Brain-state dependent astrocytic Ca2+ signals are coupled to both positive and negative BOLD-fMRI signals

Significance The role of astrocytes on brain function is controversial in many aspects. It remains challenging to specify the in vivo functional impact of astrocytic calcium signal when mediating vasodilation/constriction at varied physiological or pathophysiological conditions. Here, we applied simultaneous fMRI and GCaMP-mediated Ca2+ optical fiber recording to detect distinct astrocytic Ca2+ signals (evoked vs. intrinsic) coupled to positive and negative blood-oxygen-level-dependent signals, respectively and concurrently, with unique spatial and temporal patterns. Not only did we demonstrate the distinct neurovascular coupling events coupled to the evoked and intrinsic astrocytic calcium signals, but also revealed the thalamic regulation mechanism underlying the astrocytic calcium-mediated brain state switch. This astrocytic-relevant regulatory mechanism could underlie numerous brain disorder and injury models relevant to gliovascular disruption. Astrocytic Ca2+-mediated gliovascular interactions regulate the neurovascular network in situ and in vivo. However, it is difficult to measure directly both the astrocytic activity and fMRI to relate the various forms of blood-oxygen-level-dependent (BOLD) signaling to brain states under normal and pathological conditions. In this study, fMRI and GCaMP-mediated Ca2+ optical fiber recordings revealed distinct evoked astrocytic Ca2+ signals that were coupled with positive BOLD signals and intrinsic astrocytic Ca2+ signals that were coupled with negative BOLD signals. Both evoked and intrinsic astrocytic calcium signal could occur concurrently or respectively during stimulation. The intrinsic astrocytic calcium signal can be detected globally in multiple cortical sites in contrast to the evoked astrocytic calcium signal only detected at the activated cortical region. Unlike propagating Ca2+ waves in spreading depolarization/depression, the intrinsic Ca2+ spikes occurred simultaneously in both hemispheres and were initiated upon the activation of the central thalamus and midbrain reticular formation. The occurrence of the intrinsic astrocytic calcium signal is strongly coincident with an increased EEG power level of the brain resting-state fluctuation. These results demonstrate highly correlated astrocytic Ca2+ spikes with bidirectional fMRI signals based on the thalamic regulation of cortical states, depicting a brain-state dependency of both astrocytic Ca2+ and BOLD fMRI signals.

[1]  N. Logothetis,et al.  Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1 , 2006, Nature Neuroscience.

[2]  Bengt R. Johansson,et al.  Pericytes regulate the blood–brain barrier , 2010, Nature.

[3]  Eric A Newman,et al.  Glial Cells Dilate and Constrict Blood Vessels: A Mechanism of Neurovascular Coupling , 2006, The Journal of Neuroscience.

[4]  Rafael Yuste,et al.  Astrocytic regulation of cortical UP states , 2011, Proceedings of the National Academy of Sciences.

[5]  T. Takano,et al.  Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo , 2006, Nature Neuroscience.

[6]  O. Garaschuk,et al.  Cortical calcium waves in resting newborn mice , 2005, Nature Neuroscience.

[7]  Fang Liu,et al.  Glutamate-mediated astrocyte–neuron signalling , 1994, Nature.

[8]  M. Wilson,et al.  Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep , 2014, Proceedings of the National Academy of Sciences.

[9]  M. Nedergaard,et al.  Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. , 1994, Science.

[10]  A. Oeltermann,et al.  Hippocampal–cortical interaction during periods of subcortical silence , 2012, Nature.

[11]  M. C. Angulo,et al.  Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation , 2003, Nature Neuroscience.

[12]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[13]  Jin U. Kang,et al.  Norepinephrine Controls Astroglial Responsiveness to Local Circuit Activity , 2014, Neuron.

[14]  Stefan R. Pulver,et al.  Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics , 2013, Front. Mol. Neurosci..

[15]  J. Rossier,et al.  Cortical GABA Interneurons in Neurovascular Coupling: Relays for Subcortical Vasoactive Pathways , 2004, The Journal of Neuroscience.

[16]  M. Steriade,et al.  A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  Terrence J. Sejnowski,et al.  Astrocytes contribute to gamma oscillations and recognition memory , 2014, Proceedings of the National Academy of Sciences.

[18]  D. Attwell,et al.  Capillary pericytes regulate cerebral blood flow in health and disease , 2014, Nature.

[19]  Xenophon Papademetris,et al.  Comparison of glomerular activity patterns by fMRI and wide-field calcium imaging: Implications for principles underlying odor mapping , 2016, NeuroImage.

[20]  Maiken Nedergaard,et al.  α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. , 2013, Cell calcium.

[21]  Vishnu B. Sridhar,et al.  In vivo Stimulus-Induced Vasodilation Occurs without IP3 Receptor Activation and May Precede Astrocytic Calcium Increase , 2013, The Journal of Neuroscience.

[22]  Talia N. Lerner,et al.  Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain , 2016, Nature Methods.

[23]  M. Larkum,et al.  Frontiers in Neural Circuits Neural Circuits Methods Article , 2022 .

[24]  Kira E. Poskanzer,et al.  Astrocytes regulate cortical state switching in vivo , 2016, Proceedings of the National Academy of Sciences.

