Astrocyte switch to the hyperactive mode.

Increasing pieces of evidence have suggested that astrocyte function has a strong influence on neuronal activity and plasticity, both in physiological and pathophysiological situations. In epilepsy, astrocytes have been shown to respond to epileptic neuronal seizures; however, whether they can act as a trigger for seizures has not been determined. Here, using the copper implantation method, spontaneous neuronal hyperactivity episodes were reliably induced during the week following implantation. With near 24-h continuous recording for over 1 week of the local field potential with in vivo electrophysiology and astrocyte cytosolic Ca2+ with the fiber photometry method, spontaneous occurrences of seizure episodes were captured. Approximately 1 day after the implantation, isolated aberrant astrocyte Ca2+ events were often observed before they were accompanied by neuronal hyperactivity, suggesting the role of astrocytes in epileptogenesis. Within a single developed episode, astrocyte Ca2+ increase preceded the neuronal hyperactivity by ~20 s, suggesting that actions originating from astrocytes could be the trigger for the occurrence of epileptic seizures. Astrocyte-specific stimulation by channelrhodopsin-2 or deep-brain direct current stimulation was capable of inducing neuronal hyperactivity. Injection of an astrocyte-specific metabolic inhibitor, fluorocitrate, was able to significantly reduce the magnitude of spontaneously occurring neuronal hyperactivity. These results suggest that astrocytes have a role in triggering individual seizures and the reciprocal astrocyte-neuron interactions likely amplify and exacerbate seizures. Therefore, future epilepsy treatment could be targeted at astrocytes to achieve epilepsy control.

Neon ion (20 Ne10 + ) charged particle beams manipulate rapid tumor reoxygenation in syngeneic mouse models.

Charged particle beams induce various biological effects by creating high-density ionization through the deposition of energy along the beam's trajectory. Charged particle beams composed of neon ions (20 Ne10+ ) hold great potential for biomedical applications, but their physiological effects on living organs remain uncertain. In this study, we demonstrate that neon-ion beams expedite the process of reoxygenation in tumor models. We simulated mouse SCCVII syngeneic tumors and exposed them to either X-ray or neon-ion beams. Through an in vivo radiobiological assay, we observed a reduction in the hypoxic fraction in tumors irradiated with 8.2 Gy of neon-ion beams 30 h after irradiation compared to 6 h post-irradiation. Conversely, no significant changes in hypoxia were observed in tumors irradiated with 8.2 Gy of X-rays. To directly quantify hypoxia in the irradiated living tumors, we utilized dynamic contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging. These combined MRI techniques revealed that the non-hypoxic fraction in neon-irradiated tumors was significantly higher than that in X-irradiated tumors (69.53% vs. 47.67%). Simultaneously, the hypoxic fraction in neon-ion-irradiated tumors (2.77%) was lower than that in X-irradiated tumors (4.27%) and non-irradiated tumors (32.44%). These results support the notion that accelerated reoxygenation occurs more effectively with neon-ion beam irradiation compared to X-rays. These findings shed light on the physiological effects of neon-ion beams on tumors and their microenvironment, emphasizing the therapeutic advantage of using neon-ion charged particle beams to manipulate tumor reoxygenation.

Local brain environment changes associated with epileptogenesis.

