1
|
Keller JK, Diekhof EK. Visual cues of respiratory contagion: Their impact on neuroimmune activation and mucosal immune responses in humans. Brain Behav Immun 2025; 125:398-409. [PMID: 39870198 DOI: 10.1016/j.bbi.2025.01.016] [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: 08/16/2024] [Revised: 12/12/2024] [Accepted: 01/21/2025] [Indexed: 01/29/2025] Open
Abstract
This study investigated the neural correlates of perceiving visual contagion cues characteristic of respiratory infections through functional magnetic resonance imaging (fMRI). Sixty-two participants (32f/ 30 m; ∼25 years on average) watched short videos depicting either contagious or non-contagious everyday situations, while their brain activation was continuously measured. We further measured the release of secretory immunoglobulin A (sIgA) in saliva to examine the first-line defensive response of the mucosal immune system. Perceiving sneezing and sick individuals compared to non-contagious individuals triggered increased activation in the anterior insula and other regions of the neuroimmune axis, that have been implicated in the somatosensory representation of the respiratory tract, and further led to increased release of sIgA. In line with predictions, this contagion cue-related activation of the insula was positively correlated with both perceived contagiousness and disgust evoked by the videos, as well as with the mucosal sIgA response. In contrast, the amygdala exhibited heightened activation to all videos featuring humans, regardless of explicit signs of contagion, indicating a nonspecific alertness to human presence. Nevertheless, amygdala activation was also correlated with the disgust ratings of each video. Collectively, these findings outline a neuroimmune mechanism for the processing of respiratory contagion cues. While the insula coordinates central and peripheral immune activation to match the perceived contagion threat, supposedly by triggering both increased sIgA release and contagion-related cognitions, the amygdala may rather act as an alerting system for social situations with a heightened transmission risk. This proactive neuroimmune response may help humans to manage contagion risks, that are difficult to avoid, by activating physiological and cognitive countermeasures in reaction to typical symptoms of respiratory infection, which prepares the organism for subsequent pathogen exposure.
Collapse
Affiliation(s)
- Judith K Keller
- Department of Biology, Neuroendocrinology and Human Biology Unit, Institute for Animal Cell- and Systems Biology, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, D-22085 Hamburg, Germany.
| | - Esther K Diekhof
- Department of Biology, Neuroendocrinology and Human Biology Unit, Institute for Animal Cell- and Systems Biology, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, D-22085 Hamburg, Germany.
| |
Collapse
|
2
|
Gargus M, Ben-Azu B, Landwehr A, Dunn J, Errico JP, Tremblay MÈ. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation. Front Neurosci 2025; 18:1527842. [PMID: 39881804 PMCID: PMC11774973 DOI: 10.3389/fnins.2024.1527842] [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: 11/13/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
Collapse
Affiliation(s)
- Makenna Gargus
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Benneth Ben-Azu
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Nigeria
| | - Antonia Landwehr
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Jaclyn Dunn
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | | | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
3
|
Šakić B. The MRL Model: A Valuable Tool in Studies of Autoimmunity-Brain Interactions. Methods Mol Biol 2025; 2868:221-246. [PMID: 39546233 DOI: 10.1007/978-1-0716-4200-9_12] [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
The link between systemic autoimmunity, brain pathology, and aberrant behavior is still largely unexplored field of biomedical science. Accumulating evidence points to causal relationships between immune factors, neurodegeneration, and neuropsychiatric manifestations. By documenting autoimmunity-associated neuronal degeneration and cytotoxicity of the cerebrospinal fluid from disease-affected subjects, the murine MRL model has shown high validity in revealing principal pathogenic circuits. In addition, unlike any other autoimmune strain, MRL mice produce antibodies commonly found in patients suffering from lupus and other autoimmune disorders. This review highlights the importance of the MRL model as a useful preparation for understanding the links between the immune system and brain function.
Collapse
Affiliation(s)
- Boris Šakić
- Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.
| |
Collapse
|
4
|
Malan-Müller S, Martín-Hernández D, Caso JR, Matthijnssens J, Rodríguez-Urrutia A, Lowry CA, Leza JC. Metagenomic symphony of the intestinal ecosystem: How the composition affects the mind. Brain Behav Immun 2025; 123:510-523. [PMID: 39368785 DOI: 10.1016/j.bbi.2024.09.033] [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: 06/14/2024] [Revised: 09/04/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024] Open
Abstract
Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases.
Collapse
Affiliation(s)
- Stefanie Malan-Müller
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Research Institute of Hospital 12 de Octubre (Imas12), Instituto Universitario de Investigación Neuroquímica (IUIN-UCM), Madrid, Spain; Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain.
| | - David Martín-Hernández
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Research Institute of Hospital 12 de Octubre (Imas12), Instituto Universitario de Investigación Neuroquímica (IUIN-UCM), Madrid, Spain; Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain
| | - Javier R Caso
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Research Institute of Hospital 12 de Octubre (Imas12), Instituto Universitario de Investigación Neuroquímica (IUIN-UCM), Madrid, Spain; Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain
| | - Jelle Matthijnssens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Division of Clinical and Epidemiological Virology, Laboratory of Viral Metagenomics, Leuven, Belgium
| | - Amanda Rodríguez-Urrutia
- Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain; Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Juan C Leza
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Research Institute of Hospital 12 de Octubre (Imas12), Instituto Universitario de Investigación Neuroquímica (IUIN-UCM), Madrid, Spain; Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain
| |
Collapse
|
5
|
Cáceres E, Olivella JC, Di Napoli M, Raihane AS, Divani AA. Immune Response in Traumatic Brain Injury. Curr Neurol Neurosci Rep 2024; 24:593-609. [PMID: 39467990 PMCID: PMC11538248 DOI: 10.1007/s11910-024-01382-7] [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] [Accepted: 09/19/2024] [Indexed: 10/30/2024]
Abstract
PURPOSE OF REVIEW This review aims to comprehensively examine the immune response following traumatic brain injury (TBI) and how its disruption can impact healing and recovery. RECENT FINDINGS The immune response is now considered a key element in the pathophysiology of TBI, with consequences far beyond the acute phase after injury. A delicate equilibrium is crucial for a healthy recovery. When this equilibrium is disrupted, chronic inflammation and immune imbalance can lead to detrimental effects on survival and disability. Globally, traumatic brain injury (TBI) imposes a substantial burden in terms of both years of life lost and years lived with disability. Although its epidemiology exhibits dynamic trends over time and across regions, TBI disproportionally affects the younger populations, posing psychosocial and financial challenge for communities and families. Following the initial trauma, the primary injury is succeeded by an inflammatory response, primarily orchestrated by the innate immune system. The inflammasome plays a pivotal role during this stage, catalyzing both programmed cell death pathways and the up-regulation of inflammatory cytokines and transcription factors. These events trigger the activation and differentiation of microglia, thereby intensifying the inflammatory response to a systemic level and facilitating the migration of immune cells and edema. This inflammatory response, initially originated in the brain, is monitored by our autonomic nervous system. Through the vagus nerve and adrenergic and cholinergic receptors in various peripheral lymphoid organs and immune cells, bidirectional communication and regulation between the immune and nervous systems is established.
Collapse
Affiliation(s)
- Eder Cáceres
- Unisabana Center for Translational Science, Universidad de La Sabana, Chía, Colombia.
- School of Medicine, Universidad de La Sabana, Chía, Colombia.
- Bioscience PhD. School of Engineering, Universidad de La Sabana, Chía, Colombia.
| | | | - Mario Di Napoli
- Neurological Service, SS Annunziata Hospital, Sulmona, L'Aquila, Italy
| | - Ahmed S Raihane
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico Health Science Center, Albuquerque, NM, USA
| | - Afshin A Divani
- Department of Neurology, University of New Mexico Health Science Center, Albuquerque, NM, USA
| |
Collapse
|
6
|
Geloso MC, Zupo L, Corvino V. Crosstalk between peripheral inflammation and brain: Focus on the responses of microglia and astrocytes to peripheral challenge. Neurochem Int 2024; 180:105872. [PMID: 39362496 DOI: 10.1016/j.neuint.2024.105872] [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: 08/09/2024] [Revised: 09/18/2024] [Accepted: 09/30/2024] [Indexed: 10/05/2024]
Abstract
A growing body of evidence supports the link between peripheral inflammation and impairment of neurologic functions, including mood and cognitive abilities. The pathogenic event connecting peripheral inflammation and brain dysfunction is represented by neuroinflammation, a pathogenic phenomenon that provides an important contribution to neurodegeneration and cognitive decline also in Alzheimer's, Parkinson's, Huntington's diseases, as well as in Multiple Sclerosis. It is driven by resident brain immune cells, microglia and astrocytes, that acquire an activated phenotype in response to proinflammatory molecules moving from the periphery to the brain parenchyma. Although a huge progress has been made in clarifying cellular and molecular mechanisms bridging peripheral and central inflammation, a clear picture has not been achieved so far. Therefore, experimental models are of crucial relevance to clarify knowledge gaps in this regard. Many findings demonstrate that systemic inflammation induced by pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), is able to trigger neuroinflammation. Therefore, LPS-administration is widely considered a useful tool to study this phenomenon. On this basis, the present review will focus on in vivo studies based on acute and subacute effects of systemic administration of LPS, with special attention on the state of art of microglia and astrocyte response to peripheral challenge.
Collapse
Affiliation(s)
- Maria Concetta Geloso
- Department of Neuroscience, Section of Human Anatomy, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Rome, Italy; Gemelli Science and Technology Park (GSTeP)-Organoids Research Core Facility, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy.
| | - Luca Zupo
- Department of Neuroscience, Section of Human Anatomy, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Valentina Corvino
- Department of Neuroscience, Section of Human Anatomy, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Rome, Italy
| |
Collapse
|
7
|
Kuhn AM, Bosis KE, Wohleb ES. Looking Back to Move Forward: Research in Stress, Behavior, and Immune Function. Neuroimmunomodulation 2024; 31:211-229. [PMID: 39369707 DOI: 10.1159/000541592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024] Open
Abstract
BACKGROUND From the original studies investigating the effects of adrenal gland secretion to modern high-throughput multidimensional analyses, stress research has been a topic of scientific interest spanning just over a century. SUMMARY The objective of this review was to provide historical context for influential discoveries, surprising findings, and preclinical models in stress-related neuroimmune research. Furthermore, we summarize this work and present a current understanding of the stress pathways and their effects on the immune system and behavior. We focus on recent work demonstrating stress-induced immune changes within the brain and highlight studies investigating stress effects on microglia. Lastly, we conclude with potential areas for future investigation concerning microglia heterogeneity, bone marrow niches, and sex differences. KEY MESSAGES Stress is a phenomenon that ties together not only the central and peripheral nervous system, but the immune system as well. The cumulative effects of stress can enhance or suppress immune function, based on the intensity and duration of the stressor. These stress-induced immune alterations are associated with neurobiological changes, including structural remodeling of neurons and decreased neurogenesis, and these contribute to the development of behavioral and cognitive deficits. As such, research in this field has revealed important insights into neuroimmune communication as well as molecular and cellular mediators of complex behaviors relevant to psychiatric disorders.
