Neurovascular Coupling Mechanisms Research Articles

Vascular Signaling Plasticity Reprograms Blood Delivery Mechanisms to Meet Fluctuating Neuronal Energy Needs

Neuronal computation is metabolically expensive and depends on precision delivery of energy substrates—oxygen and glucose—via tightly coordinated blood flow to ensure that energy demands are continually met. This is facilitated by neurovascular coupling (NVC)—a range of mechanisms matching neural activity to local blood flow. These NVC mechanisms are typically considered invariant, and whether they are reshaped according to ever-changing neuronal metabolic needs has not been examined. We present evidence that neural activity continually reprograms the blood flow control mechanisms embedded in the local vasculature, a process we refer to as ‘vascular signaling plasticity’ (VSP). Using an established enrichment paradigm, we find that animals housed in conditions that increase input to the barrel cortex for 7 days exhibit profound neuronal plasticity in this region. This resculpts local vascular reactivity to elevate blood delivery. Indeed, VSP results in increased basal capillary blood flow and augmented activity of vasodilatory agents in vivo manifesting as increased red blood cell (RBC) flux responses to capillary stimulation and upstream diameter changes measured using 2-photon laser scanning microscopy. Moreover, the sensitivity of capillaries to stimulation is also dramatically elevated in an ex vivo isolated capillary-arteriole preparation. Using K+-mediated capillary-to-arteriole electrical signaling as a springboard to study the molecular underpinnings of VSP, we find that this process induces a ~70% increase in the density of strong inward rectifier K+ (Kir2.1) currents in capillary endothelial cells, which profoundly augments the retrograde hyperpolarization generated by these channels to control upstream diameter at the level of the penetrating arteriole. Through whole-cell patch clamp electrophysiology, we characterize the mechanism of VSP induction and recapitulate this phenomenon in vitro. We validate our findings through Crispr/Cas9-mediated endothelial cell-specific knockout of the transcription factor responsible for VSP induction. Our data thus recast the vasculature as a plastic, brain-wide activity sensing network that is continually reshaped at the molecular level by local neuronal input, leading to precisely-tuned blood delivery to meet continually fluctuating neural energy needs. VSP represents a new dimension to brain plasticity that may underpin a range of vital physiological processes and is likely disrupted in numerous brain pathologies with a blood flow component. This work was supported by the American Heart Association (23POST1023086), and NIH grants 1DP2NS121347, 1R01AG066645, and 5R01NS115401. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hemodynamic responses in the rat hippocampus are simultaneously controlled by at least two independently acting neurovascular coupling mechanisms

We combined electrical perforant pathway stimulation with electrophysiological and fMRI recordings in the hippocampus to investigate the effects of neuronal afterdischarges (nAD) on subsequent fMRI BOLD signals in the presence of isoflurane and medetomidine. These two drugs already alter basal hemodynamics in the hippocampus, with isoflurane being mildly vasodilatory and medetomidine being mildly vasoconstrictive. The perforant pathway was stimulated once for 8 seconds with either continuous 20 Hz pulses (continuous stimulation) or 8 bursts of 20 high-frequency pulses (burst stimulation). Burst stimulation in the presence of medetomidine elicited long-lasting nAD that coincided with a brief positive BOLD response and a subsequent long-lasting decrease in BOLD signals. Under isoflurane, this stimulation elicited only short-lasting nAD and only a short-lasting decline in BOLD signals. In contrast, continuous stimulation under isoflurane and medetomidine caused a similar duration of nAD. Under isoflurane, this caused only a sharp and prolonged decline in BOLD signals, whereas under medetomidine, again, only a brief positive BOLD response was elicited, followed by a shorter and moderate decline in BOLD signals. Our results suggest that nAD simultaneously activate different neurovascular coupling mechanisms that then independently alter local hemodynamics in the hippocampus, resulting in an even more complex neurovascular coupling mechanism.

