scholarly journals A luciferase prosubstrate and a red bioluminescent calcium indicator to image neuronal activity

2021 ◽  
Author(s):  
Xiaodong Tian ◽  
Yiyu Zhang ◽  
Xinyu Li ◽  
Ying Xiong ◽  
Tianchen Wu ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Nonspecific Esterase ◽  
New Paradigm ◽  
Fluorescent Indicators ◽  
Neuronal Ensembles ◽  
Brain Functions ◽  
Calcium Indicator ◽  
Health And Disease ◽  
The Brain

AbstractGenetically encoded fluorescent indicators have been broadly used to monitor neuronal activity in live animals, but invasive surgical procedures are required. This study presents a functional bioluminescence imaging (fBLI) method for recording the activity of neuronal ensembles in the brain in awake mice. We developed a luciferase prosubstrate activatable in vivo by nonspecific esterase to enhance the brain delivery of the luciferin. We further engineered a bright, bioluminescent indicator with robust responsiveness to calcium ions (Ca2+) and appreciable emission above 600 nm. Integration of these advantageous components enabled the imaging of Ca2+ dynamics in awake mice minimally invasively with excellent signal- to-background and subsecond temporal resolution. This study thus establishes a new paradigm for studying brain functions in health and disease.

scholarly journals Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

2019 ◽  
Author(s):  
Felix C. Nebeling ◽  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Manuel Mittag ◽  
Julia Steffen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Brain Parenchyma ◽  
Two Photon ◽  
Contact Rates ◽  
Health And Disease ◽  
The Impact ◽  
The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

scholarly journals Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

2019 ◽  
Author(s):  
Ivan-Maximiliano Kur ◽  
Pierre-Hugues Prouvot ◽  
Ting Fu ◽  
Wei Fan ◽  
Felicia Müller-Braun ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Neuronal Activity ◽  
Brain Function ◽  
Neural Transmission ◽  
Health And Disease ◽  
Vital Component ◽  
Peripheral Immune Cells ◽  
The Brain

AbstractCommunication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

scholarly journals Emergence Of Consciousness And Qualia From A Complex Brain

Folia Medica ◽  
2014 ◽  
Vol 56 (4) ◽  
pp. 289-296
Author(s):  
Jakob Korf
Keyword(s):  
System Theory ◽  
General System ◽  
Resolution Power ◽  
Brain Functions ◽  
Scientific Exploration ◽  
Brain Changes ◽  
Higher Brain Functions ◽  
The Brain

Abstract Qualia are private conscious experiences of which the associated feelings can be reported to other people. Whether qualia are amenable to scientific exploration has often been questioned, which is challenged by the present article. The following arguments are given: 1. the configuration of the brain changes continuously and irreversibly, because of genetic and environmental influences and interhuman communication; 2. qualia and consciousness are processes, rather than states; 3. private feelings, including those associated with qualia, should be positioned in the context of a personal brain as being developed during life; 4. consciousness and qualia should be understood in the context of general system theory, thus concluding that isolated, in vitro, properties of neurons and other brain constituents might marginally contribute to the understanding of higher brain functions, mind or qualia; 5. current in vivo approaches have too little resolution power - in terms of space and time - to delineate individual and subjective brain processes. When subtle personalized properties of the nervous system can be assessed in vivo or in vitro, qualia can scientifically be investigated. We discuss some approaches to overcome these barriers.

scholarly journals The restless brain: how intrinsic activity organizes brain function

2015 ◽  
Vol 370 (1668) ◽  
pp. 20140172 ◽  
Author(s):  
Marcus E. Raichle
Keyword(s):  
Brain Function ◽  
Functional Organization ◽  
Sensory Information ◽  
Intrinsic Activity ◽  
Systems Neuroscience ◽  
Brain Functions ◽  
Molecular Neuroscience ◽  
Constant State ◽  
Health And Disease ◽  
The Brain

Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease.

scholarly journals A study on Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty in a Japanese laboratory of biochemistry and molecular biology in 1990s: An attempt for TCM modernization

2021 ◽  
pp. 1-21
Author(s):  
Jiankang Liu
Keyword(s):  
Qing Dynasty ◽  
Brain Homogenate ◽  
Modern Technology ◽  
Toxicity Tests ◽  
Brain Functions ◽  
Great Progress ◽  
Theoretical Evidence ◽  
The Brain