Plastic change of the neuronal system has traditionally been assumed to be governed primarily by the long-term potentiation/depression mechanisms of synaptic transmission. However, a rather simple shift in the ambient ion, transmitter and metabolite concentrations could have a pivotal role in generating plasticity upon the physiological process of learning and memory. Local brain environment and metabolic changes could also be the cause and consequences of the pathogenesis leading to epilepsy. Governing of the local brain environment is the primal function of astrocytes. The metabolic state of the entire brain is strongly linked to the activity of the lateral hypothalamus. In this study, plastic change of astrocyte reactions in the lateral hypothalamus was examined using epileptogenesis as an extreme form of plasticity. Fluorescent sensors for calcium or pH expressed in astrocytes were examined for up to one week by in vivo fibre photometry in freely moving transgenic male mice. Optical fluctuations on a timescale of seconds is difficult to assess because these signals are heavily influenced by local brain blood volume changes and pH changes. Using a newly devised method for the analysis of the optical signals, changes in Ca2+ and pH in astrocytes and changes in local brain blood volume associated with hippocampal-stimulated epileptic seizures were extracted. Following a transient alkaline shift in the astrocyte triggered by neuronal hyperactivity, a prominent acidic shift appeared in response to intensified seizure which developed with kindling. The acidic shift was unexpected as transient increase in local brain blood volume was observed in response to intensified seizures, which should lead to efficient extrusion of the acidic CO2. The acidic shift could be a result of glutamate transporter activity and/or due to the increased metabolic load of astrocytes leading to increased CO2 and lactate production. This acidic shift may trigger additional gliotransmitter release from astrocytes leading to the exacerbation of epilepsy. As all cellular enzymic reactions are influenced by Ca2+ and pH, changes in these parameters could also have an impact on the neuronal circuit activity. Thus, controlling the astrocyte pH and/or Ca2+ could be a new therapeutic target for treatment of epilepsy or prevention of undesired plasticity associated with epileptogenesis.

Properties of REM sleep alterations with epilepsy.

It is usually assumed that individuals rest during sleep. However, coordinated neural activity that presumably requires high energy consumption is increased during REM sleep. Here, using freely moving male transgenic mice, the local brain environment and astrocyte activity during REM sleep were examined using the fibre photometry method with an optical fibre inserted deep into the lateral hypothalamus, a region that is linked with controlling sleep and metabolic state of the entire brain. Optical fluctuations of endogenous autofluorescence of the brain parenchyma or fluorescence of sensors for Ca2+ or pH expressed in astrocytes were examined. Using a newly devised method for analysis, changes in cytosolic Ca2+ and pH in astrocytes and changes in the local brain blood volume (BBV) were extracted. On REM sleep, astrocytic Ca2+ decreases, pH decreases (acidification) and BBV increases. Acidification was unexpected, as an increase in BBV would result in efficient carbon dioxide and/or lactate removal, which leads to alkalinization of the local brain environment. Acidification could be a result of increased glutamate transporter activity due to enhanced neuronal activity and/or aerobic metabolism in astrocytes. Notably, optical signal changes preceded the onset of the electrophysiological property signature of REM sleep by ∼20-30 s. This suggests that changes in the local brain environment have strong control over the state of neuronal cell activity. With repeated stimulation of the hippocampus, seizure response gradually develops through kindling. After a fully kindled state was obtained with multiple days of stimuli, the optical properties of REM sleep at the lateral hypothalamus were examined again. Although a negative deflection of the detected optical signal was observed during REM sleep after kindling, the estimated component changed. The decrease in Ca2+ and increase in BBV were minimal, and a large decrease in pH (acidification) emerged. This acidic shift may trigger an additional gliotransmitter release from astrocytes, which could lead to a state of hyperexcitable brain. As the properties of REM sleep change with the development of epilepsy, REM sleep analysis may serve as a biomarker of epileptogenesis severity. REM sleep analysis may also predict whether a specific REM sleep episode triggers post-sleep seizures.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607).

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

Optogenetic stimulus-triggered acquisition of seizure resistance.

Unlike an electrical circuit, the hardware of the brain is susceptible to change. Repeated electrical brain stimulation mimics epileptogenesis. After such "kindling" process, a moderate stimulus would become sufficient in triggering a severe seizure. Here, we report that optogenetic neuronal stimulation can also convert the rat brain to a hyperexcitable state. However, continued stimulation once again converted the brain to a state that was strongly resistant to seizure induction. Histochemical examinations showed that moderate astrocyte activation was coincident with resilience acquisition. Administration of an adenosine A1 receptor antagonist instantly reverted the brain back to a hyperexcitable state, suggesting that hyperexcitability was suppressed by adenosine. Furthermore, an increase in basal adenosine was confirmed using in vivo microdialysis. Daily neuron-to-astrocyte signaling likely prompted a homeostatic increase in the endogenous actions of adenosine. Our data suggest that a certain stimulation paradigm could convert the brain circuit resilient to epilepsy without exogenous drug administration.