Collapse
Affiliation(s)
- Alexander M Kuhn
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Kelly E Bosis
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Eric S Wohleb
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
8
|
Costa PCT, de Luna Freire MO, de Oliveira Coutinho D, Godet M, Magnani M, Antunes VR, de Souza EL, Vidal H, de Brito Alves JL. Nutraceuticals in the management of autonomic function and related disorders: A comprehensive review. Pharmacol Res 2024; 208:107368. [PMID: 39191337 DOI: 10.1016/j.phrs.2024.107368] [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: 05/21/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024]
Abstract
Nutraceuticals have been described as phytocomplexes when derived from foods of plant origin or a pool of secondary metabolites when derived from foods of animal origin, which are concentrated and administered in an appropriate form and can promote beneficial health effects in the prevention/treatment of diseases. Considering that pharmaceutical medications can cause side effects, there is a growing interest in using nutraceuticals as an adjuvant therapeutic tool for several disorders involving autonomic dysfunction, such as obesity, atherosclerosis and other cardiometabolic diseases. This review summarizes and discusses the evidence from the literature on the effects of various nutraceuticals on autonomic control, addressing the gut microbiota modulation, production of secondary metabolites from bioactive compounds, and improvement of physical and chemical properties of cell membranes. Additionally, the safety of nutraceuticals and prospects are discussed. Probiotics, resveratrol, quercetin, curcumin, nitrate, inositol, L-carnosine, and n-3 polyunsaturated fatty acids (n-3 PUFAs) are among the nutraceuticals most studied to improve autonomic dysfunction in experimental animal models and clinical trials. Further human studies are needed to elucidate the effects of nutraceuticals formulated of multitarget compounds and their underlying mechanisms of action, which could benefit conditions involving autonomic dysfunction.
Collapse
Affiliation(s)
- Paulo César Trindade Costa
- Department of Nutrition, Federal University of Paraíba, João Pessoa, PB, Brazil; Laboratoire CarMeN, INSERM U.1060, INRAe U. 1397, Université Claude Bernard Lyon1, Pierre Bénite, France
| | | | | | - Murielle Godet
- Laboratoire CarMeN, INSERM U.1060, INRAe U. 1397, Université Claude Bernard Lyon1, Pierre Bénite, France
| | - Marciane Magnani
- Department of Food Engineering, Federal University of Paraíba, João Pessoa, PB, Brazil
| | - Vagner Roberto Antunes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Hubert Vidal
- Laboratoire CarMeN, INSERM U.1060, INRAe U. 1397, Université Claude Bernard Lyon1, Pierre Bénite, France
| | | |
Collapse
|
9
|
Bihorac J, Salem Y, Lückemann L, Schedlowski M, Doenlen R, Engler H, Mark MD, Dombrowski K, Spoida K, Hadamitzky M. Investigations on the Ability of the Insular Cortex to Process Peripheral Immunosuppression. J Neuroimmune Pharmacol 2024; 19:40. [PMID: 39078442 PMCID: PMC11289148 DOI: 10.1007/s11481-024-10143-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/14/2024] [Indexed: 07/31/2024]
Abstract
The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data revealed that immune-related information under peripheral inflammatory conditions, termed as "immunengram", were represented in specific neuronal ensembles in the insular cortex (IC). Chemogenetic reactivation of these neuronal ensembles was sufficient to retrieve the inflammatory stages, indicating that the brain can store and retrieve specific immune responses. Against this background, the current approach was designed to investigate the ability of the IC to process states of immunosuppression pharmacologically induced by the mechanistic target of rapamycin (mTOR) inhibitor rapamycin. We here show that the IC perceives the initial state of immunosuppression, reflected by increased deep-brain electroencephalography (EEG) activity during acute immunosuppressive drug treatment. Following an experienced period of immunosuppression, though, diminished splenic cytokine production as formerly induced by rapamycin could not be reinstated by nonspecific chemogenetic activation or inhibition of the IC. These findings suggest that the information of a past, or experienced status of pharmacologically induced immunosuppression is not represented in the IC. Together, the present work extends the view of immune-to-brain communication during the states of peripheral immunosuppression and foster the prominent role of the IC for interoception.
Collapse
Affiliation(s)
- Julia Bihorac
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Yasmin Salem
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Raphael Doenlen
- Center of Phenogenomics, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Harald Engler
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Melanie D Mark
- Behavioral Neuroscience, Faculty for Biology and Biotechnology, Ruhr-University Bochum, Bochum, Germany
| | - Kirsten Dombrowski
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Katharina Spoida
- Department of General Zoology and Neurobiology, Ruhr-University Bochum, Bochum, Germany
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany.
| |
Collapse
|
10
|
Joana Alves M, Browe BM, Carolina Rodrigues Dias A, Torres JM, Zaza G, Bangudi S, Blackburn J, Wang W, de Araujo Fernandes-Junior S, Fadda P, Toland A, Baer LA, Stanford KI, Czeisler C, Garcia AJ, Javier Otero J. Metabolic trade-offs in Neonatal sepsis triggered by TLR4 and TLR1/2 ligands result in unique dysfunctions in neural breathing circuits. Brain Behav Immun 2024; 119:333-350. [PMID: 38561095 DOI: 10.1016/j.bbi.2024.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/05/2024] [Accepted: 03/17/2024] [Indexed: 04/04/2024] Open
Abstract
Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing.
Collapse
Affiliation(s)
- Michele Joana Alves
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Brigitte M Browe
- Institute for Integrative Physiology, Grossman Institute for Neuroscience Quantitative Biology and Human Behavior, The Neuroscience Institute, The University of Chicago, Chicago, IL, United States
| | - Ana Carolina Rodrigues Dias
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Juliet M Torres
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Giuliana Zaza
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Suzy Bangudi
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Jessica Blackburn
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Wesley Wang
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | | | - Paolo Fadda
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Amanda Toland
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States; Department of Cancer Biology and Genetics and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
| | - Lisa A Baer
- Department of Cancer Biology and Genetics and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
| | - Kristin I Stanford
- Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Catherine Czeisler
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Alfredo J Garcia
- Institute for Integrative Physiology, Grossman Institute for Neuroscience Quantitative Biology and Human Behavior, The Neuroscience Institute, The University of Chicago, Chicago, IL, United States.
| | - José Javier Otero
- Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
| |
Collapse
|
11
|
Hautala MK, Mikkonen KH, Pokka TML, Rannikko SK, Koskela UV, Rantala HMJ, Uhari MK, Glumoff V, Helander HM. Serum HMGB1 in febrile seizures. Epilepsy Res 2024; 203:107381. [PMID: 38772303 DOI: 10.1016/j.eplepsyres.2024.107381] [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: 12/21/2023] [Revised: 04/20/2024] [Accepted: 05/06/2024] [Indexed: 05/23/2024]
Abstract
The role of high-mobility group box 1 (HMGB1) in the pathogenesis of febrile seizures (FSs) is unclear. In our controlled follow-up study, we compared serum levels of HMGB1 (s-HMGB1) in the same individuals after the first FS, during febrile episodes without a FS, after recurrent FS, during healthy periods after FS, and between patients and controls. In all, 122 patients with FSs were included in the final analysis, including 18 with recurrent FSs with a complete follow-up protocol. We recruited 30 febrile children and 18 matched febrile children without seizures as controls. S-HMGB1 was lower in patients with recurrent FSs after the first FS than that in matched febrile control children (median 1.12 μg/L (0.14-2.95) vs 1.79 μg/L (0.33-47.90), P<0.04). We did not find any other differences in s-HMGB1 between the groups. S-HMGB1 did not differ in different types of FSs. We updated a meta-analysis of s-HMGB1 in patients with FSs and found that the differences were significant only in the studies conducted in East Asian populations. We conclude that S-HMGB1 does not seem to be a key factor in the pathogenesis of FSs but differences in HMGB1 concentrations could explain some of the ethnicity related susceptibility to FSs.
Collapse
Affiliation(s)
- Maria K Hautala
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland.
| | - Kirsi H Mikkonen
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland; Epilepsia Helsinki, Division of Child Neurology, Children's Hospital, and Pediatric Research Center, Helsinki University Hospital and University of Helsinki, P.O. Box 347, Helsinki 00029, Finland
| | - Tytti M L Pokka
- Research Service Unit, Oulu University Hospital, P.O. Box 10, 90029, Finland; Research Unit of Clinical Medicine, University of Oulu, P.O. Box 8000, Oulu 90014, Finland
| | - Sirpa K Rannikko
- Medical Research Laboratory Unit, University of Oulu, P.O. Box 8000, Oulu 90014, Finland
| | - Ulla V Koskela
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland
| | - Heikki M J Rantala
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland
| | - Matti K Uhari
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland
| | - Virpi Glumoff
- Medical Research Laboratory Unit, University of Oulu, P.O. Box 8000, Oulu 90014, Finland
| | - Heli M Helander
- Research Unit of Clinical Medicine, University of Oulu, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland and Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, P.O. Box 23, Oulu 90029, Finland
| |
Collapse
|
12
|
Li G, Wang Y, Qian L, Li D, Yao Y, Pan J, Fan D. C8-ceramide modulates microglia BDNF expression to alleviate postoperative cognition dysfunction via PKCδ/NF-κB signaling pathway. Exp Brain Res 2024; 242:1543-1559. [PMID: 38750371 PMCID: PMC11208206 DOI: 10.1007/s00221-024-06847-2] [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: 12/07/2023] [Accepted: 05/06/2024] [Indexed: 06/27/2024]
Abstract
Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.
Collapse
Affiliation(s)
- Guangqian Li
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Yuhao Wang
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lei Qian
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Danni Li
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Yuchen Yao
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China
| | - Jian Pan
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Dan Fan
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, #32 West Second Section, First-Ring Road, Chengdu, 610072, People's Republic of China.
| |
Collapse
|
13
|
Tran NT, Somers A, Vidinopoulos K, Azman Z, Pham Y, Zahra VA, Chan KYY, Hooper S, Crossley K, Allison BJ, Galinsky R, Polglase GR. The synergistic effects of mechanical ventilation and intrauterine inflammation on cerebral inflammation in preterm fetal sheep. Front Cell Neurosci 2024; 18:1397658. [PMID: 38962513 PMCID: PMC11220153 DOI: 10.3389/fncel.2024.1397658] [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: 03/08/2024] [Accepted: 05/31/2024] [Indexed: 07/05/2024] Open
Abstract
Background Intrauterine inflammation and the requirement for mechanical ventilation independently increase the risk of perinatal brain injury and adverse neurodevelopmental outcomes. We aimed to investigate the effects of mechanical ventilation for 24 h, with and without prior exposure to intrauterine inflammation, on markers of brain inflammation and injury in the preterm sheep brain. Methods Chronically instrumented fetal sheep at ~115 days of gestation were randomly allocated to receive a single intratracheal dose of 1 mg lipopolysaccharide (LPS) or isovolumetric saline, then further randomly allocated 1 h after to receive mechanical ventilation with room air or no mechanical ventilation (unventilated control + saline [UVC, n = 7]; in utero mechanical ventilation + saline [VENT, n = 8], unventilated control + intratracheal LPS [UVC + LPS, n = 7]; in utero ventilation + intratracheal LPS [VENT + LPS, n = 7]). Serial fetal blood and plasma samples were collected throughout the experimental protocol for assessment of blood biochemistry and plasma interleukin (IL)-6 levels. After 24 h of mechanical ventilation, fetal brains were collected for RT-qPCR and immunohistochemical analyses. Results LPS exposure increased numbers of microglia and upregulated pro-inflammatory related genes within the cortical gray matter (GM) and subcortical white matter (SCWM) (pLPS < 0.05). Mechanical ventilation alone increased astrocytic cell density in the periventricular white matter (PVWM) (pVENT = 0.03) but had no effect on pro-inflammatory gene expression. The combination of ventilation and LPS increased plasma IL-6 levels (p < 0.02 vs. UVC and VENT groups), and exacerbated expression of pro-inflammatory-related genes (IL1β, TLR4, PTGS2, CXCL10) and microglial density (p < 0.05 vs. VENT). Conclusion This study demonstrates that 24 h of mechanical ventilation after exposure to intrauterine inflammation increased markers of systemic and brain inflammation and led to the upregulation of pro-inflammatory genes in the white matter. We conclude that 24 h of mechanical ventilation following intrauterine inflammation may precondition the preterm brain toward being more susceptible to inflammation-induced injury.