[25]  J. Dreier The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease , 2011, Nature Medicine.

[26]  Alexander S. Tolpygo,et al.  Frequency-selective control of cortical and subcortical networks by central thalamus , 2015, eLife.

[27]  Ranulfo Romo,et al.  Local domains of motor cortical activity revealed by fiber-optic calcium recordings in behaving nonhuman primates , 2013, Proceedings of the National Academy of Sciences.

[28]  D. Tank,et al.  Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice , 2007, Neuron.

[29]  N. Matsuki,et al.  Large-Scale Calcium Waves Traveling through Astrocytic Networks In Vivo , 2011, The Journal of Neuroscience.

[30]  M. Nedergaard,et al.  Characterization of Cortical Depolarizations Evoked in Focal Cerebral Ischemia , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  K. Deisseroth,et al.  Tuning arousal with optogenetic modulation of locus coeruleus neurons , 2010, Nature Neuroscience.

[32]  N. Logothetis,et al.  Neurophysiological investigation of the basis of the fMRI signal , 2001, Nature.

[33]  M. Nedergaard,et al.  Distinct Functional States of Astrocytes During Sleep and Wakefulness: Is Norepinephrine the Master Regulator? , 2015, Current Sleep Medicine Reports.

[34]  Venkatesh N. Murthy,et al.  Role of Astrocytes in Neurovascular Coupling , 2011, Neuron.

[35]  M. Nedergaard,et al.  Gap junctions are required for the propagation of spreading depression. , 1995, Journal of neurobiology.

[36]  E. Newman,et al.  Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina , 2016, The Journal of Neuroscience.

[37]  M. Lauritzen,et al.  Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo , 2013, Proceedings of the National Academy of Sciences.

[38]  Hellmut Merkle,et al.  Sensory and optogenetically driven single-vessel fMRI , 2016, Nature Methods.

[39]  H. Kettenmann,et al.  Different Mechanisms Promote Astrocyte Ca2+ Waves and Spreading Depression in the Mouse Neocortex , 2003, The Journal of Neuroscience.

[40]  D. Attwell,et al.  The neural basis of functional brain imaging signals , 2002, Trends in Neurosciences.

[41]  W. D. Winters,et al.  A neurophysiological comparison of alpha-chloralose with gamma-hydroxybutyrate in cats. , 1966, Electroencephalography and clinical neurophysiology.

[42]  Grant R. Gordon,et al.  Brain metabolism dictates the polarity of astrocyte control over arterioles , 2008, Nature.

[43]  Liad Hollender,et al.  High-Resolution In Vivo Imaging of the Neurovascular Unit during Spreading Depression , 2007, Journal of Neuroscience.

[44]  C. Iadecola,et al.  Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. , 2006, Journal of applied physiology.

[45]  V. Walsh,et al.  State-dependency in brain stimulation studies of perception and cognition , 2008, Trends in Cognitive Sciences.

[46]  F. Helmchen,et al.  Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex , 2012, Nature Methods.

[47]  H. Berger,et al.  Über das Elektrenkephalogramm des Menschen , 1937, Archiv für Psychiatrie und Nervenkrankheiten.

[48]  Martin Lauritzen,et al.  Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. , 2015, Physiological reviews.

[49]  Á. Pascual-Leone,et al.  Spontaneous fluctuations in posterior alpha-band EEG activity reflect variability in excitability of human visual areas. , 2008, Cerebral cortex.

[50]  David Attwell,et al.  Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles , 2016, Nature Neuroscience.

[51]  Khaleel Bhaukaurally,et al.  Local Ca2+ detection and modulation of synaptic release by astrocytes , 2011, Nature Neuroscience.

[52]  Sharmila Venugopal,et al.  Ca2+ signaling in astrocytes from IP3R2−/− mice in brain slices and during startle responses in vivo , 2015, Nature Neuroscience.

[53]  Peyman Golshani,et al.  New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo , 2016, Neuron.

[54]  B. MacVicar,et al.  Calcium transients in astrocyte endfeet cause cerebrovascular constrictions , 2004, Nature.

[55]  D. Attwell,et al.  Glial and neuronal control of brain blood flow , 2022 .

[56]  G. Dai,et al.  Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders , 2012, Journal of neuropathology and experimental neurology.

[57]  Yevgeniy B. Sirotin,et al.  Anticipatory haemodynamic signals in sensory cortex not predicted by local neuronal activity. , 2009, Nature.

[58]  B. Hyman,et al.  Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice , 2009, Science.

[59]  D. Kleinfeld,et al.  Suppressed Neuronal Activity and Concurrent Arteriolar Vasoconstriction May Explain Negative Blood Oxygenation Level-Dependent Signal , 2007, The Journal of Neuroscience.

[60]  T. Murphy,et al.  Rapid Astrocyte Calcium Signals Correlate with Neuronal Activity and Onset of the Hemodynamic Response In Vivo , 2007, The Journal of Neuroscience.

[61]  E. Hamel Perivascular nerves and the regulation of cerebrovascular tone. , 2006, Journal of applied physiology.

[62]  M. Schölvinck,et al.  Tracking brain arousal fluctuations with fMRI , 2016, Proceedings of the National Academy of Sciences.