Rune Enger

• Bojarskaite, Laura; Nafari, Sahar; Ravnanger, Anne Katrine; Frey, Mina Martine; Skauli, Nadia & Åbjørsbråten, Knut Sindre [Vis alle 13 forfattere av denne artikkelen] (2024). Role of aquaporin-4 polarization in extracellular solute clearance. Fluids and Barriers of the CNS. ISSN 2045-8118. 21(1). doi: 10.1186/s12987-024-00527-7.
• Naik, Aditi; Jensen, Vidar; Bakketun, Cecilie Bugge; Enger, Rune; Hrabetova, Sabina & Hrabe, Jan (2023). BubbleDrive, a low-volume incubation chamber for acute brain slices. Scientific Reports. ISSN 2045-2322. 13(1). doi: 10.1038/s41598-023-45949-9. Fulltekst i vitenarkiv
• Bordoni, Luca; Thorén, Anna Elisabeth; Gutiérrez-Jiménez, Eugenio; Åbjørsbråten, Knut Sindre; Bjørnstad, Daniel Marelius & Tang, Wannan [Vis alle 12 forfattere av denne artikkelen] (2023). Deletion of aquaporin-4 improves capillary blood flow distribution in brain edema. Glia. ISSN 0894-1491. 71(11), s. 2559–2572. doi: 10.1002/glia.24439. Fulltekst i vitenarkiv
• Bojarskaite, Laura; Vallet, Alexandra Honorine Emilie; Bjørnstad, Daniel Marelius; Binder, Kristin Maria Gullestad; Cunen, Celine & Heuser, Kjell [Vis alle 9 forfattere av denne artikkelen] (2023). Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport. Nature Communications. ISSN 2041-1723. 14. doi: 10.1038/s41467-023-36643-5. Fulltekst i vitenarkiv Vis sammendrag

  Perivascular spaces are important highways for fluid and solute transport in the brain enabling efficient waste clearance during sleep. However, the underlying mechanisms augmenting perivascular flow in sleep are unknown. Using two-photon imaging of naturally sleeping male mice we demonstrate sleep cycle-dependent vascular dynamics of pial arteries and penetrating arterioles: slow, large-amplitude oscillations in NREM sleep, a vasodilation in REM sleep, and a vasoconstriction upon awakening at the end of a sleep cycle and microarousals in NREM and intermediate sleep. These vascular dynamics are mirrored by changes in the size of the perivascular spaces of the penetrating arterioles: slow fluctuations in NREM sleep, reduction in REM sleep and an enlargement upon awakening after REM sleep and during microarousals in NREM and intermediate sleep. By biomechanical modeling we demonstrate that these sleep cycle-dependent perivascular dynamics likely enhance fluid flow and solute transport in perivascular spaces to levels comparable to cardiac pulsation-driven oscillations.

• Åbjørsbråten, Knut Sindre; Skaaraas, Gry Helen Enger Syverstad; Cunen, Celine Marie Løken; Bjørnstad, Daniel Marelius; Binder, Kristin Maria Gullestad & Bojarskaite, Laura [Vis alle 15 forfattere av denne artikkelen] (2022). Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice. eLIFE. ISSN 2050-084X. doi: 10.7554/eLife.75055. Fulltekst i vitenarkiv Vis sammendrag

  Increased astrocytic Ca2+ signaling has been shown in Alzheimer’s disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca2+ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca2+ signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRABNE, we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca2+ responses. Our data points to a dysfunction in the norepinephrine–astrocyte Ca2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer’s disease.

• Ellingsrud, Ada Johanne; Dukefoss, Didrik Bakke; Enger, Rune; Halnes, Geir; Pettersen, Klas Henning & Rognes, Marie Elisabeth (2022). Validating a Computational Framework for Ionic Electrodiffusion with Cortical Spreading Depression as a Case Study. eNeuro. ISSN 2373-2822. 9(2). doi: 10.1523/ENEURO.0408-21.2022. Fulltekst i vitenarkiv Vis sammendrag

  Cortical spreading depression (CSD) is a wave of pronounced depolarization of brain tissue accompanied by substantial shifts in ionic concentrations and cellular swelling. Here, we validate a computational framework for modeling electrical potentials, ionic movement, and cellular swelling in brain tissue during CSD. We consider different model variations representing wild-type (WT) or knock-out/knock-down mice and systematically compare the numerical results with reports from a selection of experimental studies. We find that the data for several CSD hallmarks obtained computationally, including wave propagation speed, direct current shift duration, peak in extracellular K+ concentration as well as a pronounced shrinkage of extracellular space (ECS) are well in line with what has previously been observed experimentally. Further, we assess how key model parameters including cellular diffusivity, structural ratios, membrane water and/or K+ permeabilities affect the set of CSD characteristics.