Collapse
Affiliation(s)
- Nhi T. Tran
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Ainsley Somers
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Kayla Vidinopoulos
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Zahrah Azman
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Yen Pham
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Valerie A. Zahra
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Kyra Y. Y. Chan
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Stuart Hooper
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Kelly Crossley
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Beth J. Allison
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Robert Galinsky
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Graeme R. Polglase
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Paediatrics, Monash University, Clayton, VIC, Australia
| |
Collapse
|
14
|
McKay DM, Defaye M, Rajeev S, MacNaughton WK, Nasser Y, Sharkey KA. Neuroimmunophysiology of the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 2024; 326:G712-G725. [PMID: 38626403 PMCID: PMC11376980 DOI: 10.1152/ajpgi.00075.2024] [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: 03/07/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 04/18/2024]
Abstract
Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.
Collapse
Affiliation(s)
- Derek M McKay
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Manon Defaye
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sruthi Rajeev
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K MacNaughton
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Yasmin Nasser
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| |
Collapse
|
15
|
Berthoud HR, Münzberg H, Morrison CD, Neuhuber WL. Hepatic interoception in health and disease. Auton Neurosci 2024; 253:103174. [PMID: 38579493 PMCID: PMC11129274 DOI: 10.1016/j.autneu.2024.103174] [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: 12/19/2023] [Revised: 03/14/2024] [Accepted: 03/28/2024] [Indexed: 04/07/2024]
Abstract
The liver is a large organ with crucial functions in metabolism and immune defense, as well as blood homeostasis and detoxification, and it is clearly in bidirectional communication with the brain and rest of the body via both neural and humoral pathways. A host of neural sensory mechanisms have been proposed, but in contrast to the gut-brain axis, details for both the exact site and molecular signaling steps of their peripheral transduction mechanisms are generally lacking. Similarly, knowledge about function-specific sensory and motor components of both vagal and spinal access pathways to the hepatic parenchyma is missing. Lack of progress largely owes to controversies regarding selectivity of vagal access pathways and extent of hepatocyte innervation. In contrast, there is considerable evidence for glucose sensors in the wall of the hepatic portal vein and their importance for glucose handling by the liver and the brain and the systemic response to hypoglycemia. As liver diseases are on the rise globally, and there are intriguing associations between liver diseases and mental illnesses, it will be important to further dissect and identify both neural and humoral pathways that mediate hepatocyte-specific signals to relevant brain areas. The question of whether and how sensations from the liver contribute to interoceptive self-awareness has not yet been explored.
Collapse
Affiliation(s)
- Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Winfried L Neuhuber
- Institute for Anatomy and Cell Biology, Friedrich-Alexander University, Erlangen, Germany.
| |
Collapse
|
16
|
Lauten TH, Natour T, Case AJ. Innate and adaptive immune system consequences of post-traumatic stress disorder. Auton Neurosci 2024; 252:103159. [PMID: 38428324 PMCID: PMC11494466 DOI: 10.1016/j.autneu.2024.103159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/06/2024] [Accepted: 02/21/2024] [Indexed: 03/03/2024]
Abstract
In the field of psychiatry, biological markers are rarely, if ever, used in the diagnosis of mental health disorders. Clinicians rely primarily on patient histories and behavioral symptoms to identify specific psychopathologies, which makes diagnosis highly subjective. Moreover, therapies for mental health disorders are aimed specifically at attenuating behavioral manifestations, which overlooks the pathophysiological indices of the disease. This is highly evident in posttraumatic stress disorder (PTSD) where inflammation and immune system perturbations are becoming increasingly described. Further, patients with PTSD possess significantly elevated risks of developing comorbid inflammatory diseases such as autoimmune and cardiovascular diseases, which are likely linked (though not fully proven) to the apparent dysregulation of the immune system after psychological trauma. To date, there is little to no evidence that demonstrates current PTSD therapies are able to reverse the increased risk for psychological trauma-induced inflammatory diseases, which suggests the behavioral and somatic consequences of PTSD may not be tightly coupled. This observation provides an opportunity to explore unique mechanisms outside of the brain that contribute to the long-term pathology of PTSD. Herein, we provide an overview of neuroimmune mechanisms, describe what is known regarding innate and adaptive immunity in PTSD, and suggest new directions that are needed to advance the understanding, diagnosis, and treatment of PTSD moving forward.
Collapse
Affiliation(s)
- Tatlock H Lauten
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Tamara Natour
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Adam J Case
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States.
| |
Collapse
|
17
|
Radke J, Meinhardt J, Aschman T, Chua RL, Farztdinov V, Lukassen S, Ten FW, Friebel E, Ishaque N, Franz J, Huhle VH, Mothes R, Peters K, Thomas C, Schneeberger S, Schumann E, Kawelke L, Jünger J, Horst V, Streit S, von Manitius R, Körtvélyessy P, Vielhaber S, Reinhold D, Hauser AE, Osterloh A, Enghard P, Ihlow J, Elezkurtaj S, Horst D, Kurth F, Müller MA, Gassen NC, Melchert J, Jechow K, Timmermann B, Fernandez-Zapata C, Böttcher C, Stenzel W, Krüger E, Landthaler M, Wyler E, Corman V, Stadelmann C, Ralser M, Eils R, Heppner FL, Mülleder M, Conrad C, Radbruch H. Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19. Nat Neurosci 2024; 27:409-420. [PMID: 38366144 DOI: 10.1038/s41593-024-01573-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/08/2024] [Indexed: 02/18/2024]
Abstract
Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation, one neuronal with a direct focus on cranial nerve nuclei and a separate diffuse pattern affecting the whole brainstem. The latter reflects a bystander effect of the respiratory infection that spreads throughout the vascular unit and alters the transcriptional state of mainly oligodendrocytes, microglia and astrocytes, while alterations of the brainstem nuclei could reflect the connection of the immune system and the central nervous system via, for example, the vagus nerve. Our results indicate that even without persistence of severe acute respiratory syndrome coronavirus 2 in the central nervous system, local immune reactions are prevailing, potentially causing functional disturbances that contribute to neurological complications of COVID-19.
Collapse
Affiliation(s)
- Josefine Radke
- Institute of Pathology, Universitätsmedizin Greifswald, Greifswald, Germany.
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| | - Jenny Meinhardt
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Tom Aschman
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Lorenz Chua
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vadim Farztdinov
- Core Facility High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sören Lukassen
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Foo Wei Ten
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ekaterina Friebel
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Naveed Ishaque
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jonas Franz
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Valerie Helena Huhle
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ronja Mothes
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Kristin Peters
- Institute of Pathology, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Carolina Thomas
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Shirin Schneeberger
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Elisa Schumann
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Leona Kawelke
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Julia Jünger
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Viktor Horst
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Streit
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Regina von Manitius
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Péter Körtvélyessy
- Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Vielhaber
- Department of Neurology, Otto von Guerike University Magdeburg, Magdeburg, Germany
| | - Dirk Reinhold
- Institute of Molecular and Clinical Immunology, Otto von Guerike University Magdeburg, Magdeburg, Germany
| | - Anja E Hauser
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Immune Dynamics, Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Berlin, Germany
| | - Anja Osterloh
- Department of Pathology, University Medical Center Ulm, Ulm, Germany
| | - Philipp Enghard
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jana Ihlow
- Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sefer Elezkurtaj
- Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - David Horst
- Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Florian Kurth
- Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel A Müller
- Institute of Virology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Nils C Gassen
- Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
| | - Julia Melchert
- Institute of Virology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Katharina Jechow
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Camila Fernandez-Zapata
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Chotima Böttcher
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Werner Stenzel
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Elke Krüger
- Institute of Medical Biochemistry and Molecular Biology, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Markus Landthaler
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Institut für Biologie, Humboldt Universität, Berlin, Germany
| | - Emanuel Wyler
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Victor Corman
- Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Centre for Infection Research (DZIF), associated partner, Berlin, Germany
| | - Christine Stadelmann
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Markus Ralser
- Core Facility High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Roland Eils
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank L Heppner
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
- Cluster of Excellence NeuroCure, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Mülleder
- Core Facility High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Conrad
- Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Helena Radbruch
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| |
Collapse
|
18
|
Thornton T, Mills D, Bliss E. The impact of lipopolysaccharide on cerebrovascular function and cognition resulting from obesity-induced gut dysbiosis. Life Sci 2024; 336:122337. [PMID: 38072189 DOI: 10.1016/j.lfs.2023.122337] [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: 09/20/2023] [Revised: 11/23/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023]
Abstract
Obesity is a worldwide epidemic coinciding with a concomitant increase in the incidence of neurodegenerative diseases, particularly dementia. Obesity is characterised by increased adiposity, chronic low-grade systemic inflammation, and oxidative stress, which promote endothelial dysfunction. Endothelial dysfunction reduces cerebrovascular function leading to reduced cerebral blood flow and, eventually, cognitive decline, thus predisposing to a neurodegenerative disease. Obesity is also characterised by gut dysbiosis and a subsequent increase in the lipopolysaccharide which increasingly activates toll-like receptor 4 (TLR4) and further promotes chronic low-grade systemic inflammation. This also disrupts the crosstalk within the gut-brain axis, thus influencing the functions of the central nervous system, including cognition. However, the mechanisms by which obesity-related increases in oxidative stress, inflammation and endothelial dysfunction are driven by, or associated with, increased systemic lipopolysaccharide leading to reduced cerebrovascular function and cognition, beyond normal ageing, have not been elucidated. Hence, this review examines how increased concentrations of lipopolysaccharide and the subsequent increased TLR4 activation observed in obesity exacerbate the development of obesity-induced reductions in cerebrovascular function and cognition.
Collapse
Affiliation(s)
- Tammy Thornton
- School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia; Respiratory and Exercise Physiology Research Group, School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia.
| | - Dean Mills
- School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia; Respiratory and Exercise Physiology Research Group, School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia; Centre for Health Research, Institute for Resilient Regions, University of Southern Queensland, Ipswich, QLD 4305, Australia; Molecular Biomarkers Research Group, University of Southern Queensland, Toowoomba, QLD 4350, Australia
| | - Edward Bliss
- School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia; Respiratory and Exercise Physiology Research Group, School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia; Centre for Health Research, Institute for Resilient Regions, University of Southern Queensland, Ipswich, QLD 4305, Australia; Molecular Biomarkers Research Group, University of Southern Queensland, Toowoomba, QLD 4350, Australia
| |
Collapse
|
19
|
Gonçalves-Sánchez J, Sancho C, López DE, Castellano O, García-Cenador B, Servilha-Menezes G, Corchado JM, García-Cairasco N, Gonçalves-Estella JM. Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster. Int J Mol Sci 2023; 25:91. [PMID: 38203262 PMCID: PMC10778912 DOI: 10.3390/ijms25010091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/10/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1β, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.
