently been found as a fuel energy source in mammalian cells. Podocytes are an important component of the glomerular filter, and their role in maintaining the structural integrity of this structure was established. These cells rely on a constant energy supply and reservoir. The utilization of alternative energy substrates to preserve energetic homeostasis is a subject of extensive research, and lactate appears to be one such candidate. Therefore, we investigated the role of lactate as an energy substrate and characterize the lactate transport system in cultured rat podocytes during sufficient and insufficient glucose supplies. The present study, for the first time, demonstrated the presence of lactate transporters in podocytes. Moreover, we observed modified the amount of these transporters in response to limited glucose availability and after l-lactate supplementation. Simultaneously, exposure to l-lactate preserved cell survival during insufficient glucose supply. Interestingly, during glucose deprivation, lactate exposure allowed the steady flow of glycolysis and prevented glycogen reserves depletion. Summarizing, podocytes utilize lactate as an energy substrate and possess a developed system that controls lactate homeostasis, suggesting that it plays an essential role in podocyte metabolism, especially during fluctuations of energy availability.
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Affiliation(s)
- Maria Szrejder
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland.
| | - Marlena Typiak
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; University of Gdansk, Faculty of Biology, Gdansk, Poland
| | - Piotr Pikul
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland
| | - Irena Audzeyenka
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; University of Gdansk, Faculty of Chemistry, Gdańsk, Poland
| | - Patrycja Rachubik
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland
| | - Dorota Rogacka
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; University of Gdansk, Faculty of Chemistry, Gdańsk, Poland
| | | | - Agnieszka Piwkowska
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland; University of Gdansk, Faculty of Chemistry, Gdańsk, Poland
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28
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Zuccarini M, Pruccoli L, Balducci M, Giuliani P, Caciagli F, Ciccarelli R, Di Iorio P. Influence of Guanine-Based Purines on the Oxidoreductive Reactions Involved in Normal or Altered Brain Functions. J Clin Med 2023; 12:jcm12031172. [PMID: 36769818 PMCID: PMC9917437 DOI: 10.3390/jcm12031172] [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: 12/05/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The production of reactive oxygen species (ROS) in the brain is homeostatically controlled and contributes to normal neural functions. Inefficiency of control mechanisms in brain aging or pathological conditions leads to ROS overproduction with oxidative neural cell damage and degeneration. Among the compounds showing therapeutic potential against neuro-dysfunctions induced by oxidative stress are the guanine-based purines (GBPs), of which the most characterized are the nucleoside guanosine (GUO) and the nucleobase guanine (GUA), which act differently. Indeed, the administration of GUO to in vitro or in vivo models of acute brain injury (ischemia/hypoxia or trauma) or chronic neurological/neurodegenerative disorders, exerts neuroprotective and anti-inflammatory effects, decreasing the production of reactive radicals and improving mitochondrial function via multiple molecular signals. However, GUO administration to rodents also causes an amnesic effect. In contrast, the metabolite, GUA, could be effective in memory-related disorders by transiently increasing ROS production and stimulating the nitric oxide/soluble guanylate cyclase/cGMP/protein kinase G cascade, which has long been recognized as beneficial for cognitive function. Thus, it is worth pursuing further studies to ascertain the therapeutic role of GUO and GUA and to evaluate the pathological brain conditions in which these compounds could be more usefully used.
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Affiliation(s)
- Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy
| | - Letizia Pruccoli
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy
| | - Martina Balducci
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy
| | - Patricia Giuliani
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy
| | - Francesco Caciagli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy
| | - Renata Ciccarelli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy
| | - Patrizia Di Iorio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy
- Correspondence:
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29
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Casquero-Veiga M, Lamanna-Rama N, Romero-Miguel D, Rojas-Marquez H, Alcaide J, Beltran M, Nacher J, Desco M, Soto-Montenegro ML. The Poly I:C maternal immune stimulation model shows unique patterns of brain metabolism, morphometry, and plasticity in female rats. Front Behav Neurosci 2023; 16:1022622. [PMID: 36733452 PMCID: PMC9888250 DOI: 10.3389/fnbeh.2022.1022622] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 12/05/2022] [Indexed: 01/07/2023] Open
Abstract
Introduction: Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies. Methods: In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model. Imaging studies: [18F]-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses. Ex vivo study: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample T-test and 2-way-ANOVA analyses, respectively. Results: A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala. Conclusion: Our work showed in vivo the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population.