Pharmacokinetic and pharmacodynamic assessment of histamine H3 receptor occupancy by enerisant: a human PET study with a novel H3 binding ligand, [11C]TASP457.

PURPOSE: Histamine H3 receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H3 receptors. METHODS: To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. RESULTS: Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. CONCLUSION: The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill's plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug's unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Normative data of dopaminergic neurotransmission functions in substantia nigra measured with MRI and PET: Neuromelanin, dopamine synthesis, dopamine transporters, and dopamine D2 receptors.

The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[ß-11C]DOPA, [18F]FE-PE2I and [11C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D2 receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D2 receptor binding were observed in the substantia nigra.

Impact of spillover from white matter by partial volume effect on quantification of amyloid deposition with [11C]PiB PET.

High non-specific uptake of [11C]Pittsburgh compound B ([11C]PiB) in white matter and signal spillover from white matter, due to partial volume effects, confound radioactivity measured in positron emission tomography (PET) with [11C]PiB. We aimed to reveal the partial volume effect in absolute values of kinetic parameters for [11C]PiB, in terms of spillover from white matter. Dynamic data acquired in [11C]PiB PET scans with five healthy volunteers and eight patients with Alzheimer's disease were corrected with region-based and voxel-based partial volume corrections. Binding potential (BPND) was estimated using the two-tissue compartment model analysis with a plasma input function. Partial volume corrections significantly decreased cortical BPND values. The degree of decrease in healthy volunteers (-52.7±5.8%) was larger than that in Alzheimer's disease patients (-11.9±4.2%). The simulation demonstrated that white matter spillover signals due to the partial volume effect resulted in an overestimation of cortical BPND, with a greater degree of overestimation for lower BPND values. Thus, an overestimation due to partial volume effects is more severe in healthy volunteers than in Alzheimer's disease patients. Partial volume corrections may be useful for accurately quantifying Aß deposition in cortical regions.

Dynamic Flow Velocity Mapping from Fluorescent Dye Transit Times in the Brain Surface Microcirculation of Anesthetized Rats and Mice.

OBJECTIVE: This study aimed to develop a new method for mapping blood flow velocity based on the spatial evolution of fluorescent dye transit times captured with CLSFM in the cerebral microcirculation of anesthetized rodents. METHODS: The animals were anesthetized with isoflurane, and a small amount of fluorescent dye was intravenously injected to label blood plasma. The CLSFM was conducted through a closed cranial window to capture propagation of the dye in the cortical vessels. The transit time of the dye over a certain distance in a single vessel was determined with automated image analyses, and average flow velocity was mapped in each vessel. RESULTS: The average flow velocity measured in the rat pial artery and vein was 4.4 ± 1.2 and 2.4 ± 0.5 mm/sec, respectively. A similar range of flow velocity to those of the rats was observed in the mice; 4.9 ± 1.4 and 2.0 ± 0.9 mm/sec, respectively, although the vessel diameter in the mice was about half of that in the rats. CONCLUSIONS: Flow velocity in the cerebral microcirculation can be mapped based on fluorescent dye transit time measurements with conventional CLSFM in experimental animals.

[(11)C]TASP457, a novel PET ligand for histamine H3 receptors in human brain.

PURPOSE: The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [(11)C]TASP0410457 ([(11)C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. METHODS: Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [(11)C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. RESULTS: [(11)C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 - 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm(3) in the pallidum, 9 - 14 in the basal ganglia, 6 - 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [(11)C]TASP457 was 6.9 µSv/MBq. CONCLUSION: [(11)C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

Superiority illusion arises from resting-state brain networks modulated by dopamine.

The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the "superiority illusion." This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism.

[How to Apply Bayesian Theorem to the Evaluation of Myocardial Injury by Measuring High Sensitive Cardiac Troponins in the Patients with Suspected Acute Myocardial Infarction].