Collapse
Affiliation(s)
- Jaime Gonçalves-Sánchez
- Department of Cellular Biology and Pathology, School of Medicine, University of Salamanca, 37007 Salamanca, Spain; (D.E.L.); (O.C.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Institute of Neuroscience of Castilla y León, 37007 Salamanca, Spain
| | - Consuelo Sancho
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Institute of Neuroscience of Castilla y León, 37007 Salamanca, Spain
- Department of Physiology and Pharmacology, School of Medicine, University of Salamanca, 37007 Salamanca, Spain
| | - Dolores E. López
- Department of Cellular Biology and Pathology, School of Medicine, University of Salamanca, 37007 Salamanca, Spain; (D.E.L.); (O.C.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Institute of Neuroscience of Castilla y León, 37007 Salamanca, Spain
| | - Orlando Castellano
- Department of Cellular Biology and Pathology, School of Medicine, University of Salamanca, 37007 Salamanca, Spain; (D.E.L.); (O.C.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Institute of Neuroscience of Castilla y León, 37007 Salamanca, Spain
| | - Begoña García-Cenador
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Department of Surgery, School of Medicine, University of Salamanca, 37007 Salamanca, Spain
| | - Gabriel Servilha-Menezes
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, SP, Brazil; (G.S.-M.); (N.G.-C.)
| | - Juan M. Corchado
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Bioinformatics, Intelligent Systems and Educational Technology (BISITE) Research Group, 37007 Salamanca, Spain
| | - Norberto García-Cairasco
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, SP, Brazil; (G.S.-M.); (N.G.-C.)
| | - Jesús M. Gonçalves-Estella
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (C.S.); (B.G.-C.); (J.M.C.); (J.M.G.-E.)
- Department of Surgery, School of Medicine, University of Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
20
|
Jia X, Chen Q, Zhang Y, Asakawa T. Multidirectional associations between the gut microbiota and Parkinson's disease, updated information from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. Front Cell Infect Microbiol 2023; 13:1296713. [PMID: 38173790 PMCID: PMC10762314 DOI: 10.3389/fcimb.2023.1296713] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024] Open
Abstract
The human gastrointestinal tract is inhabited by a diverse range of microorganisms, collectively known as the gut microbiota, which form a vast and complex ecosystem. It has been reported that the microbiota-gut-brain axis plays a crucial role in regulating host neuroprotective function. Studies have shown that patients with Parkinson's disease (PD) have dysbiosis of the gut microbiota, and experiments involving germ-free mice and fecal microbiota transplantation from PD patients have revealed the pathogenic role of the gut microbiota in PD. Interventions targeting the gut microbiota in PD, including the use of prebiotics, probiotics, and fecal microbiota transplantation, have also shown efficacy in treating PD. However, the causal relationship between the gut microbiota and Parkinson's disease remains intricate. This study reviewed the association between the microbiota-gut-brain axis and PD from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. We found that the interactions among gut microbiota and PD are very complex, which should be "multidirectional", rather than conventionally regarded "bidirectional". To realize application of the gut microbiota-related mechanisms in the clinical setting, we propose several problems which should be addressed in the future study.
Collapse
Affiliation(s)
- Xiaokang Jia
- School of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Qiliang Chen
- School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuanyuan Zhang
- Department of Acupuncture and Moxibustion, The Affiliated Traditional Chinese Medicine (TCM) Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tetsuya Asakawa
- Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| |
Collapse
|
21
|
Klima ML, Kruger KA, Goldstein N, Pulido S, Low AYT, Assenmacher CA, Alhadeff AL, Betley JN. Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits. Cell Rep 2023; 42:113338. [PMID: 37910501 DOI: 10.1016/j.celrep.2023.113338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 07/31/2023] [Accepted: 10/10/2023] [Indexed: 11/03/2023] Open
Abstract
Caloric restriction has anti-inflammatory effects. However, the coordinated physiological actions that lead to reduced inflammation in a state of caloric deficit (hunger) are largely unknown. Using a mouse model of injury-induced peripheral inflammation, we find that food deprivation reduces edema, temperature, and cytokine responses that occur after injury. The magnitude of the anti-inflammatory effect that occurs during hunger is more robust than that of non-steroidal anti-inflammatory drugs. The effects of hunger are recapitulated centrally by activity in nutrient-sensing hypothalamic agouti-related protein (AgRP)-expressing neurons. We find that AgRP neurons projecting to the paraventricular nucleus of the hypothalamus rapidly and robustly reduce inflammation and mediate the majority of hunger's anti-inflammatory effects. Intact vagal efferent signaling is required for the anti-inflammatory action of hunger, revealing a brain-to-periphery pathway for this reduction in inflammation. Taken together, these data begin to unravel a potent anti-inflammatory pathway engaged by hypothalamic AgRP neurons to reduce inflammation.
Collapse
Affiliation(s)
- Michelle L Klima
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kayla A Kruger
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nitsan Goldstein
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Santiago Pulido
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aloysius Y T Low
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Charles-Antoine Assenmacher
- Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Amber L Alhadeff
- Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA; Monell Chemical Senses Center, Philadelphia, PA 19104, USA.
| | - J Nicholas Betley
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
22
|
Zimek D, Miklusova M, Mares J. Overview of the Current Pathophysiology of Fatigue in Multiple Sclerosis, Its Diagnosis and Treatment Options - Review Article. Neuropsychiatr Dis Treat 2023; 19:2485-2497. [PMID: 38029042 PMCID: PMC10674653 DOI: 10.2147/ndt.s429862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/03/2023] [Indexed: 12/01/2023] Open
Abstract
Fatigue is a common, debilitating and often underestimated symptom in patients with multiple sclerosis (MS). The exact pathophysiological mechanism of fatigue in MS is still unknown. However, there are many theories involving different immunological, metabolic and inflammatory mechanisms of fatigue. Owing to the subjective nature of this symptom, its diagnosis is still very limited and is still based only on diagnostic questionnaires. Although several therapeutic agents have been used in the past to try to influence fatigue in MS patients, no single effective approach for the treatment of fatigue has yet been found. This review article aims to provide the reader with information on the current theories on the origin and mechanism of fatigue in MS, as well as diagnostic procedures and, finally, current therapeutic strategies for the management of fatigue in MS patients.
Collapse
Affiliation(s)
- Dalibor Zimek
- Department of Neurology, Palacky University Hospital Olomouc, Olomouc, Czech Republic
| | - Martina Miklusova
- Department of Neurology, Palacky University Hospital Olomouc, Olomouc, Czech Republic
| | - Jan Mares
- Department of Neurology, Palacky University Hospital Olomouc, Olomouc, Czech Republic
| |
Collapse
|
23
|
Hall CV, Radford-Smith G, Savage E, Robinson C, Cocchi L, Moran RJ. Brain signatures of chronic gut inflammation. Front Psychiatry 2023; 14:1250268. [PMID: 38025434 PMCID: PMC10661239 DOI: 10.3389/fpsyt.2023.1250268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Gut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral inflammation over the natural history of inflammatory bowel disease (IBD) contributes to altered brain dynamics is poorly understood. Here, we used electroencephalography (EEG) to characterise changes in spontaneous spatiotemporal brain states in Crohn's Disease (CD) (n = 40) and Ulcerative Colitis (UC) (n = 30), compared to healthy individuals (n = 28). We first provide evidence of a significantly perturbed and heterogeneous microbial profile in CD, consistent with previous work showing enduring and long-standing dysbiosis in clinical remission. Results from our brain state assessment show that CD and UC exhibit alterations in the temporal properties of states implicating default-mode network, parietal, and visual regions, reflecting a shift in the predominance from externally to internally-oriented attentional modes. We investigated these dynamics at a finer sub-network resolution, showing a CD-specific and highly selective enhancement of connectivity between the insula and medial prefrontal cortex (mPFC), regions implicated in cognitive-interoceptive appraisal mechanisms. Alongside overall higher anxiety scores in CD, we also provide preliminary support to suggest that the strength of chronic interoceptive hyper-signalling in the brain co-occurs with disease duration. Together, our results demonstrate that a long-standing diagnosis of CD is, in itself, a key factor in determining the risk of developing altered brain network signatures.
Collapse
Affiliation(s)
- Caitlin V. Hall
- Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Graham Radford-Smith
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Gut Health Research Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Department of Gastroenterology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
| | - Emma Savage
- Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Conor Robinson
- Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Luca Cocchi
- Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Rosalyn J. Moran
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom
| |
Collapse
|
24
|
Plaschke K, Brenner T, Fiedler MO, Hölle T, von der Forst M, Wolf RC, Kopitz J, Gebert J, Weigand MA. Extracellular Vesicles as Possible Plasma Markers and Mediators in Patients with Sepsis-Associated Delirium-A Pilot Study. Int J Mol Sci 2023; 24:15781. [PMID: 37958765 PMCID: PMC10649316 DOI: 10.3390/ijms242115781] [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: 10/03/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.
Collapse
Affiliation(s)
- Konstanze Plaschke
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
| | - Thorsten Brenner
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Mascha O. Fiedler
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
| | - Tobias Hölle
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
| | - Maik von der Forst
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
| | - Robert Christian Wolf
- Center for Psychosocial Medicine, Department of General Psychiatry, University Hospital Heidelberg, Vossstraße 4, 69115 Heidelberg, Germany;
| | - Jürgen Kopitz
- Department of Applied Tumor Biology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (J.K.); (J.G.)
| | - Johannes Gebert
- Department of Applied Tumor Biology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (J.K.); (J.G.)
| | - Markus A. Weigand
- Department of Anesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (T.B.); (M.O.F.); (T.H.); (M.v.d.F.)
| |
Collapse
|
25
|
Vidinopoulos K, Azman Z, Somers A, Zahra VA, Thiel A, Lu H, Pham Y, Tran NT, Allison BJ, Herlenius E, Hooper S, Galinsky R, Polglase GR. Mechanical ventilation induces brainstem inflammation in preterm fetal sheep. Front Pediatr 2023; 11:1225294. [PMID: 37936886 PMCID: PMC10626530 DOI: 10.3389/fped.2023.1225294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/25/2023] [Indexed: 11/09/2023] Open
Abstract
Background Preterm infants have immature respiratory drive and often require prolonged periods of mechanical ventilation. Prolonged mechanical ventilation induces systemic inflammation resulting in ventilation-induced brain injury, however its effect on brainstem respiratory centers is unknown. We aimed to determine the effects of 24 h of mechanical ventilation on inflammation and injury in brainstem respiratory centres of preterm fetal sheep. Methods Preterm fetal sheep at 110 ± 1 days (d) gestation were instrumented to provide mechanical ventilation in utero. At 112 ± 1 d gestation, fetuses received either mechanical ventilation (VENT; n = 7; 3 ml/kg) for 24 h, or no ventilation (CONT; n = 6). At post-mortem, fetal brainstems were collected for assessment of mRNA and histological markers of inflammation and injury. Results In utero ventilation (IUV) did not alter any blood-gas parameters. IUV significantly increased systemic IL-6 and IL-8 concentrations over the 24 h period compared to CONT. The number of ameboid microglia within the nucleus tractus solitarius and the raphe nucleus increased in VENT fetuses (p < 0.05 for both vs. control). The % area fraction of GFAP + staining was not significantly higher within the preBötzinger complex (p = 0.067) and retrotrapezoid nucleus and parafacial respiratory group (p = 0.057) in VENT fetuses compared to CONT. Numbers of caspase-3 and TUNEL-positive cells were similar between groups. Gene expression (mRNA) levels of inflammation, injury, cell death and prostaglandin synthesis within the brainstem were similar between groups. Conclusion Mechanical ventilation induces a systemic inflammatory response with only moderate inflammatory effects within the brainstem respiratory centres of preterm fetal sheep.