Traditional Chinese Medicine (TCM) modernization has been proposed for many years, but the progress is still slow due to both ideological and technical obstacles. When I went to Japan in 1989, I found Japan has made a great progress on TCM by using modern technology. Therefore, I have studied a fine extract prepared from medicinal herbs (renamed Yi-Zhi-Yi-Shou, YZYS), a prescription of Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty, with the current drug investigation strategies. I examined its antioxidant activity both in vitro and in vivo. The in-vitro studies found that YZYS possesses strong antioxidant capacity, such as scavenging various kinds of free radicals, and inhibits free radical-induced peroxidation of brain homogenate, microsomes, mitochondria, amino acids, deoxyribose and DNA. The in-vivo study with immobilization-induced emotional stress in rats, showed that YZYS effectively inhibits stress-induced stomach ulcers and oxidative damage in plasma and the brain. In addition, YZYS is shown to be non-toxic in both acute and chronic toxicity tests. These studies demonstrate that YZYS is a potent natural antioxidant and offer theoretical evidence for the beneficial effect of YZYS on health and brain functions, and that TCM prescriptions can be studied scientifically as modern medical drugs.

Biophysical basis of brain activity: implications for neuroimaging

2002 ◽  
Vol 35 (3) ◽  
pp. 287-325 ◽  
Author(s):  
Robert G. Shulman ◽  
Fahmeed Hyder ◽  
Douglas L. Rothman
Keyword(s):  
Energy Consumption ◽  
Magnetic Resonance ◽  
Neuronal Activity ◽  
Glucose Oxidation ◽  
Activity Level ◽  
Quantitative Relation ◽  
Cerebral Function ◽  
Level Of Activity ◽  
The Brain

1. Summary 2882. Introduction 2883. Relationship between neuroenergetics and neurotransmitter flux 2944. A model of coupling between neuroenergetics and neurotransmission 2965. Relationship between neuroenergetics and neural spiking frequency 2976. Comparison with previous electrophysiological and fMRI measurements 2987. Contributions of non-oxidative energetics to a primarily oxidative brain 2998. Possible explanation for non-oxidative energetics contributions 3009. A model of total neuronal activity to support cerebral function 30210. Implications for interpretation of fMRI studies 30511. The restless brain 30612. Acknowledgements 31013. Appendix A. CMRO2by13C-MRS 31014. Appendix B.Vcycand test of model 31315. Appendix C. CMRO2by calibrated BOLD 31616. Appendix D. Comparison of spiking activity of a neuronal ensemble with CMRO231817. References 320In vivo13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively assessed rates of glutamate–glutamine cycle (Vcyc) and glucose oxidation (CMRGlc(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in vivo13C-MRS results demonstrate that glutamate recycling is a major metabolic pathway, inseparable from its actions of neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain, Vcyc and CMRGlc(ox) are stoichiometrically related, where more than two thirds of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain measured at rest and its quantitative relation to neurotransmission reflects a sizeable activity level for the resting brain. The high activity of the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral function that leads to reinterpreting functional imaging data because the large baseline signal is commonly discarded in cognitive neuroscience paradigms. Changes in energy consumption (ΔCMRO2%) can also be obtained from magnetic resonance imaging (MRI) experiments, using the blood oxygen level- dependent (BOLD) image contrast, provided that all the separate parameters contributing to the functional MRI (fMRI) signal are measured. The BOLD-derived ΔCMRO2% when compared with alterations in neuronal spiking rate (Δν%) during sensory stimulation in the rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence fMRI when calibrated so as to provide ΔCMRO2% can provide high spatial resolution evaluation of neuronal activity. Our studies of quantitative measurements of changes in neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary amount of activity in a localized region, rather a total level of activity is required where the increment is inversely related to the level of activity in the non-stimulated condition. These biophysical experiments have established relationships between energy consumption and neuronal activity that provide novel insights into the nature of brain function and the interpretation of fMRI data.

scholarly journals A ligand motif enables differential vascular targeting of endothelial junctions between brain and retina