Neurovascular Interaction and Exercise Training for Bone Regeneration

The nervous and vascular systems are widely distributed in the skeletal system and play an important role in bone metabolism and bone formation, respectively. Their independent impact on the skeletal system has received keen attention in bone-related research over the decade. However, the mechanism of neurovascular coupling during physiological bone remodeling and regeneration has recently been highlighted, considering the importance of spatial relationships between bone-associated skeletal nerves and blood vessels. In addition, the positive effect of exercise on the bones has been continuously emphasized, as evident by the improved number and function of skeletal nerves and blood vessels following exercise training. Skeletal nerve-vascular crosstalk and exercise training are essential for bone development and regeneration, respectively; however, the effect of exercise on neurovascular interactions has not yet been studied. This review aims to summarize the regulatory roles of the nerves and blood vessels in bone metabolism and regeneration and to highlight a combination of potential cellular processes of neurogenesis and angiogenesis in bone regeneration. Moreover, given the significance of the spatial relationship between nerves and blood vessels in bones and the role of exercise training, this review aims to discuss the potential physiological neurovascular coupling that occurs following exercise and physical activity.

Cerebrovascular glycocalyx damage and microcirculation impairment in patients with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is increasingly associated with blood-brain barrier dysfunction and microvascular alterations, yet the pathophysiological link is missing. An important barrier function is exerted by the glycocalyx, a gel-like layer coating the endothelium. To explore such associations, we used intraoperative videomicroscopy to quantify glycocalyx and microcirculation properties of the neocortex and hippocampus of 15 patients undergoing resective brain surgery as treatment for drug-resistant TLE, and 15 non-epileptic controls. Fluorescent lectin staining of neocortex and hippocampal tissue was used for blood vessel surface area quantification. Neocortical perfused boundary region, the thickness of the glycocalyx’ impaired layer, was higher in patients (2.64 ± 0.52 µm) compared to controls (1.31 ± 0.29 µm), P < 0.01, indicative of reduced glycocalyx integrity in patients. Moreover, erythrocyte flow velocity analysis revealed an impaired ability of TLE patients to (de-)recruit capillaries in response to changing metabolic demands (R2 = 0.75, P < 0.01), indicating failure of neurovascular coupling mechanisms. Blood vessel quantification comparison between intraoperative measurements and resected tissue showed strong correlation (R2 = 0.94, P < 0.01). This is the first report on in vivo assessment of glycocalyx and microcirculation properties in TLE patients, confirming the pivotal role of cerebrovascular changes. Further assessment of the cerebral microcirculation in relation to epileptogenesis might open avenues for new therapeutic targets for drug-resistant epilepsy.

Altered neurovascular coupling in the children with attention-deficit/hyperactivity disorder: a comprehensive fMRI analysis.

The coupling between resting-state cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signals reflects the mechanism of neurovascular coupling (NVC), which have not been illustrated in attention-deficit/hyperactivity disorder (ADHD). Fifty ADHD and 42 age- and gender-matched typically developing controls (TDs) were enrolled. The NVC imaging metrics were investigated by exploring the Pearson correlation coefficients between CBF and BOLD-derived quantitative maps (ALFF, fALFF, DCP maps). Three types of NVC metrics (CBF-ALFF, CBF-fALFF, CBF-DCP coupling) were compared between ADHD and TDs group, and the inner association between altered NVC metrics and clinical variables in ADHD group was further analyzed. Compared to TDs, ADHD showed significantly reduced whole-brain CBF-ALFF coupling (P < 0.001). Among regional level (all PFDR < 0.05), ADHD showed significantly lower CBF-ALFF coupling in bilateral thalamus, default-mode network (DMN) involving left anterior cingulate (ACG.L) and right parahippocampal gyrus (PHG.R), execution control network (ECN) involving right middle orbital frontal gyrus (ORBmid.R) and right inferior frontal triangular gyrus (IFGtriang.R), and increased CBF-ALFF coupling in attention network (AN)-related left superior temporal gyrus (STG.L) and somatosensory network (SSN))-related left rolandic operculum (ROL.L). Furthermore, increased CBF-fALFF coupling was found in the visual network (VN)-related left cuneus and negatively correlated with the concentration index of ADHD (R = - 0.299, PFDR = 0.035). Abnormal regional NVC metrics were at widespread neural networks in ADHD, mainly involved in DMN, ECN, SSN, AN, VN and bilateral thalamus. Notably, this study reinforced the insights into the neural basis and pathophysiological mechanism underlying ADHD.