Collapse
Affiliation(s)
- Kayla Vidinopoulos
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Zahrah Azman
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Ainsley Somers
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Valerie A. Zahra
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Alison Thiel
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Hui Lu
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Yen Pham
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Nhi Thao Tran
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Beth J. Allison
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Eric Herlenius
- Department of Women’s and Children’s Health, Astrid Lindgren Children’s Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Stuart Hooper
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Robert Galinsky
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Graeme R. Polglase
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| |
Collapse
|
26
|
Dehdar K, Raoufy MR. Brain structural and functional alterations related to anxiety in allergic asthma. Brain Res Bull 2023; 202:110727. [PMID: 37562517 DOI: 10.1016/j.brainresbull.2023.110727] [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: 05/01/2023] [Revised: 07/29/2023] [Accepted: 08/03/2023] [Indexed: 08/12/2023]
Abstract
Psychiatric disorders are common in patients with allergic asthma, and they can have a significant impact on their quality of life and disease control. Recent studies have suggested that there may be potential immune-brain communication mechanisms in asthma, which can activate inflammatory responses in different brain areas, leading to structural and functional alterations and behavioral changes. However, the precise mechanisms underlying these alterations remain unclear. In this paper, we comprehensively review the relevant research on asthma-induced brain structural and functional alterations that lead to the initiation and promotion of anxiety. We summarize the possible pathways for peripheral inflammation to affect the brain's structure and function. Our review highlights the importance of addressing neuropsychiatric disorders in the clinical guidelines of asthma, to improve the quality of life of these patients. We suggest that a better understanding of the mechanisms underlying psychiatric comorbidities in asthma could lead to the development of more effective treatments for these patients.
Collapse
Affiliation(s)
- Kolsoum Dehdar
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Reza Raoufy
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
27
|
Shaffer C, Barrett LF, Quigley KS. Signal processing in the vagus nerve: Hypotheses based on new genetic and anatomical evidence. Biol Psychol 2023; 182:108626. [PMID: 37419401 PMCID: PMC10563766 DOI: 10.1016/j.biopsycho.2023.108626] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 06/25/2023] [Accepted: 07/03/2023] [Indexed: 07/09/2023]
Abstract
Each organism must regulate its internal state in a metabolically efficient way as it interacts in space and time with an ever-changing and only partly predictable world. Success in this endeavor is largely determined by the ongoing communication between brain and body, and the vagus nerve is a crucial structure in that dialogue. In this review, we introduce the novel hypothesis that the afferent vagus nerve is engaged in signal processing rather than just signal relay. New genetic and structural evidence of vagal afferent fiber anatomy motivates two hypotheses: (1) that sensory signals informing on the physiological state of the body compute both spatial and temporal viscerosensory features as they ascend the vagus nerve, following patterns found in other sensory architectures, such as the visual and olfactory systems; and (2) that ascending and descending signals modulate one another, calling into question the strict segregation of sensory and motor signals, respectively. Finally, we discuss several implications of our two hypotheses for understanding the role of viscerosensory signal processing in predictive energy regulation (i.e., allostasis) as well as the role of metabolic signals in memory and in disorders of prediction (e.g., mood disorders).
Collapse
Affiliation(s)
- Clare Shaffer
- Department of Psychology, College of Science, Northeastern University, Boston, MA, USA.
| | - Lisa Feldman Barrett
- Department of Psychology, College of Science, Northeastern University, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Karen S Quigley
- Department of Psychology, College of Science, Northeastern University, Boston, MA, USA.
| |
Collapse
|
28
|
Schreiber LS, Wozniak D, Scheller E, Böttcher E, Pelz JO, Schmidt FM. Enlarged cross-sectional area of the left vagus nerve in patients with major depressive disorder. Front Psychiatry 2023; 14:1237983. [PMID: 37583842 PMCID: PMC10423806 DOI: 10.3389/fpsyt.2023.1237983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 07/14/2023] [Indexed: 08/17/2023] Open
Abstract
Purpose Autonomic dysfunction and a chronic low-grade inflammation are supposed to play a role in the etiology of major depressive disorder (MDD). The vagus nerves (VN) form a major part of the parasympathetic nervous system and of the gut-brain axis. They are supposed to exert anti-inflammatory and epithelial barrier protective effects in the gut. A reduced vagal activity was described in patients with MDD. We aimed to examine the VN in patients with MDD with high-resolution ultrasound (HRUS) and hypothesized that the cross-sectional area (CSA) and the echogenicity of the VNs were altered in comparison to healthy controls. Materials and methods The echogenicity (gray scale mean) and the CSA of the cervical VNs at the level of the thyroid gland and both median nerves were examined with HRUS in 50 patients with MDD and 50 matched healthy controls. Results The left VN-CSA was significantly larger in the MDD group compared to the control group (1.7 ± 0.4 mm2 versus 1.5 ± 0.4 mm2; p = 0.045). The CSA of the right VN and both median nerves (MN) were similar between groups. In MDD subgroup analyses, recurrent depressive disorders were the main contributing factor for the left VN-CSA enlargement. Echogenicity was not altered in the VN and MN between groups. Conclusion The enlargement of the left VN-CSA in patients with MDD, and especially in these patients with recurrent depressive disorders, might turn out as a promising imaging biomarker. Longitudinal studies are warranted to examine whether the VNs-CSA change in the course of MDD.
Collapse
Affiliation(s)
- Lisa Sofie Schreiber
- Department of Psychiatry and Psychotherapy, Leipzig University Hospital, Leipzig, Germany
| | - David Wozniak
- Department of Psychiatry and Psychotherapy, Leipzig University Hospital, Leipzig, Germany
| | - Erik Scheller
- Department of Psychiatry and Psychotherapy, Leipzig University Hospital, Leipzig, Germany
| | - Elise Böttcher
- Department of Psychiatry and Psychotherapy, Leipzig University Hospital, Leipzig, Germany
| | - Johann Otto Pelz
- Department of Neurology, Leipzig University Hospital, Leipzig, Germany
| | - Frank M. Schmidt
- Department of Psychiatry and Psychotherapy, Leipzig University Hospital, Leipzig, Germany
| |
Collapse
|
29
|
Zouali M. Pharmacological and Electroceutical Targeting of the Cholinergic Anti-Inflammatory Pathway in Autoimmune Diseases. Pharmaceuticals (Basel) 2023; 16:1089. [PMID: 37631004 PMCID: PMC10459025 DOI: 10.3390/ph16081089] [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: 07/02/2023] [Revised: 07/23/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. In the cholinergic anti-inflammatory pathway, the vagus nerve, its pivotal neurotransmitter acetylcholine, together with the corresponding receptors play a key role in modulating the immune response of mammals. Through communications of peripheral nerves with immune cells, it modulates proliferation and differentiation activities of various immune cell subsets. As a result, this pathway represents a potential target for treating autoimmune diseases characterized by overt inflammation and a decrease in vagal tone. Consistently, converging observations made in both animal models and clinical trials revealed that targeting the cholinergic anti-inflammatory pathway using pharmacologic approaches can provide beneficial effects. In parallel, bioelectronic medicine has recently emerged as an alternative approach to managing systemic inflammation. In several studies, nerve electrostimulation was reported to be clinically relevant in reducing chronic inflammation in autoimmune diseases, including rheumatoid arthritis and diabetes. In the future, these new approaches could represent a major therapeutic strategy for autoimmune and inflammatory diseases.
Collapse
Affiliation(s)
- Moncef Zouali
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
| |
Collapse
|
30
|
Rusch JA, Layden BT, Dugas LR. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2023; 14:1130689. [PMID: 37404311 PMCID: PMC10316519 DOI: 10.3389/fendo.2023.1130689] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/25/2023] [Indexed: 07/06/2023] Open
Abstract
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
Collapse
Affiliation(s)
- Jody A. Rusch
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa
- C17 Chemical Pathology Laboratory, Groote Schuur Hospital, National Health Laboratory Service, Cape Town, South Africa
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States
| | - Lara R. Dugas
- Division of Epidemiology and Biostatistics, School of Public Health, University of Cape Town, Cape Town, South Africa
- Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, United States
| |
Collapse
|
31
|
Jo D, Jung YS, Song J. Lipocalin-2 Secreted by the Liver Regulates Neuronal Cell Function Through AKT-Dependent Signaling in Hepatic Encephalopathy Mouse Model. Clin Nutr Res 2023; 12:154-167. [PMID: 37214781 PMCID: PMC10193436 DOI: 10.7762/cnr.2023.12.2.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 05/24/2023] Open
Abstract
Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.
Collapse
Affiliation(s)
- Danbi Jo
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
| | - Yoon Seok Jung
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
| |
Collapse
|
32
|
Tian QQ, Cheng C, Liu PH, Yin ZX, Zhang MK, Cui YP, Zhao R, Deng H, Lu LM, Tang CZ, Xu NG, Yang XJ, Sun JB, Qin W. Combined effect of transcutaneous auricular vagus nerve stimulation and 0.1 Hz slow-paced breathing on working memory. Front Neurosci 2023; 17:1133964. [PMID: 36968483 PMCID: PMC10034029 DOI: 10.3389/fnins.2023.1133964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
BackgroundPrevious research has found that transcutaneous auricular vagus nerve stimulation (taVNS) can improve working memory (WM) performance. It has also been shown that 0.1 Hz slow-paced breathing (SPB, i.e., breathing at a rate of approximately 6 breaths/min) can significantly influence physical state and cognitive function via changes in autonomic afferent activity. In the present study, we investigated the synergistic effects of taVNS and SPB on WM performance.MethodsA total of 96 healthy people participated in this within-subjects experiment involving four conditions, namely taVNS, SPB, combined taVNS with SPB (taVNS + SPB), and sham. Each participant underwent each intervention for 30 min and WM was compared pre- and post-intervention using the spatial and digit n-back tasks in a random order four times. Permutation-based analysis of variance was used to assess the interaction between time and intervention.ResultsFor the spatial 3-back task, a significant interaction between time and intervention was found for the accuracy rate of matching trials (mACC, p = 0.03). Post hoc analysis suggested that both taVNS and taVNS + SPB improved WM performance, however, no significant difference was found in the SPB or sham groups.ConclusionThis study has replicated the effects of taVNS on WM performance reported in previous studies. However, the synergistic effects of combined taVNS and SPB warrant further research.