2019 ◽  
Vol 116 (6) ◽  
pp. 2300-2305 ◽  
Author(s):  
Fenny H. F. Tang ◽  
Fernanda I. Staquicini ◽  
André A. R. Teixeira ◽  
Jussara S. Michaloski ◽  
Gislene M. Namiyama ◽  
...  
Keyword(s):  
Binding Sites ◽  
Combinatorial Screening ◽  
Vascular Lumen ◽  
Transmission Electron ◽  
Endothelial Junctions ◽  
Endothelial Heterogeneity ◽  
Health And Disease ◽  
Preclinical And Clinical Studies ◽  
The Brain

Endothelial heterogeneity has important implications in health and disease. Molecular markers selectively expressed in the vasculature of different organs and tissues are currently being explored in targeted therapies with promising results in preclinical and clinical studies. Noteworthy is the role that combinatorial approaches such as phage display have had in identifying such markers by using phage as nanoparticles and surrogates for billions of different peptides, screening noninvasively the vascular lumen for binding sites. Here, we show that a new peptide motif that emerged from such combinatorial screening of the vasculature binds selectively to blood vessels in the brain in vivo but not to vessels in other organs. Peptides containing a conserved motif in which amino acids Phenylalanine−Arginine−Tryptophan (FRW) predominate could be visualized by transmission electron microscopy bound to the junctions between endothelial cells in all areas of the brain, including the optic nerve, but not in other barrier-containing tissues, such as intestines and testis. Remarkably, peptides containing the motif do not bind to vessels in the retina, implying an important molecular difference between these two vascular barriers. Furthermore, the peptide allows for in vivo imaging, demonstrating that new tools for studying and imaging the brain are likely to emerge from this motif.

scholarly journals Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1208 ◽  
Author(s):  
Michael J. Garabedian ◽  
Charles A. Harris ◽  
Freddy Jeanneteau
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Health And Disease ◽  
And Behavior ◽  
External Signals ◽  
The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

scholarly journals Protein lactylation induced by neural excitation

2021 ◽  
Author(s):  
Hideo Hagihara ◽  
Hirotaka Shoji ◽  
Hikari Otabi ◽  
Atsushi Toyoda ◽  
Kaoru Katoh ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Monocarboxylate Transporter ◽  
Brain Cells ◽  
Post Translational Modification ◽  
High Potassium ◽  
Neural Excitation ◽  
Lactate Levels ◽  
The Brain ◽  
Prefrontal Cortices

AbstractLactate is known to have diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions, such as learning and memory and regulation of mood. Recently, a novel post-translational modification called lysine lactylation has been found in histone H3 of mouse macrophages, and the lactylation levels paralleled the intracellular lactate levels1. However, it is unknown whether lysine lactylation occurs in brain cells, and if it does, whether lactylation is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that lysine lactylation in brain cells is regulated by systemic changes in lactate levels, neural excitation, and behaviorally relevant stimuli. Lysine lactylation levels were increased by lactate treatment and by high-potassium-induced depolarization in cultured primary neurons; these increases were attenuated by pharmacological inhibition of monocarboxylate transporter 2 and lactate dehydrogenase, respectively, suggesting that both cell-autonomous and non-cell-autonomous neuronal mechanisms are involved in overall lysine lactylation. In vivo, electroconvulsive stimulation increased lysine lactylation levels in the prefrontal cortices of mice, and its levels were positively correlated with the expression levels of the neuronal activity marker c-Fos on an individual cell basis. In the social defeat stress model of depression in which brain lactate levels increase, lactylation levels were increased in the prefrontal cortices of the defeated mice, which was accompanied by increased c-Fos expression, decreased social behaviors, and increased anxiety-like behaviors, suggesting that stress-induced neuronal excitation may induce lysine lactylation, thereby affecting mood-related behaviors. Further, we identified 63 candidate lysine-lactylated proteins in the mouse cortex and found that lactylation levels in histone H1 increased in response to defeat stress. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.

scholarly journals Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling

2020 ◽  
Author(s):  
Pratish Thakore ◽  
Michael G. Alvarado ◽  
Sher Ali ◽  
Amreen Mughal ◽  
Paulo W. Pires ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neuronal Activity ◽  
Transient Receptor Potential ◽  
Neurovascular Coupling ◽  
Laser Scanning Microscopy ◽  
K Channel ◽  
Transitional Region ◽  
Capillary Endothelial Cells ◽  
The Brain

Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.

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