118 consecutive patients of suspected acute myocardial infarction with acute chest pain and shortness of breath visiting our emergency room were subjected for this clinical study. Based on final diagnosis of acute myocardial infarction (AMI) comprehensively determined by medical record, physical examination, ECG, echocardiography, cardiac catheterization, etc., except for cardiac biomarkers, the patients were classified into two groups, with AMI group (1) and without AMI group (0) and then ROC curve analysis was performed between without AMI group (1) and with AMI group (0). As a result of ROC curve analysis, AUC, cutoff value, sensitivity, specificity and likelihood ratio (LR) were calculated as shown in Fig. 4 (1-7) and Table 2 (1-7). Based on calculating equation led from Bayesian rules, post-test odds were calculated as product of pre-test odds and LR at the cutoff value in each biomarker such as hsCTnT, hsCTnI, h-FABP CK, CKMB activity and CKMB mass. As a result, post-test probability was improved from predictive pre-test probability 30% to post-test probability 89% and 86% in hsCTnT and hsTnI, respectively but less improved from 30% to 68% in h-FABP and unexpectedly improved from 30% to 82% in CKMB mass compared with hsCTnT and hsTnI. Based on Bayesian rule, it is very valuable to predict post-test probability from predictive pre-test probability 30% by calculation in particular, when post-test probability is over 85-90%. In conclusion, we believe that prediction of post-test probability by Bayesian rule can be surely used to evaluate clinical quality of biomarkers which are not depend on at least, specialty and experience of physicians.

Vasodilation Mechanism of Cerebral Microvessels Induced by Neural Activation under High Baseline Cerebral Blood Flow Level Results from Hypercapnia in Awake Mice.

OBJECTIVE: We investigated the effects of the baseline CBF level at resting state on neurovascular coupling. METHODS: Diameters of arterioles, capillaries, and venulas in awake mouse brain were measured by a two-photon microscope. Vasodilation in each of the cerebral vessels was caused by three experimental conditions: (1) sensory stimulation, (2) 5% CO2 inhalation (hypercapnia), (3) simultaneous exposure to sensory stimulation and 5% CO2 inhalation. CBF and CBV were also measured by a microscope and a CCD camera. RESULTS: Increases in CBF and CBV were observed under all experimental conditions. After the increases in CBF and CBV due to hypercapnia, additional increases in CBF and CBV occurred during sensory stimulation. Diameter changes in arterioles were significantly larger than those in capillaries and venulas under both sensory stimulation and 5% CO2 inhalation. Additional vasodilation from sensory stimulation was observed under hypercapnia. The diameter change in each vessel type during sensory stimulation was maintained under simultaneous exposure to sensory stimulation and hypercapnia. CONCLUSIONS: The diameter change of cerebral vessels during neural activation is reproducible regardless of whether baseline CBF has increased or not. Our finding directly demonstrates the concept of uncoupling between energy consumption and energy supply during cortical activation.

[(11)C]Raclopride binding in the striatum of minimally restrained and free-walking awake mice in a positron emission tomography study.

Anesthesia and restraint stress have profound impacts on brain functions, including neural activity and cerebrovascular function, possibly influencing functional and neurochemical positron emission tomography (PET) imaging data. For circumventing this effect, we developed an experimental system enabling PET imaging of free-walking awake mice with minimal restraints by fixing the head to a holder. The applicability of this system was investigated by performing PET imaging of D2 dopamine receptors with [(11)C]raclopride under the following three different conditions: (1) free-walking awake state; (2) 1.5% isoflurane anesthesia; and (3) whole-body restraint without anesthesia. [(11)C]raclopride binding potential (BP(ND)) values under isoflurane anesthesia and restrained awake state were significantly lower than under free-walking awake state (P < 0.01). Heart rates in restrained awake mice were significantly higher than those in free-walking awake mice (P < 0.01), suggesting that free-walking awake state minimized restraint stress during the PET scan. [(11)C] raclopride-PET with methamphetamine (METH) injection was also performed in awake and anesthetized mice. METH-induced reduction of [(11)C]raclopride BP(ND) in anesthetized mice showed a trend to be less than that in free-walking awake mice, implying that pharmacological modulation of dopaminergic transmissions could be sensitively captured by PET imaging of free-walking awake mice. We concluded that our system is of utility as an in vivo assaying platform for studies of brain functions and neurotransmission elements in small animals, such as those modeling neuropsychiatric disorders.

Plastic vasomotion entrainment.

The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel 'shadow' was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

Anxiety control by astrocytes in the lateral habenula.