Collapse
Affiliation(s)
- Qian-Qian Tian
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Chen Cheng
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Peng-Hui Liu
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Zi-Xin Yin
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Meng-Kai Zhang
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Ya-Peng Cui
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
| | - Rui Zhao
- School of Electronics and Information, Xi’an Polytechnic University, Xi’an, Shaanxi, China
| | - Hui Deng
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
- Guangzhou Institute of Technology, Xidian University, Xi’an, Shaanxi, China
| | - Li-Ming Lu
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chun-Zhi Tang
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng-Gui Xu
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue-Juan Yang
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
- Guangzhou Institute of Technology, Xidian University, Xi’an, Shaanxi, China
- Xue-Juan Yang,
| | - Jin-Bo Sun
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
- Guangzhou Institute of Technology, Xidian University, Xi’an, Shaanxi, China
- *Correspondence: Jin-Bo Sun,
| | - Wei Qin
- Intelligent Non-Invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi’an, Shaanxi, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China
- Guangzhou Institute of Technology, Xidian University, Xi’an, Shaanxi, China
| |
Collapse
|
33
|
Transcutaneous auricular vagus stimulation (taVNS) improves human working memory performance under sleep deprivation stress. Behav Brain Res 2023; 439:114247. [PMID: 36473677 DOI: 10.1016/j.bbr.2022.114247] [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: 08/06/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Many human activities require high cognitive performance over long periods, while impairments induced by sleep deprivation influence various aspects of cognitive abilities, including working memory (WM), attention, and processing speed. Based on previous research, vagal nerve stimulation can modulate cognitive abilities, attention, and arousal. Two experiments were conducted to assess the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) to relieve the deleterious effects of sleep deprivation. In the first experiment, 35 participants completed N-back tasks at 8:00 a.m. for two consecutive days in a within-subject study. Then, the participants received either taVNS or earlobe stimulation (active control) intervention in two sessions at random orders after 24 h of sustained wakefulness. Then, they completed the N-back tasks again. In the second experiment, 30 participants completed the psychomotor vigilance task (PVT), and 32 completed the N-back tasks at 8:00 a.m. on the first and second days. Then, they received either taVNS or earlobe stimulation at random orders and finished the N-back and PVT tasks immediately after one hour. In Experiment 1, taVNS could significantly improve the accuracy rate of participants in spatial 3-back tasks compared to active control, which was consistent with experiment 2. However, taVNS did not specifically enhance PVT performance. Therefore, taVNS could be a powerful intervention for acute sleep deprivation as it can improve performance on high cognitive load tasks and is easy to administer.
Collapse
|
34
|
Han JY, Han SB. Pathogenetic and etiologic considerations of febrile seizures. Clin Exp Pediatr 2023; 66:46-53. [PMID: 36635899 PMCID: PMC9899550 DOI: 10.3345/cep.2021.01039] [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: 07/26/2021] [Accepted: 07/22/2022] [Indexed: 01/14/2023] Open
Abstract
Febrile seizure (FS), which occurs in febrile children without underlying health problems, is the most common type of seizure disorder in children. The suggested pathogenesis of FS derived from several animal and human studies is multifactorial and debatable. Neuronal hyperexcitability, which develops during inflammatory responses that accompany fever, provokes seizures. However, the exact role of each inflammatory mediator (e.g., cytokines) is undefined in terms of the connection between systemic or local inflammation and the central nervous system, and the mechanisms by which cytokines increase neuronal excitability remain unclear. In contrast, the cause of fever in most children with FS is usually mild respiratory virus infection (e.g., rhinovirus, influenza virus, adenovirus, and enterovirus) rather than severe bacterial infections. In temperate regions, the major causative respiratory viruses seem to mirror seasonally prevalent respiratory viruses in the community. Therefore, vigorous efforts to identify the causative pathogen of fever may not be necessary in children with FS. Genetic factors seem to play a role in neuronal hyperexcitability, and some types of genetic variation have been identified in several genes encoding ion channels of neurons that participate in neuronal excitation. Although most children with FS have benign outcomes, some characteristics such as complex FS, febrile status epilepticus, consecutive afebrile seizures, and the presence of neurodevelopmental disabilities may require further genetic and neurologic evaluations.
Collapse
Affiliation(s)
- Ji Yoon Han
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Pediatrics, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Seung Beom Han
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Pediatrics, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Korea
| |
Collapse
|
35
|
Alvarez MR, Alarcon JM, Roman CA, Lazaro D, Bobrowski-Khoury N, Baena-Caldas GP, Esber GR. Can a basic solution activate the inflammatory reflex? A review of potential mechanisms, opportunities, and challenges. Pharmacol Res 2023; 187:106525. [PMID: 36441036 DOI: 10.1016/j.phrs.2022.106525] [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: 08/31/2022] [Revised: 10/09/2022] [Accepted: 10/25/2022] [Indexed: 11/24/2022]
Abstract
Stimulation of the inflammatory reflex (IR) is a promising strategy to treat systemic inflammatory disorders. However, this strategy is hindered by the cost and side effects of traditional IR activators. Recently, oral intake of sodium bicarbonate (NaHCO3) has been suggested to activate the IR, providing a safe and inexpensive alternative. Critically, the mechanisms whereby NaHCO3 might achieve this effect and more broadly the pathways underlying the IR remain poorly understood. Here, we argue that the recognition of NaHCO3 as a potential IR activator presents exciting clinical and research opportunities. To aid this quest, we provide an integrative review of our current knowledge of the neural and cellular pathways mediating the IR and discuss the status of physiological models of IR activation. From this vantage point, we derive testable hypotheses on potential mechanisms whereby NaHCO3 might stimulate the IR and compare NaHCO3 with classic IR activators. Elucidation of these mechanisms will help determine the therapeutic value of NaHCO3 as an IR activator and provide new insights into the IR circuitry.
Collapse
Affiliation(s)
- Milena Rodriguez Alvarez
- Department of Internal Medicine, Division of Rheumatology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
| | - Juan Marcos Alarcon
- Department of Pathology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
| | - Christopher A Roman
- Department of Cell Biology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY 11203, USA
| | - Deana Lazaro
- Division of Rheumatology, Department of Internal Medicine, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY, USA
| | | | | | | |
Collapse
|
36
|
Klyushnik TP, Golimbet VE, Ivanov SV. [Immune mechanisms of complicity of somatic pathology in the pathogenesis of mental disorders]. Zh Nevrol Psikhiatr Im S S Korsakova 2023; 123:20-27. [PMID: 37141125 DOI: 10.17116/jnevro202312304220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Understanding the mechanisms of the relationship between the nervous and immune systems within the framework of the concept of the key role of inflammation, taking into account the involved genetic factors in the development of a wide range of combined forms of somatic and mental diseases, is of interest for research as well as for the development of new approaches to early diagnosis and more effective treatment of these diseases. This review analyzes the immune mechanisms of the development of mental disorders in patients with somatic diseases, in particular, the transmission of an inflammatory signal from the periphery to the CNS and the implementation of the influence of inflammatory factors on neurochemical systems that determine the characteristics of mental functioning. Particular attention is paid to the processes underlying the disruption of the blood-brain barrier caused by peripheral inflammation. Modulation of neurotransmission, changes in neuroplasticity, changes in regional activity of the brain in areas associated with the functions of threat recognition, cognitive processes and memory function, the effect of cytokines on the hypothalamic-pituitary-adrenal system are considered as mechanisms of action of inflammatory factors in the brain. The need to take into account variations in the genes of pro-inflammatory cytokines, which may be the cause of increased genetic vulnerability associated with the risk mental disorders in patients suffering from a certain somatic disease, is emphasized.
Collapse
Affiliation(s)
| | | | - S V Ivanov
- Mental Health Research Center, Moscow, Russia
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| |
Collapse
|
37
|
From Low-Grade Inflammation in Osteoarthritis to Neuropsychiatric Sequelae: A Narrative Review. Int J Mol Sci 2022; 23:ijms232416031. [PMID: 36555670 PMCID: PMC9784931 DOI: 10.3390/ijms232416031] [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: 11/14/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Nowadays, osteoarthritis (OA), a common, multifactorial musculoskeletal disease, is considered to have a low-grade inflammatory pathogenetic component. Lately, neuropsychiatric sequelae of the disease have gained recognition. However, a link between the peripheral inflammatory process of OA and the development of neuropsychiatric pathology is not completely understood. In this review, we provide a narrative that explores the development of neuropsychiatric disease in the presence of chronic peripheral low-grade inflammation with a focus on its signaling to the brain. We describe the development of a pro-inflammatory environment in the OA-affected joint. We discuss inflammation-signaling pathways that link the affected joint to the central nervous system, mainly using primary sensory afferents and blood circulation via circumventricular organs and cerebral endothelium. The review describes molecular and cellular changes in the brain, recognized in the presence of chronic peripheral inflammation. In addition, changes in the volume of gray matter and alterations of connectivity important for the assessment of the efficacy of treatment in OA are discussed in the given review. Finally, the narrative considers the importance of the use of neuropsychiatric diagnostic tools for a disease with an inflammatory component in the clinical setting.
Collapse
|
38
|
Simpson JB, Redinbo MR. Multi-omic analysis of host-microbial interactions central to the gut-brain axis. Mol Omics 2022; 18:896-907. [PMID: 36169030 DOI: 10.1039/d2mo00205a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The gut microbiota impact numerous aspects of human physiology, including the central nervous system (CNS). Emerging work is now focusing on the microbial factors underlying the bi-directional communication network linking host and microbial systems within the gastrointestinal tract to the CNS, the "gut-brain axis". Neurotransmitters are key coordinators of this network, and their dysregulation has been linked to numerous neurological disease states. As the bioavailability of neurotransmitters is modified by gut microbes, it is critical to unravel the influence of the microbiota on neurotransmitters in the context of the gut-brain axis. Here we review foundational studies that defined molecular relationships between the microbiota, neurotransmitters, and the gut-brain axis. We examine links between the gut microbiome, behavior, and neurological diseases, as well as microbial influences on neurotransmitter bioavailability and physiology. Finally, we review multi-omics technologies uniquely applicable to this area, including high-throughput genetics, modern metabolomics, structure-guided metagenomics, targeted proteomics, and chemogenetics. Interdisciplinary studies will continue to drive the discovery of molecular mechanisms linking the gut microbiota to clinical manifestations of neurobiology.
Collapse
Affiliation(s)
- Joshua B Simpson
- Department of Chemistry, University of North Carolina at Chapel Hill, USA
| | - Matthew R Redinbo
- Department of Chemistry, University of North Carolina at Chapel Hill, USA
- Department of Biochemistry & Biophysics, Department of Microbiology & Immunology, and the Integrated Program in Biological & Genome Sciences, University of North Carolina at Chapel Hill, USA.
| |
Collapse
|
39
|
Pavlov VA, Tracey KJ. Bioelectronic medicine: Preclinical insights and clinical advances. Neuron 2022; 110:3627-3644. [PMID: 36174571 PMCID: PMC10155266 DOI: 10.1016/j.neuron.2022.09.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 07/28/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022]
Abstract
The nervous system maintains homeostasis and health. Homeostatic disruptions underlying the pathobiology of many diseases can be controlled by bioelectronic devices targeting CNS and peripheral neural circuits. New insights into the regulatory functions of the nervous system and technological developments in bioelectronics drive progress in the emerging field of bioelectronic medicine. Here, we provide an overview of key aspects of preclinical research, translation, and clinical advances in bioelectronic medicine.
Collapse
Affiliation(s)
- Valentin A Pavlov
- Institute of Bioelectronic Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
| | - Kevin J Tracey
- Institute of Bioelectronic Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
| |
Collapse
|
40
|
Neuromodulation Applied to Diseases: The Case of HRV Biofeedback. J Clin Med 2022; 11:jcm11195927. [PMID: 36233794 PMCID: PMC9571900 DOI: 10.3390/jcm11195927] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
The vagus or “wandering” nerve is the main branch of the parasympathetic nervous system (PNS), innervating most internal organs crucial for health. Activity of the vagus nerve can be non-invasively indexed by heart-rate variability parameters (HRV). Specific HRV parameters predict less all-cause mortality, lower risk of and better prognosis after myocardial infarctions, and better survival in cancer. A non-invasive manner for self-activating the vagus is achieved by performing a slow-paced breathing technique while receiving visual feedback of one’s HRV, called HRV-biofeedback (HRV-B). This article narratively reviews the biological mechanisms underlying the role of vagal activity and vagally mediated HRV in hypertension, diabetes, coronary heart disease (CHD), cancer, pain, and dementia. After searching the literature for HRV-B intervention studies in each condition, we report the effects of HRV-B on clinical outcomes in these health conditions, while evaluating the methodological quality of these studies. Generally, the levels of evidence for the benefits of HRV-B is high in CHD, pain, and hypertension, moderate in cancer, and poor in diabetes and dementia. Limitations and future research directions are discussed.