• Ellingsrud, Ada Johanne; Enger, Rune; Dukefoss, Didrik Bakke; Halnes, Geir; Pettersen, Klas Henning & Rognes, Marie Elisabeth (2021). Validating a computational framework for ionic electrodiffusion with cortical spreading depression as a case study. bioRxiv. ISSN 2692-8205. doi: 10.1101/2021.11.29.470301.
• Heuser, Kjell & Enger, Rune (2021). Astrocytic Ca2+ Signaling in Epilepsy. Frontiers in Cellular Neuroscience. ISSN 1662-5102. 15. doi: 10.3389/fncel.2021.695380. Fulltekst i vitenarkiv
• Bjørnstad, Daniel Marelius; Åbjørsbråten, Knut Sindre; Hennestad, Eivind; Cunen, Celine; Hermansen, Gudmund Horn & Bojarskaite, Laura [Vis alle 9 forfattere av denne artikkelen] (2021). Begonia - a two-photon imaging analysis pipeline for astrocytic Ca2+ signals. Frontiers in Cellular Neuroscience. ISSN 1662-5102. 15. doi: 10.3389/fncel.2021.681066. Fulltekst i vitenarkiv
• Hagen, Espen; Chambers, Anna; Einevoll, Gaute; Pettersen, Klas Henning; Enger, Rune & Stasik, Alexander Johannes (2021). RippleNet: a Recurrent Neural Network for Sharp Wave Ripple (SPW-R) Detection. Neuroinformatics. ISSN 1539-2791. 19, s. 493–514. doi: 10.1007/s12021-020-09496-2. Fulltekst i vitenarkiv Vis sammendrag

  Hippocampal sharp wave ripples (SPW-R) have been identified as key bio-markers of important brain functions such as memory consolidation and decision making. Understanding their underlying mechanisms in healthy and pathological brain function and behaviour rely on accurate SPW-R detection. In this multidisciplinary study, we propose a novel, self-improving artificial intelligence (AI) detection method in the form of deep Recurrent Neural Networks (RNN) with Long Short-Term memory (LSTM) layers that can learn features of SPW-R events from raw, labeled input data. The approach contrasts conventional routines that typically relies on hand-crafted, heuristic feature extraction and often laborious manual curation. The algorithm is trained using supervised learning on hand-curated data sets with SPW-R events obtained under controlled conditions. The input to the algorithm is the local field potential (LFP), the low-frequency part of extracellularly recorded electric potentials from the CA1 region of the hippocampus. Its output predictions can be interpreted as time-varying probabilities of SPW-R events for the duration of the inputs. A simple thresholding applied to the output probabilities is found to identify times of SPW-R events with high precision. The non-causal, or bidirectional variant of the proposed algorithm demonstrates consistently better accuracy compared to the causal, or unidirectional counterpart. Reference implementations of the algorithm, named ‘RippleNet’, are open source, freely available, and implemented using a common open-source framework for neural networks (tensorflow.keras) and can be easily incorporated into existing data analysis workflows for processing experimental data.

• Hagen, Espen; Chambers, Anna; Einevoll, Gaute; Pettersen, Klas Henning; Enger, Rune & Stasik, Alexander Johannes (2020). RippleNet: A Recurrent Neural Network for Sharp Wave Ripple (SPW-R) Detection. bioRxiv. ISSN 2692-8205. doi: 10.1101/2020.05.11.087874. Fulltekst i vitenarkiv Vis sammendrag