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Affiliation(s)
- Marta Casquero-Veiga
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,Cardiovascular Imaging and Population Studies, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Nicolás Lamanna-Rama
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,Departamento de Bioingeniería e Ingeniería Aeroespacial, Escuela Técnica Superior de Ingeniería, Universidad Carlos III de Madrid, Madrid, Spain
| | - Diego Romero-Miguel
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,Departamento de Bioingeniería e Ingeniería Aeroespacial, Escuela Técnica Superior de Ingeniería, Universidad Carlos III de Madrid, Madrid, Spain
| | - Henar Rojas-Marquez
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain,Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Julia Alcaide
- Neurobiology Unit, Cell Biology Departament, BIOTECMED Institute, Universitat de València, Burjassot, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain
| | - Marc Beltran
- Neurobiology Unit, Cell Biology Departament, BIOTECMED Institute, Universitat de València, Burjassot, Spain
| | - Juan Nacher
- Neurobiology Unit, Cell Biology Departament, BIOTECMED Institute, Universitat de València, Burjassot, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain
| | - Manuel Desco
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,Advanced Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain,Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Campus de Getafe, Madrid, Spain,*Correspondence: Manuel Desco Maria Luisa Soto-Montenegro
| | - Maria Luisa Soto-Montenegro
- Laboratorio de Imagen Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,CIBER de Salud Mental (CIBERSAM), Madrid, Spain,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut), University Rey Juan Carlos (URJC), Alcorcón, Spain,*Correspondence: Manuel Desco Maria Luisa Soto-Montenegro
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Abild Meyer C, De Dios Andres P, Brodszkij E, Westensee IN, Lyons J, Vaz SH, Städler B. Astrocytes in Paper Chips and Their Interaction with Hybrid Vesicles. Adv Biol (Weinh) 2023; 7:e2200209. [PMID: 36328791 DOI: 10.1002/adbi.202200209] [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: 07/22/2022] [Revised: 10/03/2022] [Indexed: 11/06/2022]
Abstract
The role of astrocytes in brain function has received increased attention lately due to their critical role in brain development and function under physiological and pathophysiological conditions. However, the biological evaluation of soft material nanoparticles in astrocytes remains unexplored. Here, the interaction of crosslinked hybrid vesicles (HVs) and either C8-D1A astrocytes or primary astrocytes cultured in polystyrene tissue culture or floatable paper-based chips is investigated. The amphiphilic block copolymer poly(cholesteryl methacrylate)-block-poly(2-carboxyethyl acrylate) (P1) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine lipids are used for the assembly of HVs with crosslinked membranes. The assemblies show no short-term toxicity towards the C8-D1A astrocytes and the primary astrocytes, and both cell types internalize the HVs when cultured in 2D cell culture. Further, it is demonstrated that both the C8-D1A astrocytes and the primary astrocytes could mature in paper-based chips with preserved calcium signaling and glial fibrillary acidic protein expression. Last, it is confirmed that both types of astrocytes could internalize the HVs when cultured in paper-based chips. These findings lay out a fundamental understanding of the interaction between soft material nanoparticles and astrocytes, even when primary astrocytes are cultured in paper-based chips offering a 3D environment.
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Affiliation(s)
- Cathrine Abild Meyer
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
| | - Paula De Dios Andres
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
| | - Edit Brodszkij
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
| | - Isabella N Westensee
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
| | - Joseph Lyons
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
| | - Sandra H Vaz
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisboa, Portugal.,Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Brigitte Städler
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000, Aarhus, Denmark
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31
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Munger EL, Edler MK, Hopkins WD, Hof PR, Sherwood CC, Raghanti MA. Comparative analysis of astrocytes in the prefrontal cortex of primates: Insights into the evolution of human brain energetics. J Comp Neurol 2022; 530:3106-3125. [PMID: 35859531 PMCID: PMC9588662 DOI: 10.1002/cne.25387] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte-neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human-specific metabolic processing and cognition.
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Affiliation(s)
- Emily L. Munger
- Department of Anthropology, School of Biomedical Sciences, and Brain Health Research Institute, Kent State University, Kent, OH
| | - Melissa K. Edler
- Department of Anthropology, School of Biomedical Sciences, and Brain Health Research Institute, Kent State University, Kent, OH
| | - William D. Hopkins
- Department of Comparative Medicine, University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - Patrick R. Hof
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chet C. Sherwood
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, DC, USA
| | - Mary Ann Raghanti
- Department of Anthropology, School of Biomedical Sciences, and Brain Health Research Institute, Kent State University, Kent, OH
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The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes. eNeuro 2022; 9:ENEURO.0040-22.2022. [PMID: 36096650 PMCID: PMC9536859 DOI: 10.1523/eneuro.0040-22.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 08/24/2022] [Accepted: 08/31/2022] [Indexed: 12/15/2022] Open
Abstract
Severe brain metabolic dysfunction and amyloid-β accumulation are key hallmarks of Alzheimer's disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of AD patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the catalytic upregulation of the enzyme exacerbates astrocytic damage, reactive oxygen species (ROS) generation and mitochondrial network alterations during amyloidogenic stress. On the other hand, 17βHSD10 inhibition through AG18051 counters most of these effects. In conclusion, our data represents novel insights into the role of astrocytic mitochondria in metabolic and amyloidogenic stress with implications of 17βHSD10 in multiple neurodegenerative mechanisms.
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33
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Lin LY, Horng JL, Cheng CA, Chang CY, Cherng BW, Liu ST, Chou MY. Sublethal ammonia induces alterations of emotions, cognition, and social behaviors in zebrafish (Danio rerio). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 244:114058. [PMID: 36108432 DOI: 10.1016/j.ecoenv.2022.114058] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/27/2022] [Accepted: 09/03/2022] [Indexed: 06/15/2023]
Abstract
Ammonia pollutants were usually found in aquatic environments is due to urban sewage, industrial wastewater discharge, and agricultural runoff and concentrations as high as 180 mg/L (NH4+) have been reported in rivers. High ammonia levels are known to impair multiple tissue and cell functions and cause fish death. Although ammonia is a potent neurotoxin, how sublethal concentrations of ammonia influence the central nervous system (CNS) and the complex behaviors of fish is still unclear. In the present study, we demonstrated that acute sublethal ammonia exposure can change social behavior of adult zebrafish. The exposure to 90 mg /L of (NH4+) for 4 h induced a strong fear response and lower shoaling cohesion; exposure to 180 mg /L of (NH4+) for 4 h reduced the aggressiveness, and social recognition, while the anxiety, social preference, learning, and short-term memory were not affected. Messenger RNA expressions of glutaminase and glutamate dehydrogenase in the brain were induced, suggesting that ammonia exposure altered glutamate neurotransmitters in the CNS. Our findings in zebrafish provided delicate information of ammonia neurotoxicity in complex higher-order social behaviors, which has not been revealed previously. In conclusion, sublethal and acute ammonia exposure can change specific behaviors of fish, which might lead to reductions in individual and population fitness levels.