An EEG-fNIRS neurovascular coupling analysis method to investigate cognitive-motor interference

Background and Objective:The simultaneous execution of a motor and cognitive dual task may lead to the deterioration of task performance in one or both tasks due to cognitive-motor interference (CMI). Neuroimaging techniques are promising ways to reveal the underlying neural mechanism of CMI. However, existing studies have only explored CMI from a single neuroimaging modality, which lack built-in validation and comparison of analysis results. This work is aimed to establish an effective analysis framework to comprehensively investigate the CMI by exploring the electrophysiological and hemodynamic activities as well as their neurovascular coupling. Methods:Experiments including an upper limb single motor task, single cognitive task, and cognitive-motor dual task were designed and performed with 16 healthy young participants. Bimodal signals of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) were recorded simultaneously during the experiments. A novel bimodal signal analysis framework was proposed to extract the task-related components for EEG and fNIRS signals respectively and analyze their correlation. Indicators including within-class similarity and between-class distance were utilized to validate the effectiveness of the proposed analysis framework compared to the canonical channel-averaged method. Statistical analysis was performed to investigate the difference in the behavior and neural correlates between the single and dual tasks. Results:Our results revealed that the extra cognitive interference caused divided attention in the dual task, which led to the decreased neurovascular coupling between fNIRS and EEG in all theta, alpha, and beta rhythms. The proposed framework was demonstrated to have a better ability in characterizing the neural patterns than the canonical channel-averaged method with significantly higher within-class similarity and between-class distance indicators. Conclusions:This study proposed a method to investigate CMI by exploring the task-related electrophysiological and hemodynamic activities as well as their neurovascular coupling. Our concurrent EEG-fNIRS study provides new insight into the EEG-fNIRS correlation analysis and novel evidence for the mechanism of neurovascular coupling in the CMI.

Alpha 7-nicotinic cholinergic regulation of pericyte-containing retinal capillaries.

Local blood flow regulation relies mostly on the coordination between neurons and pericyte-containing capillaries. Pericyte relaxation and contraction are influenced by various vasoactive substances and regulated by neurotransmitters. α7 nicotinic acetylcholine receptors (α7-nAChRs), involved in the regulation of vascular function and inhibitory GABA systems, have neuroprotective effects against central nervous system diseases. Although α7-nAChRs are found throughout the retina, their contribution to the retinal capillary tone remains unknown. Here we investigate the neurovascular coupling mechanism underlying α7-nAChR-mediated retinal capillary tone regulation. Changes in capillary diameter and transverse diameter of pericytes during drug perfusion were observed using differential interference contrast microscopy (DIC) to elucidate signaling pathways underlying α7-nAChR-mediated regulation of capillary blood flow at the whole retinal level. Patch clamp technique was used to investigate α7-nAChRs-mediated regulation of the γ-aminobutyric acid (GABA) synaptic circuit. Immunofluorescence was used to explore the expression of α7-nAChRs and GABA receptors. Activating α7-nAChRs on the endothelial cell membrane caused perinuclear accumulation of eNOS. This resulted in dilated retinal capillaries and pericytes via the NOS/NO-cGMP signaling pathway. Neuronal α7-nAChRs activation relaxed retinal capillaries and pericytes via a neurovascular coupling mechanism. α7-nAChR increased the vesicular release of GABA, possibly promoting the release of NO by binding to GABAA receptors in retinal ganglionic cells (RGCs), and relaxation of blood vessels via eNOS-NO by binding to GABAB receptors on retinal capillary endothelial cells. α7-nAChR activation causes vasorelaxation of retinal capillaries.

Sex Difference in General Cognition Associated with Coupling of Whole-brain Functional Connectivity Strength to Cerebral Blood Flow Changes During Alzheimer’s Disease Progression

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder that results in irreversible cognitive impairments. Nonetheless, there are numerous sex-dependent differences in clinical course. We examined potential contributions of neurovascular coupling deficits to sex differences in AD progression. T1-weighted three-dimensional structural magnetic resonance images, functional blood oxygen level dependent and arterial spin labeling images were acquired from 50 AD patients (28 females), 52 amnesic mild cognitive impairment patients (31 females), and 59 healthy controls (36 females). Short- and long-range functional connectivity strength (FCS) and cerebral blood flow (CBF) values were calculated for all participants. Then, the CBF/FCS coupling ratio, which represented the amount of blood supply per unit of connectivity strength, was calculated for each voxel. Two-way ANOVA was performed to identify group × sex interactions and main effects of group. Correlation analysis was used to assess associations between CBF/FCS ratios and Mini-Mental State Examination (MMSE). There were significant group × sex interaction effects on short-range coupling ratios of right middle temporal gyrus, left angular gyrus, left inferior orbital frontal gyrus, and left superior frontal gyrus as well as on the long-range coupling ratios of right middle temporal gyrus, left precuneus, left posterior cingulate cortex, and left angular gyrus. There were significant negative correlations between MMSE scores and CBF/FCS ratios for all regions with significant group × sex interactions among female patients, while positive correlations were found among male patients. Our results demonstrate significant sex differences in neurovascular coupling mechanisms associated with cognitive function during the course of AD.