Collapse
|
41
|
Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
Collapse
Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
| |
Collapse
|
42
|
Bosancic Z, Spies CD, Müller A, Winterer G, Piper SK, Heinrich M. Association of cholinesterase activities and POD in older adult abdominal surgical patients. BMC Anesthesiol 2022; 22:293. [PMID: 36114455 PMCID: PMC9479414 DOI: 10.1186/s12871-022-01826-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 08/26/2022] [Indexed: 12/05/2022] Open
Abstract
Background Postoperative delirium (POD) is a frequent complication after surgery. Older adult patients undergoing abdominal surgery are at higher risk for developing POD. Studies on the association of cholinesterase activities and POD are rare, but leading hypotheses implicate that the cholinergic pathway might play an important role in neuroinflammation and development of POD. The objective of this study was to figure out if there is an association between the development of POD and acetyl- and butyrylcholinesterase (AChE and BuChE) activities in older adult patients undergoing abdominal surgery. Methods The investigation was performed with a subpopulation of BioCog study patients. The BioCog project (http://www.biocog.eu) is a prospective multicenter observational study in older adult surgical patients. Patients ≥ 65 years undergoing elective surgery of at least 60 minutes who scored more than 23 points in the Mini-Mental-State-Examination were included. POD was assessed twice a day on seven consecutive days after the surgery, using the test instruments Nursing Delirium Screening Scale (Nu-Desc) and Confusion Assessment Method (CAM and CAM-ICU) and a patient chart review. Pre- and postoperative blood cholinesterase activities were measured with a photometric rapid-point-of-care-testing. The association between cholinesterase activities and POD was analyzed in a subpopulation of abdominal surgical patients using multivariable logistic regression analysis adjusting for confounders. Results One hundred twenty-seven patients were included for analysis (mean age 73 years, 59% female). Fifty-two patients (41%) fulfilled the criteria of POD. These patients were significantly older, had a longer time of surgery and anesthesia and achieved higher comorbidity scores compared to patients without POD. After adjusting for age, duration of surgery and charlson comorbity index, we found an association between pre- and postoperative AChE activity (U/gHb) and the development of POD (Odds ratio (OR), [95% confidence interval (CI)], preoperative 0.95 [0.89–1.00], postoperative 0.94 [0.89–1.00]). Conclusions We found an association between POD and AChE activity and provided new information considering patients with abdominal surgery. Future analyses should examine course dynamics of postoperative cholinesterase activities in order to clarify interactions between the cholinergic system and pathophysiological mechanisms leading to POD. Trial registration ClinicalTrials.gov: NCT02265263. Supplementary Information The online version contains supplementary material available at 10.1186/s12871-022-01826-y.
Collapse
|
43
|
Lin M, Stewart MT, Zefi S, Mateti KV, Gauthier A, Sharma B, Martinez LR, Ashby CR, Mantell LL. Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19. Free Radic Biol Med 2022; 190:247-263. [PMID: 35964839 PMCID: PMC9367207 DOI: 10.1016/j.freeradbiomed.2022.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 07/31/2022] [Accepted: 08/02/2022] [Indexed: 11/23/2022]
Abstract
Clinical studies have shown a significant positive correlation between age and the likelihood of being infected with SARS-CoV-2. This increased susceptibility is positively correlated with chronic inflammation and compromised neurocognitive functions. Postmortem analyses suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), with systemic and lung hyperinflammation, can cause significant morbidity and mortality in COVID-19 patients. Supraphysiological supplemental oxygen, also known as hyperoxia, is commonly used to treat decreased blood oxygen saturation in COVID-19 patients. However, prolonged exposure to hyperoxia alone can cause oxygen toxicity, due to an excessive increase in the levels of reactive oxygen species (ROS), which can overwhelm the cellular antioxidant capacity. Subsequently, this causes oxidative cellular damage and increased levels of aging biomarkers, such as telomere shortening and inflammaging. The oxidative stress in the lungs and brain can compromise innate immunity, resulting in an increased susceptibility to secondary lung infections, impaired neurocognitive functions, and dysregulated hyperinflammation, which can lead to ALI/ARDS, and even death. Studies indicate that lung inflammation is regulated by the central nervous system, notably, the cholinergic anti-inflammatory pathway (CAIP), which is innervated by the vagus nerve and α7 nicotinic acetylcholine receptors (α7nAChRs) on lung cells, particularly lung macrophages. The activation of α7nAChRs attenuates oxygen toxicity in the lungs and improves clinical outcomes by restoring hyperoxia-compromised innate immunity. Mechanistically, α7nAChR agonist (e.g., GAT 107 and GTS-21) can regulate redox signaling by 1) activating Nrf2, a master regulator of the antioxidant response and a cytoprotective defense system, which can decrease cellular damage caused by ROS and 2) inhibiting the activation of the NF-κB-mediated inflammatory response. Notably, GTS-21 has been shown to be safe and it improves neurocognitive functions in humans. Therefore, targeting the α7nAChR may represent a viable therapeutic approach for attenuating dysregulated hyperinflammation-mediated ARDS and sepsis in COVID-19 patients receiving prolonged oxygen therapy.
Collapse
Affiliation(s)
- Mosi Lin
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Maleka T Stewart
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Sidorela Zefi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Kranthi Venkat Mateti
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Alex Gauthier
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Bharti Sharma
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Lauren R Martinez
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA
| | - Lin L Mantell
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
| |
Collapse
|
44
|
Sipahioglu H, Esmaoglu A, Kiris A, Dursun ZB, Kuzuguden S, Cavus MA, Artan C. Does serum butyrylcholinesterase level determine the severity and mortality of COVID-19 pneumonia?: Prospective study. Front Med (Lausanne) 2022; 9:940533. [PMID: 35957846 PMCID: PMC9357934 DOI: 10.3389/fmed.2022.940533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/08/2022] [Indexed: 01/08/2023] Open
Abstract
BackgroundThe WHO emphasized the importance of knowing the risk factors for the severity of the disease in the COVID-19 pandemic. Our aim in this study was to determine the relationship between serum Butyrylcholinesterase (BChE) level, which is rapidly affected by inflammation, and the severity of COVID-19 pneumonia and mortality.MethodsPatients diagnosed with COVID-19 pneumonia between March and May 2021 were included in the study. The patients were divided into two groups as severe and mild to moderate pneumonia according to the WHO's guidelines. Serum BChE levels were studied by ELISA method from the blood samples taken from the patients on the day of hospitalization. The severity of the disease and other factors affecting hospital mortality were also evaluated.Results147 patients with COVID-19 pneumonia were included in this study. Of these patients, 58% had severe pneumonia and 42% had mild to moderate pneumonia. The BChE level was median 13 (IQR: 11.2–21.5)ng/ml in patients with severe COVID-19 pneumonia and median 20 (IQR: 10–35.7)ng/ml in patients with mild to moderate pneumonia (p: 0.001). Hospital with mortality rate was higher in patients with low BChE levels. However, statistically, BChE hasn't associated mortality in COVID-19 pneumonia [OR 1.002 (0.957–1.049) p: 0.490]. CRP, procalcitonin, lactate, and D-dimer levels were associated mortality in COVID-19 pneumonia.ConclusionBeing not statistically significant, the mortality rate was higher in patients with low BChE levels. BChE level is an important marker in determining the severity of COVID-19 pneumonia. Early prediction of the severity of COVID-19 pneumonia will enable early planning of the treatment process.
Collapse
Affiliation(s)
- Hilal Sipahioglu
- Kayseri Education and Research Hospital, Kayseri, Turkey
- *Correspondence: Hilal Sipahioglu
| | - Aliye Esmaoglu
- Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Ayse Kiris
- Kayseri Education and Research Hospital, Kayseri, Turkey
| | | | | | | | - Cem Artan
- Kayseri Education and Research Hospital, Kayseri, Turkey
| |
Collapse
|
45
|
Zhao R, He ZY, Cheng C, Tian QQ, Cui YP, Chang MY, Wang FM, Kong Y, Deng H, Yang XJ, Sun JB. Assessing the Effect of Simultaneous Combining of Transcranial Direct Current Stimulation and Transcutaneous Auricular Vagus Nerve Stimulation on the Improvement of Working Memory Performance in Healthy Individuals. Front Neurosci 2022; 16:947236. [PMID: 35928012 PMCID: PMC9344917 DOI: 10.3389/fnins.2022.947236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
A previous study found that combining transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) could evoke significantly larger activation on a range of cortical and subcortical brain regions than the numerical summation of tDCS and taVNS effects. In this study, two within-subject experiments were employed to investigate its effects on working memory (WM). In experiment 1, the WM modulatory effects of tDCS over the left dorsolateral prefrontal cortex (DLPFC), taVNS, and simultaneous joint simulation of tDCS over the left DLPFC and taVNS (SJS-L) were compared among 60 healthy subjects. They received these three interventions between the baseline test and post-test in a random manner three times. In spatial 3-back task, there was a significant interaction between time and stimulations in the accuracy rate of matching trials (mACC, p=0.018). MACCs were significantly improved by SJS (p = 0.001) and taVNS (p = 0.045), but not by tDCS (p = 0.495). Moreover, 41 subjects in the SJS group showed improvement, which was significantly larger than that in the taVNS group (29 subjects) and tDCS group (26 subjects). To further investigate the generalization effects of SJS, 72 students were recruited in experiment 2. They received tDCS over the right DLPFC, taVNS, simultaneous joint simulation of tDCS over the right DLPFC and taVNS (SJS-R), and sham stimulation in a random manner four times. No significant results were found, but there was a tendency similar to experiment 1 in the spatial 3-back task. In conclusion, combining tDCS and taVNS might be a potential non-invasive neuromodulation technique which is worthy of study in future.