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Affiliation(s)
- Li-Yih Lin
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Jiun-Lin Horng
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
| | - Chieh-An Cheng
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Chun-Yung Chang
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan
| | - Bor-Wei Cherng
- Department of Life Science, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan
| | - Sian-Tai Liu
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan
| | - Ming-Yi Chou
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.
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34
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Liu L, Li W, Wang L, Gong P, Lyu T, Liu D, Zhang Y, Guo Y, Liu X, Tang M, Hu H, Liu C, Li B. Proteomic and metabolomic profiling of acupuncture for migraine reveals a correlative link via energy metabolism. Front Neurosci 2022; 16:1013328. [PMID: 36248663 PMCID: PMC9557737 DOI: 10.3389/fnins.2022.1013328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 08/31/2022] [Indexed: 11/17/2022] Open
Abstract
Migraine is a neurovascular disease with a high disability rate. Acupuncture treatment has emerged as a safe and viable alternative prophylactic therapy that can effectively alleviate the duration and frequency of migraine attacks. However, the therapeutic mechanisms underlying the effects of acupuncture are yet to be systematically elucidated. In this study, we enrolled female patients with migraine without aura (n = 20) and healthy controls (n = 10). Patients received acupuncture treatment on DU20, DU24, bilateral GB13, GB8, and GB20, applied three times per week over the course of 4 weeks for 12 sessions in total. Blood samples were collected from the median cubital vein before and after acupuncture treatment. Proteomic and metabolomic profiling was performed using liquid chromatography-mass spectrometry to determine the characteristics of differentially expressed molecules and expression of their corresponding biological pathways as well as to elucidate the pathogenesis of migraine and the biological effects underlying the treatment of migraine with acupuncture. Proteomic and metabolomic profiling of plasma samples from patients with migraine without aura before and after acupuncture treatment revealed enrichment of immune-related pathway functions and the arginine synthesis pathway. Joint pathway analyses revealed significant enrichment of the pentose phosphate and glycolysis/gluconeogenesis pathways in patients with migraine. The glycolysis/gluconeogenesis and riboflavin metabolism pathways were significantly enriched after acupuncture treatment. The expression levels of various key proteins and metabolites, including α-D-glucose, flavin adenine dinucleotide, biliverdin reductase B, and L-glutamate, were significantly differentially expressed before and after acupuncture treatment in patients with migraine without aura. Treatment of migraine with acupuncture was associated with significant changes in key molecules and pathways, indicative of physiological changes in the trigeminovascular system, glutamate neurotoxicity, and other migraine-related physiological changes. Overall, our comprehensive analysis using proteomic and metabolomic profiling demonstrates that energy metabolism may serve as a key correlative link in the occurrence of migraine and the therapeutic effects of acupuncture treatment. Our findings may facilitate the identification of diagnostic and therapeutic modalities in the ongoing search for effective treatments for migraine attacks.
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Affiliation(s)
- Lu Liu
- Beijing Key Laboratory of Acupuncture Neuromodulation, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Weizheng Li
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Linpeng Wang
- Beijing Key Laboratory of Acupuncture Neuromodulation, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Pengyun Gong
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Tianli Lyu
- Beijing Key Laboratory of Acupuncture Neuromodulation, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Dapeng Liu
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yajie Zhang
- Shanxi Hospital of Integrated Traditional and Western Medicine, Taiyuan, China
| | - Yijie Guo
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Xiang Liu
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Min Tang
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Hongke Hu
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
| | - Chao Liu
- School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine, Beihang University, Ministry of Industry and Information Technology, Beijing, China
- *Correspondence: Chao Liu,
| | - Bin Li
- Beijing Key Laboratory of Acupuncture Neuromodulation, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Bin Li,
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Gu X, Zhang G, Wang Q, Song J, Li Y, Xia C, Zhang T, Yang L, Sun J, Zhou M. Integrated network pharmacology and hepatic metabolomics to reveal the mechanism of Acanthopanax senticosus against major depressive disorder. Front Cell Dev Biol 2022; 10:900637. [PMID: 35990602 PMCID: PMC9389016 DOI: 10.3389/fcell.2022.900637] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/11/2022] [Indexed: 11/23/2022] Open
Abstract
Objective:Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) is a traditional herbal medicine widely known for its antifatigue and antistress effects, as well as tonifying qi, invigorating spleen and kidney, and tranquilizing the mind. Recent evidence suggests that ASH has a therapeutic effect on major depressive disorder (MDD), but its mechanism is still unclear. The current study aimed to investigate the effect of ASH on MDD and potential therapeutic mechanisms. Materials and Methods: The chemical compound potential target network was predicted based on network pharmacology. Simultaneously, chronic unpredictable mild stress (CUMS) model mice were orally administrated ASH with three dosages (400, 200, and 100 mg/kg) for 6 weeks, and hepatic metabolomics based on gas chromatography–mass spectrometry (GC–MS) was carried out to identify differential metabolites and related metabolic pathways. Next, the integrated analysis of metabolomics and network pharmacology was applied to find the key target. Finally, molecular docking technology was employed to define the combination of the key target and the corresponding compounds. Results: A total of 13 metabolites and four related metabolic pathways were found in metabolomics analysis. From the combined analysis of network pharmacology and metabolomics, six targets (DAO, MAOA, MAOB, GAA, HK1, and PYGM) are the overlapping targets and two metabolic pathways (glycine, serine, and threonine metabolism and starch and sucrose metabolism) are the most related pathways. Finally, DAO, MAOA, MAOB, GAA, HK1, and PYGM were verified bounding well to their corresponding compounds including isofraxidin, eleutheroside B1, eleutheroside C, quercetin, kaempferol, and acacetin. Conclusion: Based on these results, it was implied that the potential mechanism of ASH on MDD was related to the regulation of metabolism of several excitatory amino acids and carbohydrates, as well as the expression of DAO, MAOA, MAOB, GAA, HK1, and PYGM.