Simultaneous Functional Magnetic Resonance and Optoacoustic Imaging of Brain-Wide Sensory Responses in Mice.

Functional magnetic resonance imaging (fMRI) has massively contributed to the understanding of mammalian brain function. However, the origin and interpretation of the blood oxygen level-dependent (BOLD) signals retrieved by fMRI remain highly disputed. This article reports on the development of a fully hybridized system enabling concurrent functional magnetic resonance optoacoustic tomography (MROT) measurements of stimulus-evoked brain-wide sensory responses in mice. The highly complementary angiographic and soft tissue contrasts of both modalities along with simultaneous multi-parametric readings of stimulus-evoked hemodynamic responses are leveraged in order to establish unequivocal links between the various counteracting physiological and metabolic processes in the brain. The results indicate that the BOLD signals are highly correlated, both spatially and temporally, with the total hemoglobin readings resolved with volumetric multi-spectral optoacoustic tomography. Furthermore, the differential oxygenated and deoxygenated hemoglobin optoacoustic readings exhibit superior sensitivity as compared to the BOLD signals when detecting stimulus-evoked hemodynamic responses. The fully hybridized MROT approach greatly expands the neuroimaging toolset to comprehensively study neurovascular and neurometabolic coupling mechanisms and related diseases.

Multimodal Noninvasive Functional Neurophotonic Imaging of Murine Brain-Wide Sensory Responses.

Modern optical neuroimaging approaches are expanding the ability to elucidate complex brain function. Diverse imaging contrasts enable direct observation of neural activity with functional sensors along with the induced hemodynamic responses. To date, decoupling the complex interplay of neurovascular coupling and dynamical physiological states has remained challenging when employing single‐modality functional neuroimaging readings. A hybrid fluorescence optoacoustic tomography platform combined with a custom data processing pipeline based on statistical parametric mapping is devised, attaining the first noninvasive observation of simultaneous calcium and hemodynamic activation patterns using optical contrasts. Correlated changes in the oxy‐ and deoxygenated hemoglobin, total hemoglobin, oxygen saturation, and rapid GCaMP6f fluorescence signals are observed in response to peripheral sensory stimulation. While the concurrent epifluorescence serves to corroborate and complement the functional optoacoustic observations, the latter further aids in decoupling the rapid calcium responses from the slowly varying background in the fluorescence recordings mediated by hemodynamic changes. The hybrid imaging platform expands the capabilities of conventional neuroimaging methods to provide more comprehensive functional readings for studying neurovascular and neurometabolic coupling mechanisms and related diseases.

Extracting electrophysiological correlates of functional magnetic resonance imaging data using the canonical polyadic decomposition.

The relation between electrophysiology and BOLD‐fMRI requires further elucidation. One approach for studying this relation is to find time‐frequency features from electrophysiology that explain the variance of BOLD time‐series. Convolution of these features with a canonical hemodynamic response function (HRF) is often required to model neurovascular coupling mechanisms and thus account for time shifts between electrophysiological and BOLD‐fMRI data. We propose a framework for extracting the spatial distribution of these time‐frequency features while also estimating more flexible, region‐specific HRFs. The core component of this method is the decomposition of a tensor containing impulse response functions using the Canonical Polyadic Decomposition. The outputs of this decomposition provide insight into the relation between electrophysiology and BOLD‐fMRI and can be used to construct estimates of BOLD time‐series. We demonstrated the performance of this method on simulated data while also examining the effects of simulated measurement noise and physiological confounds. Afterwards, we validated our method on publicly available task‐based and resting‐state EEG‐fMRI data. We adjusted our method to accommodate the multisubject nature of these datasets, enabling the investigation of inter‐subject variability with regards to EEG‐to‐BOLD neurovascular coupling mechanisms. We thus also demonstrate how EEG features for modelling the BOLD signal differ across subjects.

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer's disease.

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation.Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer’s disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer’s disease.

