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      Constraints of vigilance‐dependent noradrenergic signaling to mouse cerebellar Bergmann glia

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          Abstract

          Behavioral state plays an important role in determining astroglia Ca 2+ signaling. In particular, locomotion‐mediated elevated vigilance has been found to trigger norepinephrine‐dependent whole cell Ca 2+ elevations in astroglia throughout the brain. For cerebellar Bergmann glia it has recently been found that locomotion‐induced transient Ca 2+ elevations depend on their α 1A‐adrenergic receptors. With increasing availability and implementation of locomotion as behavioral parameter it becomes important to understand the constraints of noradrenergic signaling to astroglia. Here we evaluated the effect of speed, duration and interval of locomotion on Ca 2+ signals in Bergmann glia as well as cerebellar noradrenergic axon terminals. We found almost no dependence on locomotion speed, but following the initial Ca 2+ transient prolonged locomotion events revealed a steady‐state Ca 2+ elevation. Comparison of time course and recovery of transient Bergmann glia and noradrenergic terminal Ca 2+ dynamics suggested that noradrenergic terminal Ca 2+ activity determines Bergmann glia Ca 2+ activation and does not require noradrenergic receptor desensitization to account for attenuation during prolonged locomotion. Further, analyzing the correlation among Ca 2+ dynamics within regions within the field of observation we found that coordinated activity among noradrenergic terminals accounts for fluctuations of steady‐state Bergmann glia Ca 2+ activity. Together, our findings will help to better understand astroglia Ca 2+ dynamics during less controlled awake behavior and may guide the identification of behavioral contexts preferably dependent on astroglia Ca 2+ signaling.

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          Most cited references35

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          Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance.

          An increasingly powerful approach for studying brain circuits relies on targeting genetically encoded sensors and effectors to specific cell types. However, current approaches for this are still limited in functionality and specificity. Here we utilize several intersectional strategies to generate multiple transgenic mouse lines expressing high levels of novel genetic tools with high specificity. We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. High functionality was shown in example mouse lines for GCaMP6, YCX2.60, VSFP Butterfly 1.2, and Jaws. These novel transgenic lines greatly expand the ability to monitor and manipulate neuronal activities with increased specificity.
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            Imaging large-scale neural activity with cellular resolution in awake, mobile mice.

            We report a technique for two-photon fluorescence imaging with cellular resolution in awake, behaving mice with minimal motion artifact. The apparatus combines an upright, table-mounted two-photon microscope with a spherical treadmill consisting of a large, air-supported Styrofoam ball. Mice, with implanted cranial windows, are head restrained under the objective while their limbs rest on the ball's upper surface. Following adaptation to head restraint, mice maneuver on the spherical treadmill as their heads remain motionless. Image sequences demonstrate that running-associated brain motion is limited to approximately 2-5 microm. In addition, motion is predominantly in the focal plane, with little out-of-plane motion, making the application of a custom-designed Hidden-Markov-Model-based motion correction algorithm useful for postprocessing. Behaviorally correlated calcium transients from large neuronal and astrocytic populations were routinely measured, with an estimated motion-induced false positive error rate of <5%.
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              The cerebellum and cognition

              What the cerebellum does to sensorimotor and vestibular control, it also does to cognition, emotion, and autonomic function. This hypothesis is based on the theories of dysmetria of thought and the universal cerebellar transform, which hold that the cerebellum maintains behavior around a homeostatic baseline, automatically, without conscious awareness, informed by implicit learning, and performed according to context. Functional topography within the cerebellum facilitates the modulation of distributed networks subserving multiple different functions. The sensorimotor cerebellum is represented in the anterior lobe with a second representation in lobule VIII, and lesions of these areas lead to the cerebellar motor syndrome of ataxia, dysmetria, dysarthria and impaired oculomotor control. The cognitive / limbic cerebellum is in the cerebellar posterior lobe, with current evidence pointing to three separate topographic representations, the nature of which remain to be determined. Posterior lobe lesions result in the cerebellar cognitive affective syndrome (CCAS), the hallmark features of which include deficits in executive function, visual spatial processing, linguistic skills and regulation of affect. The affective dyscontrol manifests in autism spectrum and psychosis spectrum disorders, and disorders of emotional control, attentional control, and social skill set. This report presents an overview of the rapidly growing field of the clinical cognitive neuroscience of the cerebellum. It commences with a brief historical background, then discusses tract tracing experiments in animal models and functional imaging observations in humans that subserve the cerebellar contribution to neurological function. Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the CCAS in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Glia
                Glia
                Wiley
                0894-1491
                1098-1136
                June 2023
                February 15 2023
                June 2023
                : 71
                : 6
                : 1451-1465
                Affiliations
                [1 ] Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio Texas USA
                [2 ] Center for Biomedical Neuroscience University of Texas Health Science Center at San Antonio San Antonio Texas USA
                [3 ] Xiangya School of Medicine Central South University Changsha China
                Article
                10.1002/glia.24350
                36790089
                0eb1e754-2799-47c6-a97d-1d5383123837
                © 2023

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