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Affiliation(s)
- Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guanying Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Song
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Li
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Yang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jijia Sun
- Department of Mathematics and Physics, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Jijia Sun, ; Mingmei Zhou,
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Jijia Sun, ; Mingmei Zhou,
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Stanescu S, Bravo-Alonso I, Belanger-Quintana A, Pérez B, Medina-Diaz M, Ruiz-Sala P, Flores NP, Buenache R, Arrieta F, Rodríguez-Pombo P. Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature. Orphanet J Rare Dis 2022; 17:243. [PMID: 35729663 PMCID: PMC9215049 DOI: 10.1186/s13023-022-02389-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/06/2022] [Indexed: 12/03/2022] Open
Abstract
Background Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete. Results The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia. Conclusions These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02389-4.
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Affiliation(s)
- Sinziana Stanescu
- Unidad de Enfermedades Metabólicas, Hospital Universitario Ramón y Cajal, IRYCIS, Crta de Colmenar Viejo, km 9,100, 28034, Madrid, Spain.
| | - Irene Bravo-Alonso
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPAZ, C/Francisco Tomás y Valiente, 7, 28049, Madrid, Spain
| | - Amaya Belanger-Quintana
- Unidad de Enfermedades Metabólicas, Hospital Universitario Ramón y Cajal, IRYCIS, Crta de Colmenar Viejo, km 9,100, 28034, Madrid, Spain
| | - Belen Pérez
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPAZ, C/Francisco Tomás y Valiente, 7, 28049, Madrid, Spain
| | - Montserrat Medina-Diaz
- Department of Neuroradiology, Hospital Universitario Ramón y Cajal, IRYCIS, Crta de Colmenar Viejo, km 9,100, 28034, Madrid, Spain
| | - Pedro Ruiz-Sala
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Universidad Autónoma de Madrid, CIBERER, IdiPAZ, C/Francisco Tomás y Valiente, 7, 28049, Madrid, Spain
| | - Nathaly Paola Flores
- Paediatric Department, Hospital General La Mancha Centro, Av. Constitución, 3, 13600, Alcázar de San Juan, Ciudad Real, Spain
| | - Raquel Buenache
- Neuropediatric Department, Hospital Universitario Ramón y Cajal, IRYCIS, Crta de Colmenar Viejo, km 9,100, 28034, Madrid, Spain
| | - Francisco Arrieta
- Unidad de Enfermedades Metabólicas, Hospital Universitario Ramón y Cajal, IRYCIS, CIBER-OBN, Crta de Colmenar Viejo, km 9,100, 28034, Madrid, Spain
| | - Pilar Rodríguez-Pombo
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPAZ, C/Francisco Tomás y Valiente, 7, 28049, Madrid, Spain
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Rocha A, Bellaver B, Souza DG, Schu G, Fontana IC, Venturin GT, Greggio S, Fontella FU, Schiavenin ML, Machado LS, Miron D, da Costa JC, Rosa-Neto P, Souza DO, Pellerin L, Zimmer ER. Clozapine induces astrocyte-dependent FDG-PET hypometabolism. Eur J Nucl Med Mol Imaging 2022; 49:2251-2264. [PMID: 35122511 DOI: 10.1007/s00259-022-05682-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/09/2022] [Indexed: 01/30/2023]
Abstract
PURPOSE Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
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Affiliation(s)
- Andréia Rocha
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Bruna Bellaver
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Débora G Souza
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Guilherme Schu
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
- Proaction Laboratory, Faculty of Psychology and Education Sciences, University of Coimbra, Coimbra, Portugal
| | - Igor C Fontana
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Gianina T Venturin
- Preclinical Research Center, Brain Institute (BraIns) of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Samuel Greggio
- Preclinical Research Center, Brain Institute (BraIns) of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Fernanda U Fontella
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Manoela L Schiavenin
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Luiza S Machado
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Diogo Miron
- Faculty of Pharmacy, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Jaderson C da Costa
- Preclinical Research Center, Brain Institute (BraIns) of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Pedro Rosa-Neto
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montreal, Canada
- Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada
| | - Diogo O Souza
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
- Department of Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - Luc Pellerin
- Inserm U1313, Université et CHU de Poitiers, Poitiers, France
| | - Eduardo R Zimmer
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
- Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
- Department of Pharmacology, Universidade Federal Do Rio Grande Do Sul, (UFRGS), 2600 Ramiro Barcelos St, Porto Alegre, RS, 90035-003, Brazil.
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Palombit A, Silvestri E, Volpi T, Aiello M, Cecchin D, Bertoldo A, Corbetta M. Variability of regional glucose metabolism and the topology of functional networks in the human brain. Neuroimage 2022; 257:119280. [PMID: 35525522 DOI: 10.1016/j.neuroimage.2022.119280] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/04/2022] [Accepted: 05/02/2022] [Indexed: 11/17/2022] Open
Abstract
The brain consumes the most energy per relative mass amongst the organs in the human body. Theoretical and empirical studies have shown that behavioral processes are relatively inexpensive metabolically, and that most energy goes to maintaining the status quo, i.e., the balance of cell membranes' resting potentials and subthreshold spontaneous activity. Spontaneous activity fluctuates across brain regions in a correlated fashion that defines multi-scale hierarchical networks called resting-state networks (RSNs). Different regions of the brain display different metabolic consumption, but the relationship between regional brain metabolism and RSNs is still under investigation. Here, we examine the variability of glucose metabolism across brain regions, measured with the relative standard uptake value (SUVR) using 18F-FDG PET, and the topology of RSNs, measured through graph analysis applied to fMRI resting-state functional connectivity (FC). We found a moderate linear relationship between the strength (STR) of pairwise regional FC and metabolism. Moreover, the linear correlation between SUVR and STR grew stronger as we considered more connected regions (hubs). Regions connecting different RSNs, or connector hubs, showed higher SUVR than regions connecting nodes within the same RSN, or provincial hubs. Our results show that functional connections as probed by fMRI are related to glucose metabolism, especially in a system of provincial and connector hubs.