Modeling the Hemodynamic Response Function Using EEG-fMRI Data During Eyes-Open Resting-State Conditions and Motor Task Execution

Being able to accurately quantify the hemodynamic response function (HRF) that links the blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) signal to the underlying neural activity is important both for elucidating neurovascular coupling mechanisms and improving the accuracy of fMRI-based functional connectivity analyses. In particular, HRF estimation using BOLD-fMRI is challenging particularly in the case of resting-state data, due to the absence of information about the underlying neuronal dynamics. To this end, using simultaneously recorded electroencephalography (EEG) and fMRI data is a promising approach, as EEG provides a more direct measure of neural activations. In the present work, we employ simultaneous EEG-fMRI to investigate the regional characteristics of the HRF using measurements acquired during resting conditions. We propose a novel methodological approach based on combining distributed EEG source space reconstruction, which improves the spatial resolution of HRF estimation and using block-structured linear and nonlinear models, which enables us to simultaneously obtain HRF estimates and the contribution of different EEG frequency bands. Our results suggest that the dynamics of the resting-state BOLD signal can be sufficiently described using linear models and that the contribution of each band is region specific. Specifically, it was found that sensory-motor cortices exhibit positive HRF shapes, whereas the lateral occipital cortex and areas in the parietal cortex, such as the inferior and superior parietal lobule exhibit negative HRF shapes. To validate the proposed method, we repeated the analysis using simultaneous EEG-fMRI measurements acquired during execution of a unimanual hand-grip task. Our results reveal significant associations between BOLD signal variations and electrophysiological power fluctuations in the ipsilateral primary motor cortex, particularly for the EEG beta band, in agreement with previous studies in the literature.

Neurovascular coupling analysis of working memory based on electroencephalography and functional near-infrared spectroscopy

Working memory is an important foundation for advanced cognitive function. The paper combines the spatiotemporal advantages of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to explore the neurovascular coupling mechanism of working memory. In the data analysis, the convolution matrix of time series of different trials in EEG data and hemodynamic response function (HRF) and the blood oxygen change matrix of fNIRS are extracted as the coupling characteristics. Then, canonical correlation analysis (CCA) is used to calculate the cross correlation between the two modal features. The results show that CCA algorithm can extract the similar change trend of related components between trials, and fNIRS activation of frontal pole region and dorsolateral prefrontal lobe are correlated with the delta, theta, and alpha rhythms of EEG data. This study reveals the mechanism of neurovascular coupling of working memory, and provides a new method for fusion of EEG data and fNIRS data.

CO2 signaling mediates neurovascular coupling in the cerebral cortex

Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in the somatosensory cortex are prevented by saturation of the CO2-sensitive vasodilatory brain mechanism with surplus of exogenous CO2 or disruption of brain CO2/HCO3− transport by genetic knockdown of electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) expression in astrocytes. A systematic review of the literature data shows that CO2 and increased neuronal activity recruit the same vasodilatory signaling pathways. These results and analysis suggest that CO2 mediates signaling between neurons and the cerebral vasculature to regulate brain blood flow in accord with changes in the neuronal activity.

Molecular mechanism and regulation of neurovascular coupling in the human brain: The influence of thermoheliox

An experimental study of the dynamics of the BOLD (blood oxygen level dependent) signal by functional magnetic resonance imaging was carried out. It was found that the dynamic responses of the BOLD-signal, have a biphasic character. Through kinetic modeling methods, it was shown that the biphasic nature of the hemodynamic response is based on negative feedback, with Ca2+ pulse inhibited by vasodilation products (NO and prostaglandins). The effect of thermoheliox (inhalation of a mixture of helium and oxygen at 70 °C) on functional hemodynamics was studied. It was shown that preliminary inhalation of thermoheliox stimulates and prolongs hemodynamic impulses.

Parameter Sensitivity and Experimental Validation for Fractional-Order Dynamical Modeling of Neurovascular Coupling.