Collapse
Affiliation(s)
- Rui Zhao
- School of Electronics and Information, Xi'an Polytechnic University, Xi'an, China
| | - Zhao-Yang He
- School of Electronics and Information, Xi'an Polytechnic University, Xi'an, China
| | - Chen Cheng
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
| | - Qian-Qian Tian
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Ya-Peng Cui
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Meng-Ying Chang
- School of Electronics and Information, Xi'an Polytechnic University, Xi'an, China
| | - Fu-Min Wang
- School of Electronics and Information, Xi'an Polytechnic University, Xi'an, China
| | - Yao Kong
- School of Electronics and Information, Xi'an Polytechnic University, Xi'an, China
| | - Hui Deng
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China
- Guangzhou Institute of Technology, Xidian University, Xi'an, China
| | - Xue-Juan Yang
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China
- Guangzhou Institute of Technology, Xidian University, Xi'an, China
| | - Jin-Bo Sun
- Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University, Xi'an, China
- Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China
- Guangzhou Institute of Technology, Xidian University, Xi'an, China
- *Correspondence: Jin-Bo Sun
| |
Collapse
|
46
|
Ahmad F. Medicinal nicotine in COVID-19 acute respiratory distress syndrome, the new corticosteroid. World J Crit Care Med 2022; 11:228-235. [PMID: 36051943 PMCID: PMC9305679 DOI: 10.5492/wjccm.v11.i4.228] [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: 11/14/2021] [Revised: 04/23/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
The cholinergic anti-inflammatory pathway (CAP) refers to the anti-inflammatory effects mediated by the parasympathetic nervous system. Existence of this pathway was first demonstrated when acetylcholinesterase inhibitors showed benefits in animal models of sepsis. CAP functions via the vagus nerve. The systemic anti-inflammatory effects of CAP converges on the α7 nicotinic acetylcholine receptor on splenic macrophages, leading to suppression of pro-inflammatory cytokines and simultaneous stimulation of anti-inflammatory cytokines, including interleukin 10. CAP offers a novel mechanism to mitigate inflammation. Electrical vagal nerve stimulation has shown benefits in patients suffering from rheumatoid arthritis. Direct agonists like nicotine and GTS-1 have also demonstrated anti-inflammatory properties in models of sepsis and acute respiratory distress syndrome, as have acetylcholinesterase inhibitors like Galantamine and Physostigmine. Experience with coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome indicates that immunomodulators have a protective role in patient outcomes. Dexamethasone is the only medication currently in use that has shown to improve clinical outcomes. This is likely due to the suppression of what is referred to as a cytokine storm, which is implicated in the lethality of viral pneumonia. Nicotine transdermal patch activates CAP and harvests its anti-inflammatory potential by means of an easily administered depot delivery mechanism. It could prove to be a promising, safe and inexpensive additional tool in the currently limited armamentarium at our disposal for management of COVID-19 induced acute hypoxic respiratory failure.
Collapse
Affiliation(s)
- Farrukh Ahmad
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
| |
Collapse
|
47
|
Wilkie L, Fisher Z, Kemp AH. The Complex Construct of Wellbeing and the Role of Vagal Function. Front Integr Neurosci 2022; 16:925664. [PMID: 35875509 PMCID: PMC9301262 DOI: 10.3389/fnint.2022.925664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/21/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Lowri Wilkie
- School of Psychology, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, United Kingdom
- Regional Neuropsychology and Community Brain Injury Service, Morriston Hospital, Swansea, United Kingdom
| | - Zoe Fisher
- Regional Neuropsychology and Community Brain Injury Service, Morriston Hospital, Swansea, United Kingdom
- Health and Wellbeing Academy, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, United Kingdom
| | - Andrew H. Kemp
- School of Psychology, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, United Kingdom
- Regional Neuropsychology and Community Brain Injury Service, Morriston Hospital, Swansea, United Kingdom
| |
Collapse
|
48
|
Xue B, Xue J, Yu Y, Wei SG, Beltz TG, Felder RB, Johnson AK. Predator Scent-Induced Sensitization of Hypertension and Anxiety-like Behaviors. Cell Mol Neurobiol 2022; 42:1141-1152. [PMID: 33201417 PMCID: PMC8126575 DOI: 10.1007/s10571-020-01005-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022]
Abstract
Post-traumatic stress disorder (PTSD), an anxiety-related syndrome, is associated with increased risk for cardiovascular diseases. The present study investigated whether predator scent (PS) stress, a model of PTSD, induces sensitization of hypertension and anxiety-like behaviors and underlying mechanisms related to renin-angiotensin systems (RAS) and inflammation. Coyote urine, as a PS stressor, was used to model PTSD. After PS exposures, separate cohorts of rats were studied for hypertensive response sensitization (HTRS), anxiety-like behaviors, and changes in plasma levels and mRNA expression of several components of the RAS and proinflammatory cytokines (PICs) in the lamina terminalis (LT), paraventricular nucleus (PVN), and amygdala (AMY). Rats exposed to PS as compared to control animals exhibited (1) a significantly greater hypertensive response (i.e., HTRS) when challenged with a slow-pressor dose of angiotensin (ANG) II, (2) significant decrease in locomotor activity and increase in time spent in the closed arms of a plus maze as well as general immobility (i.e., behavioral signs of increased anxiety), (3) upregulated plasma levels of ANG II and interleukin-6, and (4) increased expression of message for components of the RAS and PICs in key brain nuclei. All the PS-induced adverse effects were blocked by pretreatment with either an angiotensin-converting enzyme antagonist or a tumor necrosis factor-α inhibitor. The results suggest that PS, used as an experimental model of PTSD, sensitizes ANG II-induced hypertension and produces behavioral signs of anxiety, probably through upregulation of RAS components and inflammatory markers in plasma and brain areas associated with anxiety and blood pressure control.
Collapse
Affiliation(s)
- Baojian Xue
- Department of Psychological and Brain Sciences, University of Iowa, PBSB, 340 Iowa Ave, Iowa City, IA, 52242, USA.
| | - Jiarui Xue
- Department of Psychological and Brain Sciences, University of Iowa, PBSB, 340 Iowa Ave, Iowa City, IA, 52242, USA
| | - Yang Yu
- Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
| | - Shun-Guang Wei
- Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
- The Franҫois M. Abboud Cardiovascular Research Center University of Iowa, Iowa City, IA, 52242, USA
| | - Terry G Beltz
- Department of Psychological and Brain Sciences, University of Iowa, PBSB, 340 Iowa Ave, Iowa City, IA, 52242, USA
| | - Robert B Felder
- Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
- The Franҫois M. Abboud Cardiovascular Research Center University of Iowa, Iowa City, IA, 52242, USA
| | - Alan Kim Johnson
- Department of Psychological and Brain Sciences, University of Iowa, PBSB, 340 Iowa Ave, Iowa City, IA, 52242, USA
- Health and Human Physiology, University of Iowa, Iowa City, IA, 52242, USA
- Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, 52242, USA
- The Franҫois M. Abboud Cardiovascular Research Center University of Iowa, Iowa City, IA, 52242, USA
| |
Collapse
|
49
|
Vore AS, Barney TM, Deak MM, Varlinskaya EI, Deak T. Adolescent intermittent ethanol exposure produces Sex-Specific changes in BBB Permeability: A potential role for VEGFA. Brain Behav Immun 2022; 102:209-223. [PMID: 35245677 PMCID: PMC9277567 DOI: 10.1016/j.bbi.2022.02.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/31/2022] [Accepted: 02/27/2022] [Indexed: 12/20/2022] Open
Abstract
Binge drinking that typically begins during adolescence can have long-lasting neurobehavioral consequences, including alterations in the central and peripheral immune systems. Central and peripheral inflammation disrupts blood-brain barrier (BBB) integrity and exacerbates pathology in diseases commonly associated with disturbed BBB function. Thus, the goal of the present studies was to determine long-lasting effects of adolescent intermittent ethanol (AIE) on BBB integrity. For AIE, male and female Sprague Dawley rats were repeatedly exposed to ethanol (4 g/kg, intragastrically) or water during adolescence between postnatal day (P) 30 and P50. In adulthood (∼P75), rats were challenged with fluorescein isothiocyanate (FITC)-tagged Dextran of varying molecular weights (4, 20, & 70 kDa) for assessment of BBB permeability using gross tissue fluorometry (Experiment 1). Experiment 2 extended these effects using immunofluorescence, adding an adult ethanol-exposed group to test for a specific developmental vulnerability. Finally, as a first test of hypothesized mechanism, Experiment 3 examined the effect of AIE on Vascular Endothelial Growth Factor A (VEGFA) and its co-localization with pericytes (identified through expression of platelet derived growth factor receptor beta (PDGFRβ), a key regulatory cell embedded within the BBB. Male, but not female, rats with a history of AIE showed significantly increased dextran permeability in the nucleus accumbens (NAc), cingulate prefrontal cortex (cPFC), and amygdala (AMG). Similar increases in dextran were observed in the hippocampus (HPC) and ventral tegmental area (VTA) of male rats with a history of AIE or equivalent ethanol exposure during adulthood. No changes in BBB permeability were evident in females. When VEGFa expression was examined, male rats exposed to AIE were challenged with 3.5 g/kg ethanol (i.p.) or vehicle acutely in adulthood to assess long-lasting versus acute actions of ethanol. Adult rats with a history of AIE showed significantly fewer total cells expressing VEGFa in the AMG and dHPC following the acute ethanol challenge in adulthood. They also showed a significant reduction in the number of PDGFRβ positive cells that also expressed VEGFa signal. The anatomical distribution of these effects corresponded with increased BBB permeability after AIE (i.e., differential effects in the PVN, AMG, and dHPC). These studies demonstrated sex-specific effects of AIE, with males, but not females, demonstrating long-term increases in BBB permeability that correlated with changes in VEGFa and PDGFRβ protein, two factors known to influence BBB permeability.
Collapse
Affiliation(s)
| | | | | | | | - Terrence Deak
- Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton, NY 13902-6000.
| |
Collapse
|
50
|
Zhang W, Li Z, Li Z, Sun T, He Z, Manyande A, Xu W, Xiang H. The Role of the Superior Cervical Sympathetic Ganglion in Ischemia Reperfusion-Induced Acute Kidney Injury in Rats. Front Med (Lausanne) 2022; 9:792000. [PMID: 35530034 PMCID: PMC9069004 DOI: 10.3389/fmed.2022.792000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Acute kidney injury (AKI) has been found to be a serious clinical problem with high morbidity and mortality, and is associated with acute inflammatory response and sympathetic activation that subsequently play an important role in the development of AKI. It is well known that the sympathetic nervous system (SNS) and immune system intensely interact and mutually control each other in order to maintain homeostasis in response to stress or injury. Evidence has shown that the superior cervical sympathetic ganglion (SCG) participates in the bidirectional network between the immune and the SNS, and that the superior cervical ganglionectomy has protective effect on myocardial infarction, however, the role of the SCG in the setting of renal ischemic reperfusion injury has not been studied. Here, we sought to determine whether or not the SCG modulates renal ischemic reperfusion (IR) injury in rats. Our results showed that bilateral superior cervical ganglionectomy (SCGx) 14 days before IR injury markedly reduced the norepinephrine (NE) in plasma, and down-regulated the increased expression of tyrosine hydroxylase (TH) in the kidney and hypothalamus. Sympathetic denervation by SCGx in the AKI group increased the level of blood urea nitrogen (BUN) and kidney injury molecule-1 (KIM-1), and exacerbated renal pathological damage. Sympathetic denervation by SCGx in the AKI group enhanced the expression of pro-inflammatory cytokines in plasma, kidney and hypothalamus, and increased levels of Bax in denervated rats with IR injury. In addition, the levels of purinergic receptors, P2X3R and P2X7R, in the spinal cord were up-regulated in the denervated rats of the IR group. In conclusion, these results demonstrate that the sympathetic denervation by SCGx aggravated IR-induced AKI in rats via enhancing the inflammatory response, thus, the activated purinergic signaling in the spinal cord might be the potential mechanism in the aggravated renal injury.
Collapse
Affiliation(s)
- Wencui Zhang
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zhen Li
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zhixiao Li
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Tianning Sun
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zhigang He
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Anne Manyande
- School of Human and Social Sciences, University of West London, London, United Kingdom
| | - Weiguo Xu
- Department of Orthopedics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Weiguo Xu,
| | - Hongbing Xiang
- Department of Anesthesiology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hongbing Xiang,
| |
Collapse
|