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Affiliation(s)
- Alessandro Palombit
- Department of Information Engineering, University of Padova, 35131 Padova, Italy; Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy
| | - Erica Silvestri
- Department of Information Engineering, University of Padova, 35131 Padova, Italy; Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy
| | - Tommaso Volpi
- Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy; Department of Neuroscience, University of Padova, 35128 Padova, Italy
| | | | - Diego Cecchin
- Unit of Nuclear Medicine, Department of Medicine, University of Padova, Padova, Italy; Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy
| | - Alessandra Bertoldo
- Department of Information Engineering, University of Padova, 35131 Padova, Italy; Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy
| | - Maurizio Corbetta
- Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy; Department of Neuroscience, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM) Biomedical Foundation, 35128 Padova, Italy.
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González A, Calfío C, Churruca M, Maccioni RB. Glucose metabolism and AD: evidence for a potential diabetes type 3. Alzheimers Res Ther 2022; 14:56. [PMID: 35443732 PMCID: PMC9022265 DOI: 10.1186/s13195-022-00996-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/27/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes. METHODS We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis. CONCLUSIONS In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.
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Affiliation(s)
- Andrea González
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile
| | - Camila Calfío
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile
| | - Macarena Churruca
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile.
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile.
- Department of Neurology, Faculty of Medicine East Campus Hospital Salvador, University of Chile, Salvador 486, Providencia, Santiago, Chile.
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Tripathi R, Aggarwal T, Lindberg FA, Klemm AH, Fredriksson R. SLC38A10 Regulate Glutamate Homeostasis and Modulate the AKT/TSC2/mTOR Pathway in Mouse Primary Cortex Cells. Front Cell Dev Biol 2022; 10:854397. [PMID: 35450293 PMCID: PMC9017388 DOI: 10.3389/fcell.2022.854397] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/15/2022] [Indexed: 12/13/2022] Open
Abstract
Glutamate acts as a critical regulator of neurotransmitter balance, recycling, synaptic function and homeostasis in the brain and glutamate transporters control glutamate levels in the brain. SLC38A10 is a member of the SLC38 family and regulates protein synthesis and cellular stress responses. Here, we uncover the role of SLC38A10 as a transceptor involved in glutamate-sensing signaling pathways that control both the glutamate homeostasis and mTOR-signaling. The culture of primary cortex cells from SLC38A10 knockout mice had increased intracellular glutamate. In addition, under nutrient starvation, KO cells had an impaired response in amino acid-dependent mTORC1 signaling. Combined studies from transcriptomics, protein arrays and metabolomics established that SLC38A10 is involved in mTOR signaling and that SLC38A10 deficient primary cortex cells have increased protein synthesis. Metabolomic data showed decreased cholesterol levels, changed fatty acid synthesis, and altered levels of fumaric acid, citrate, 2-oxoglutarate and succinate in the TCA cycle. These data suggests that SLC38A10 may act as a modulator of glutamate homeostasis, and mTOR-sensing and loss of this transceptor result in lower cholesterol, which could have implications in neurodegenerative diseases.
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Affiliation(s)
- Rekha Tripathi
- Department of Pharmaceutical Bioscience, Unit of Molecular Neuropharmacology, Uppsala University, Uppsala, Sweden
- *Correspondence: Rekha Tripathi,
| | - Tanya Aggarwal
- Department of Pharmaceutical Bioscience, Unit of Molecular Neuropharmacology, Uppsala University, Uppsala, Sweden
| | - Frida A. Lindberg
- Department of Pharmaceutical Bioscience, Unit of Molecular Neuropharmacology, Uppsala University, Uppsala, Sweden
| | - Anna H. Klemm
- BioImage Informatics Facility, SciLifeLab, Division of Visual Information and Interaction, Department of Information Technology, Uppsala, Sweden
| | - Robert Fredriksson
- Department of Pharmaceutical Bioscience, Unit of Molecular Neuropharmacology, Uppsala University, Uppsala, Sweden
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Fluoxetine-induced neurotoxicity at environmentally relevant concentrations in adult zebrafish Danio rerio. Neurotoxicology 2022; 90:121-129. [PMID: 35304135 DOI: 10.1016/j.neuro.2022.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/08/2021] [Accepted: 03/14/2022] [Indexed: 01/21/2023]
Abstract
Fluoxetine (FLX) exerts its therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. Nonetheless, at high concentrations of this drug, adverse effects occur in the brain of exposed organisms. Bearing this into account, the objective of this study was to evaluate the neurotoxic effects of the fluoxetine through the evaluation of behavior (Novel tank test), determination of oxidative stress, and determination of acetylcholinesterase (AChE) activity in adult zebrafish Danio rerio. For this purpose, Danio rerio adults were exposed to three environmentally relevant concentrations (5, 10, 16ngL-1) of FLX for 96h. Our results demonstrate fish presented a significant disruption in their behavior, as they remained long-lasting time frozen at the top of the tank. Since we observed a significant reduction of AChE activity in the brain of fish, we believe the above described anxiety-like state is the result of this enzyme impairment. Moreover, as FLX-exposed fish showed a significant increase in the levels of oxidative damage biomarkers, we suggest this AChE disruption is associated with the oxidative stress response fish exhibited. Based on our findings, we believe the environmentally relevant concentration of FLX alters the redox status of the brain, impairing this way the behavior of fish and making them more vulnerable to predation.