Goal: Modeling neurovascular coupling is very important to understand brain functions, yet challenging due to the complexity of the involved phenomena. An alternative approach was recently proposed where the framework of fractional-order modeling is employed to characterize the complex phenomena underlying the neurovascular. Due to its nonlocal property, a fractional derivative is suitable for modeling delayed and power-law phenomena. Methods: In this study, we analyze and validate a fractional-order model, which characterizes the neurovascular coupling mechanism. To show the added value of the fractional-order parameters of the proposed model, we perform a parameter sensitivity analysis of the fractional model compared to its integer counterpart. Moreover, the model was validated using neural activity-CBF data related to both event and block design experiments that were acquired using electrophysiology and laser Doppler flowmetry recordings, respectively. Results: The validation results show the aptitude and flexibility of the fractional-order paradigm in fitting a more comprehensive range of well-shaped CBF response behaviors while maintaining a low model complexity. Comparison with the standard integer-order models shows the added value of the fractional-order parameters in capturing various key determinants of the cerebral hemody-namic response, e.g., post-stimulus undershoot. This investigation authenticates the ability and adaptability of the fractional-order framework to characterize a wider range of well-shaped cerebral blood flow responses while preserving low model complexity through a series of unconstrained and constrained optimizations. Conclusions: The analysis of the proposed fractional-order model demonstrates that the proposed framework yields a powerful tool for a flexible characterization of the neurovascular coupling mechanism.

Brief neuronal afterdischarges in the rat hippocampus lead to transient changes in oscillatory activity and to a very long-lasting decline in BOLD signals without inducing a hypoxic state

The effects of hippocampal neuronal afterdischarges (nAD) on hemodynamic parameters, such as blood-oxygen-level-dependent (BOLD) signals) and local cerebral blood volume (CBV) changes, as well as neuronal activity and metabolic parameters in the dentate gyrus, was investigated in rats by combining in vivo electrophysiology with functional magnetic resonance imaging (fMRI) or 1H-nuclear magnetic resonance spectroscopy (1H-NMRS). Brief electrical high-frequency pulse-burst stimulation of the right perforant pathway triggered nAD, a seizure-like activity, in the right dentate gyrus with a high incidence, a phenomenon that in turn caused a sustained decrease in BOLD signals for more than 30 min. The decrease was associated with a reduction in CBV but not with signs of hypoxic metabolism. nAD also triggered transient changes mainly in the low gamma frequency band that recovered within 20 min, so that the longer-lasting altered hemodynamics reflected a switch in blood supply rather than transient changes in ongoing neuronal activity. Even in the presence of reduced baseline BOLD signals, neurovascular coupling mechanisms remained intact, making long-lasting vasospasm unlikely. Subsequently generated nAD did not further alter the baseline BOLD signals. Similarly, nAD did not alter baseline BOLD signals when acetaminophen was previously administered, because acetaminophen alone had already caused a similar decrease in baseline BOLD signals as observed after the first nAD. Thus, at least two different blood supply states exist for the hippocampus, one low and one high, with both states allowing similar neuronal activity. Both acetaminophen and nAD switch from the high to the low blood supply state. As a result, the hemodynamic response function to an identical stimulus differed after nAD or acetaminophen, although the triggered neuronal activity was similar.

Dilation of cortical capillaries is not related to astrocyte calcium signaling.

The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca2+ signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca2+ signaling, but previous work suggests that Ca2+ increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca2+ signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca2+ signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca2+ signaling is substantially reduced. Compared to WT mice at rest, Ca2+ signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca2+ signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca2+ signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca2+ events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca2+ increases in the cerebral cortex.

Emerging Roles of Microglia in Neuro-vascular Unit: Implications of Microglia-Neurons Interactions.

Microglia, which serve as the defensive interface of the nervous system, are activated in many neurological diseases. Their role as immune responding cells has been extensively studied in the past few years. Recent studies have demonstrated that neuronal feedback can be shaped by the molecular signals received and sent by microglia. Altered neuronal activity or synaptic plasticity leads to the release of various communication messages from neurons, which in turn exert effects on microglia. Research on microglia-neuron communication has thus expanded from focusing only on neurons to the neurovascular unit (NVU). This approach can be used to explore the potential mechanism of neurovascular coupling across sophisticated receptor systems and signaling cascades in health and disease. However, it remains unclear how microglia-neuron communication happens in the brain. Here, we discuss the functional contribution of microglia to synapses, neuroimmune communication, and neuronal activity. Moreover, the current state of knowledge of bidirectional control mechanisms regarding interactions between neurons and microglia are reviewed, with a focus on purinergic regulatory systems including ATP-P2RY12R signaling, ATP-adenosine-A1Rs/A2ARs, and the ATP-pannexin 1 hemichannel. This review aims to organize recent studies to highlight the multifunctional roles of microglia within the neural communication network in health and disease.