The potential role of astrocytes in lateral habenula (LHb) in modulating anxiety was explored in this study. The habenula are a pair of small nuclei located above the thalamus, known for their involvement in punishment avoidance and anxiety. Herein, we observed an increase in theta-band oscillations of local field potentials (LFPs) in the LHb when mice were exposed to anxiety-inducing environments. Electrical stimulation of LHb at theta-band frequency promoted anxiety-like behavior. Calcium (Ca2+) levels and pH in the cytosol of astrocytes and local brain blood volume changes were studied in mice expressing either a Ca2+ or a pH sensor protein specifically in astrocytes and mScarlet fluorescent protein in the blood plasma using fiber photometry. An acidification response to anxiety was observed. Photoactivation of archaerhopsin-T (ArchT), an optogenetic tool that acts as an outward proton pump, results in intracellular alkalinization. Photostimulation of LHb in astrocyte-specific ArchT-expressing mice resulted in dissipation of theta-band LFP oscillation in an anxiogenic environment and suppression of anxiety-like behavior. These findings provide evidence that LHb astrocytes modulate anxiety and may offer a new target for treatment of anxiety disorders.

Graphic plot analysis for estimating binding potential of translocator protein (TSPO) in positron emission tomography studies with [¹8F]FEDAA1106.

PURPOSE: [(18)F]FEDAA1106 is expected to be used for evaluating the regional density of the peripheral benzodiazepine receptor (also called TSPO) in several neurodegenerative disorders. Regarding the quantification, direct binding potential (BP(ND)) has been reported to be preferable because of the variation of nondisplaceable distribution volume (V(ND)) among individuals. However, the precise calculation of BP(ND) is difficult in small regions or at voxel levels due to noise. Recently, a new graphical analysis (GA) was proposed to estimate V(ND) in a direct way. In this paper, we evaluated two types of GA for reliable quantification of BP(ND) in PET study with [(18)F]FEDAA1106 using computer simulations and human data. METHODS: In the simulations, time-activity curves were generated with various rate constants and noise levels, and the errors of BP(ND) estimated by GA were analyzed by comparing with true values calculated from rate constants given for the simulations. Thereafter, in a human study with [(18)F]FEDAA1106 for healthy volunteers, BP(ND) was estimated by two types of GA for region-of-interest (ROI) data. Parametric images of BP(ND) were generated by two types of GA with or without wavelet-denoising. RESULTS: Simulations showed that BP(ND) by GA was well correlated with true values, despite an underestimation. GA reduced unreasonable estimates compared with a conventional nonlinear least-square fitting (NLS), although larger variation of BP(ND) estimates was observed. In a ROI-based analysis of data obtained in a human study, BP(ND)s estimated by GA were well correlated with those generated by NLS, though they were underestimated. Parametric BP(ND) images by GA could be improved with wavelet-denoising. CONCLUSION: Graphical analysis could provide BP(ND) values with high stability and simple calculation in both ROI-based and voxel-based analyses of [(18)F]FEDAA1106 data.

Glial tone of aggression.

Anger transition is often abrupt. In this study, we investigated the mechanisms responsible for switching and modulating aggression levels. The cerebellum is considered a center for motor coordination and learning; however, its connection to social behavior has long been observed. Here, we used the resident-intruder paradigm in male mice and examined local field potential (LFP) changes, glial cytosolic ion fluctuations, and vascular dynamics in the cerebellar vermis throughout various phases of a combat sequence. Notably, we observed the emergence of theta band oscillations in the LFP and sustained elevations in glial Ca2+ levels during combat breakups. When astrocytes, including Bergmann glial cells, were photoactivated using channelrhodopsin-2, the theta band emerged and an early combat breakup occurred. Within a single combat sequence, rapid alteration of offensive (fight) and passive (flight) responses were observed, which roughly correlated with decreases and increases in glial Ca2+, respectively. Neuron-glial interactions in the cerebellar vermis may play a role in adjusting Purkinje cell excitability and setting the tone of aggression. Future anger management strategies and clinical control of excessive aggression and violent behavior may be realized by developing a therapeutic strategy that adjusts glial activity in the cerebellum.