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Fanton S, Sandström A, Tour J, Kadetoff D, Schalling M, Jensen KB, Sitnikov R, Ellerbrock I, Kosek E. The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and γ-aminobutyric acid in fibromyalgia and healthy subjects: a multimodal neuroimaging study. Pain 2022; 163:274-286. [PMID: 34142769 PMCID: PMC8756347 DOI: 10.1097/j.pain.0000000000002309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 03/16/2021] [Accepted: 04/07/2021] [Indexed: 11/16/2022]
Abstract
ABSTRACT A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene (rs6971) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). The influence of TSPO on endogenous pain modulation presented in the form of TSPO HABs, as opposed to MLABs, displaying less efficient descending pain inhibition and expectancy-induced reduction of pain. Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non-FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.
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Affiliation(s)
- Silvia Fanton
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Angelica Sandström
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Jeanette Tour
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Diana Kadetoff
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
- Stockholm Spine Center, Löwenströmska Hospital, Upplands Väsby, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Karin B. Jensen
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Rouslan Sitnikov
- MRI Research Center, Karolinska University Hospital, Stockholm, Sweden
| | - Isabel Ellerbrock
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Eva Kosek
- Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Rafique SA, Steeves JKE. Modulating intrinsic functional connectivity with visual cortex using low-frequency repetitive transcranial magnetic stimulation. Brain Behav 2022; 12:e2491. [PMID: 35049143 PMCID: PMC8865167 DOI: 10.1002/brb3.2491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 12/20/2021] [Accepted: 12/30/2021] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION Intrinsic network connectivity becomes altered in pathophysiology. Noninvasive brain stimulation can modulate pathological functional networks in an attempt to restore the inherent response. To determine its usefulness for visual-related disorders, we developed procedures investigating repetitive transcranial magnetic stimulation (rTMS) protocols targeting the visual cortex on modulating connectivity associated with the visual network and default mode network (DMN). METHODS We compared two low-frequency (1 Hz) rTMS protocols to the visual cortex (V1)-a single 20 min session and five successive 20 min sessions (accelerated/within-session rTMS)-using multi-echo resting-state functional magnetic resonance whole-brain imaging and resting-state functional connectivity (rsFC). We also explored the relationship between rsFC and rTMS-induced changes in key inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate. GABA (GABA+) and glutamate (Glx) concentrations were measured in vivo using magnetic resonance spectroscopy. RESULTS Acute disruption with a single rTMS session caused widespread connectivity reconfiguration with nodes of interest. Changes were not evident immediately post-rTMS but were observed at 1 h post-rTMS. Accelerated sessions resulted in weak alterations in connectivity, producing a relatively homeostatic response. Changes in GABA+ and Glx concentrations with network connectivity were dependent on the rTMS protocol. CONCLUSIONS This proof-of-concept study offers new perspectives to assess stimulation-induced neural processes involved in intrinsic functional connectivity and the potential for rTMS to modulate nodes interconnected with the visual cortex. The differential effects of single-session and accelerated rTMS on physiological markers are crucial for furthering the advancement of treatment modalities in visual cortex related disorders.
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Affiliation(s)
- Sara A Rafique
- Department of Psychology and Centre for Vision Research, York University, Toronto, Canada
| | - Jennifer K E Steeves
- Department of Psychology and Centre for Vision Research, York University, Toronto, Canada
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Correia SC, Moreira PI. Oxygen Sensing and Signaling in Alzheimer's Disease: A Breathtaking Story! Cell Mol Neurobiol 2022; 42:3-21. [PMID: 34510330 PMCID: PMC11441261 DOI: 10.1007/s10571-021-01148-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/07/2021] [Indexed: 10/20/2022]
Abstract
Oxygen sensing and homeostasis is indispensable for the maintenance of brain structural and functional integrity. Under low-oxygen tension, the non-diseased brain has the ability to cope with hypoxia by triggering a homeostatic response governed by the highly conserved hypoxia-inducible family (HIF) of transcription factors. With the advent of advanced neuroimaging tools, it is now recognized that cerebral hypoperfusion, and consequently hypoxia, is a consistent feature along the Alzheimer's disease (AD) continuum. Of note, the reduction in cerebral blood flow and tissue oxygenation detected during the prodromal phases of AD, drastically aggravates as disease progresses. Within this scenario a fundamental question arises: How HIF-driven homeostatic brain response to hypoxia "behaves" during the AD continuum? In this sense, the present review is aimed to critically discuss and summarize the current knowledge regarding the involvement of hypoxia and HIF signaling in the onset and progression of AD pathology. Importantly, the promises and challenges of non-pharmacological and pharmacological strategies aimed to target hypoxia will be discussed as a new "hope" to prevent and/or postpone the neurodegenerative events that occur in the AD brain.
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Affiliation(s)
- Sónia C Correia
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Rua Larga, Polo I, 1st Floor, 3004-504, Coimbra, Portugal.
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
- Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
| | - Paula I Moreira
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Rua Larga, Polo I, 1st Floor, 3004-504, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Laboratory of Physiology, Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
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45
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Strakosas X, Donahue MJ, Hama A, Braendlein M, Huerta M, Simon DT, Berggren M, Malliaras GG, Owens RM. Biostack: Nontoxic Metabolite Detection from Live Tissue. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2101711. [PMID: 34741447 PMCID: PMC8805579 DOI: 10.1002/advs.202101711] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/17/2021] [Indexed: 05/29/2023]
Abstract
There is increasing demand for direct in situ metabolite monitoring from cell cultures and in vivo using implantable devices. Electrochemical biosensors are commonly preferred due to their low-cost, high sensitivity, and low complexity. Metabolite detection, however, in cultured cells or sensitive tissue is rarely shown. Commonly, glucose sensing occurs indirectly by measuring the concentration of hydrogen peroxide, which is a by-product of the conversion of glucose by glucose oxidase. However, continuous production of hydrogen peroxide in cell media with high glucose is toxic to adjacent cells or tissue. This challenge is overcome through a novel, stacked enzyme configuration. A primary enzyme is used to provide analyte sensitivity, along with a secondary enzyme which converts H2 O2 back to O2 . The secondary enzyme is functionalized as the outermost layer of the device. Thus, production of H2 O2 remains local to the sensor and its concentration in the extracellular environment does not increase. This "biostack" is integrated with organic electrochemical transistors to demonstrate sensors that monitor glucose concentration in cell cultures in situ. The "biostack" renders the sensors nontoxic for cells and provides highly sensitive and stable detection of metabolites.
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Affiliation(s)
- Xenofon Strakosas
- Laboratory of Organic ElectronicsDepartment of Science and TechnologyLinköping UniversityNorrköping601 74Sweden
| | - Mary J. Donahue
- Laboratory of Organic ElectronicsDepartment of Science and TechnologyLinköping UniversityNorrköping601 74Sweden
| | - Adel Hama
- King Abdullah University of Science and TechnologyKAUSTThuwal23955‐6900Saudi Arabia
| | | | - Miriam Huerta
- Robert F. Smith School of Chemical and Biomolecular EngineeringCornell UniversityIthacaNY14853USA
| | - Daniel T. Simon
- Laboratory of Organic ElectronicsDepartment of Science and TechnologyLinköping UniversityNorrköping601 74Sweden
| | - Magnus Berggren
- Laboratory of Organic ElectronicsDepartment of Science and TechnologyLinköping UniversityNorrköping601 74Sweden
| | | | - Roisin M. Owens
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeUKUSA
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Maheshwari M, Deshmukh T, Leuthardt EC, Shimony JS. Task-based and Resting State Functional MRI in Children. Magn Reson Imaging Clin N Am 2021; 29:527-541. [PMID: 34717843 DOI: 10.1016/j.mric.2021.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Functional MR imaging (MRI) is a valuable tool for presurgical planning and is well established in adult patients. The use of task-based fMRI is increasing in pediatric populations because it provides similar benefits for pre-surgical planning in children. This article reviews special adaptations that are required for successful applications of task-based fMRI in children, especially in the motor and language systems. The more recently introduced method of resting state fMRI is reviewed and its relative advantages and disadvantages discussed. Common pitfalls and other systems and networks that may be of interest in special circumstances also are reviewed.
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Affiliation(s)
- Mohit Maheshwari
- Department of Radiology, Medical College of Wisconsin, Children's Wisconsin, MS - 721, 9000 W Wisconsin Avenue, Milwaukee, WI 53226, USA.
| | - Tejaswini Deshmukh
- Department of Radiology, Medical College of Wisconsin, Children's Wisconsin, MS - 721, 9000 W Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Eric C Leuthardt
- Department of Neurosurgery, Washington University, 4525 Scott Avenue Campus Box 8131, St Louis, MO 63141, USA
| | - Joshua S Shimony
- Mallinckrodt Institute of Radiology, Washington University, 4525 Scott Avenue Campus Box 8131, St Louis, MO 63141, USA
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Aczél T, Körtési T, Kun J, Urbán P, Bauer W, Herczeg R, Farkas R, Kovács K, Vásárhelyi B, Karvaly GB, Gyenesei A, Tuka B, Tajti J, Vécsei L, Bölcskei K, Helyes Z. Identification of disease- and headache-specific mediators and pathways in migraine using blood transcriptomic and metabolomic analysis. J Headache Pain 2021; 22:117. [PMID: 34615455 PMCID: PMC8493693 DOI: 10.1186/s10194-021-01285-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks. METHODS Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit. RESULTS We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks. CONCLUSIONS It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation.
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Affiliation(s)
- Timea Aczél
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Group and Centre for Neuroscience, University of Pécs Szentágothai Research Centre, University of Pécs Medical School, Szigeti út 12, Pécs, H-7624, Hungary
| | - Tamás Körtési
- Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
- MTA-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, Szeged, H-6726, Hungary
| | - József Kun
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Group and Centre for Neuroscience, University of Pécs Szentágothai Research Centre, University of Pécs Medical School, Szigeti út 12, Pécs, H-7624, Hungary
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Ifjúság útja 20, Pécs, H-7624, Hungary
| | - Péter Urbán
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Ifjúság útja 20, Pécs, H-7624, Hungary
| | - Witold Bauer
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Ifjúság útja 20, Pécs, H-7624, Hungary
| | - Róbert Herczeg
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Ifjúság útja 20, Pécs, H-7624, Hungary
| | - Róbert Farkas
- Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Krisztián Kovács
- Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Barna Vásárhelyi
- Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Gellért B Karvaly
- Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Attila Gyenesei
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Ifjúság útja 20, Pécs, H-7624, Hungary
| | - Bernadett Tuka
- Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
- MTA-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
| | - János Tajti
- Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
| | - László Vécsei
- Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
- MTA-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, Szeged, H-6725, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Group and Centre for Neuroscience, University of Pécs Szentágothai Research Centre, University of Pécs Medical School, Szigeti út 12, Pécs, H-7624, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Group and Centre for Neuroscience, University of Pécs Szentágothai Research Centre, University of Pécs Medical School, Szigeti út 12, Pécs, H-7624, Hungary.
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Benaroya H. Brain energetics, mitochondria, and traumatic brain injury. Rev Neurosci 2021; 31:363-390. [PMID: 32004148 DOI: 10.1515/revneuro-2019-0086] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/13/2019] [Indexed: 12/13/2022]
Abstract
We review current thinking about, and draw connections between, brain energetics and metabolism, and between mitochondria and traumatic brain injury. Energy is fundamental to proper brain function. Its creation in a useful form for neurons and glia, and consistently in response to the brain's high energy needs, is critical for physiological pathways. Dysfunction in the mechanisms of energy production is at the center of neurological and neuropsychiatric pathologies. We examine the connections between energetics and mitochondria - the organelle responsible for almost all the energy production in the cell - and how secondary pathologies in traumatic brain injury result from energetic dysfunction. This paper interweaves these topics, a necessity since they are closely coupled, and identifies where there exist a lack of understanding and of data. In addition to summarizing current thinking in these disciplines, our goal is to suggest a framework for the mathematical modeling of mechanisms and pathways based on optimal energetic decisions.
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Affiliation(s)
- Haym Benaroya
- Department of Mechanical and Aerospace Engineering, Rutgers University, 98 Brett Road, Piscataway, NJ 08854, USA
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49
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Verger A, Grimaldi S, Ribeiro MJ, Frismand S, Guedj E. Single Photon Emission Computed Tomography/Positron Emission Tomography Molecular Imaging for Parkinsonism: A Fast-Developing Field. Ann Neurol 2021; 90:711-719. [PMID: 34338333 PMCID: PMC9291534 DOI: 10.1002/ana.26187] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/30/2021] [Accepted: 07/31/2021] [Indexed: 11/26/2022]
Abstract
The early differential diagnosis of Parkinson disease and atypical parkinsonism is a major challenge. The use of single photon emission computed tomography (SPECT)/positron emission tomography (PET) molecular imaging to investigate parkinsonism is a fast‐developing field. Imaging biomarker research may potentially lead to more accurate disease detection, enabling earlier diagnosis and treatment. This review summarizes recent SPECT/PET advances in radiopharmaceuticals and imaging technologies/analyses that improve the diagnosis of neurodegenerative parkinsonism. We are currently witnessing a turning point in the field. Integrating molecular imaging as a diagnostic technique represents an opportunity to reassess the strategies for diagnosing neurodegenerative parkinsonism. ANN NEUROL 2021;90:711–719
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Affiliation(s)
- Antoine Verger
- Department of Nuclear Medicine & Nancyclotep Imaging Platform, Centre Hospitalier Régional Universitaire Nancy, Lorraine University, Nancy, France.,Imagerie Adaptative Diagnostique et Interventionnelle, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1254, Lorraine University, Nancy, France
| | - Stephan Grimaldi
- Department of Neurology and Movement Disorders, Public Assistance Hospitals of Marseille, Timone University Hospital, Marseille, France
| | - Maria-Joao Ribeiro
- Unité Mixte de Recherche 1253, iBrain, University of Tours, Institut National de la Santé et de la Recherche Médicale Centre d'Investigation Clinique 1415, Centre Hospitalier Régional Universitaire Tours, Tours, France
| | - Solène Frismand
- Department of Neurology, Centre Hospitalier Régional Universitaire Nancy, Lorraine University, Nancy, France
| | - Eric Guedj
- Aix-Marseille University, Centre National de Recherche Scientifique, Central School of Marseille, Unité Mixte de Recherche 7249, Fresnel Institute, Marseille, France.,Department of Nuclear Medicine, Public Assistance Hospitals of Marseille, Timone University Hospital, Marseille, France.,Centre Européen de Recherche en Imagerie Médicale, Aix-Marseille University, Marseille, France
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50
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Sánchez-Puelles C, Calleja-Felipe M, Ouro A, Bougamra G, Arroyo A, Diez I, Erramuzpe A, Cortés J, Martínez-Hernández J, Luján R, Navarrete M, Venero C, Chan A, Morales M, Esteban JA, Knafo S. PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior. Cereb Cortex 2021; 30:505-524. [PMID: 31240311 DOI: 10.1093/cercor/bhz103] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/29/2019] [Accepted: 04/25/2019] [Indexed: 12/11/2022] Open
Abstract
Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior.
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Affiliation(s)
- Cristina Sánchez-Puelles
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.,Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - María Calleja-Felipe
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain
| | - Alberto Ouro
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain
| | - Ghassen Bougamra
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain
| | - Ana Arroyo
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain
| | - Ibai Diez
- Computational Neuroimaging Laboratory, Biocruces Health Research Institute, 48903 Barakaldo, Spain
| | - Asier Erramuzpe
- Computational Neuroimaging Laboratory, Biocruces Health Research Institute, 48903 Barakaldo, Spain
| | - Jesús Cortés
- Computational Neuroimaging Laboratory, Biocruces Health Research Institute, 48903 Barakaldo, Spain.,Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
| | - José Martínez-Hernández
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
| | - Rafael Luján
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
| | - Marta Navarrete
- Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - César Venero
- Department of Psychobiology, Universidad Nacional de Educación a Distancia, 28040 Madrid, Spain
| | - Andrew Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Miguel Morales
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain
| | - José A Esteban
- Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Shira Knafo
- Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.,Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.,Department of Physiology and Cell Biology and National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410501 Israel
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