  Hippocampal sharp wave ripples (SPW-R) have been identified as key bio-markers of important brain functions such as memory consolidation and decision making. SPW-R detection typically relies on hand-crafted feature extraction, and laborious manual curation is often required. In this multidisciplinary study, we propose a novel, self-improving artificial intelligence (AI) method in the form of deep Recurrent Neural Networks (RNN) with Long Short-Term memory (LSTM) layers that can learn features of SPW-R events from raw, labeled input data. The algorithm is trained using supervised learning on hand-curated data sets with SPW-R events. The input to the algorithm is the local field potential (LFP), the low-frequency part of extracellularly recorded electric potentials from the CA1 region of the hippocampus. The output prediction can be interpreted as the time-varying probability of SPW-R events for the duration of the input. A simple thresholding applied to the output probabilities is found to identify times of events with high precision. The reference implementation of the algorithm, named ‘RippleNet’, is open source, freely available, and implemented using a common open-source framework for neural networks (tensorflow.keras) and can be easily incorporated into existing data analysis workflows for processing experimental data.

• Bojarskaite, Laura; Bjørnstad, Daniel Marelius; Pettersen, Klas Henning; Cunen, Celine; Hermansen, Gudmund Horn & Åbjørsbråten, Knut Sindre [Vis alle 12 forfattere av denne artikkelen] (2020). Astrocytic Ca2+ signaling is reduced during sleep and is involved in the regulation of slow wave sleep. Nature Communications. ISSN 2041-1723. 11. doi: 10.1038/s41467-020-17062-2. Fulltekst i vitenarkiv
• Eide, Per Kristian; Hasan-Olive, Md Mahdi; Hansson, Hans-Arne & Enger, Rune (2020). Increased occurrence of pathological mitochondria in astrocytic perivascular endfoot processes and neurons of idiopathic intracranial hypertension. Journal of Neuroscience Research. ISSN 0360-4012. 99(2), s. 467–480. doi: 10.1002/jnr.24743.
• Hasan-Olive, Md Mahdi; Enger, Rune; Hansson, Hans-Arne; Nagelhus, Erlend Arnulf & Eide, Per Kristian (2019). Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients. Fluids and Barriers of the CNS. ISSN 2045-8118. 16:39, s. 1–16. doi: 10.1186/s12987-019-0160-7. Fulltekst i vitenarkiv
• Eilert-Olsen, Martine; Hjukse, Jarand Berg; Thoren, Anna; Tang, Wannan; Enger, Rune & Jensen, Vidar [Vis alle 8 forfattere av denne artikkelen] (2019). Astroglial endfeet exhibit distinct Ca2+ signals during hypoosmotic conditions. Glia. ISSN 0894-1491. 67(12), s. 2399–2409. doi: 10.1002/glia.23692. Fulltekst i vitenarkiv
• Hasan-Olive, Md Mahdi; Hansson, Hans-Arne; Enger, Rune; Nagelhus, Erlend Arnulf & Eide, Per Kristian (2019). Blood-Brain Barrier Dysfunction in Idiopathic Intracranial Hypertension. Journal of Neuropathology and Experimental Neurology. ISSN 0022-3069. 78(9), s. 808–818. doi: 10.1093/jnen/nlz063.
• Rosic, Brana; Dukefoss, Didrik Bakke; Åbjørsbråten, Knut Sindre; Tang, Wannan; Jensen, Vidar & Ottersen, Ole Petter [Vis alle 8 forfattere av denne artikkelen] (2019). Aquaporin-4-independent volume dynamics of astroglial endfeet during cortical spreading depression. Glia. ISSN 0894-1491. 67(6), s. 1113–1121. doi: 10.1002/glia.23604. Fulltekst i vitenarkiv Vis sammendrag

  Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of gray matter. This phenomenon is believed to underlie the migraine aura and similar waves of depolarization may exacerbate injury in a number of neurological disease states. CSD is characterized by massive ion dyshomeostasis, cell swelling, and multiphasic blood flow changes. Recently, it was shown that CSD is associated with a closure of the paravascular space (PVS), a proposed exit route for brain interstitial fluid and solutes, including excitatory and inflammatory substances that increase in the wake of CSD. The PVS closure was hypothesized to rely on swelling of astrocytic endfeet due to their high expression of aquaporin‐4 (AQP4) water channels. We investigated whether CSD is associated with swelling of endfeet around penetrating arterioles in the cortex of living mice. Endfoot cross‐sectional area was assessed by two‐photon microscopy of mice expressing enhanced green fluorescent protein in astrocytes and related to the degree of arteriolar constriction. In anesthetized mice CSD triggered pronounced endfoot swelling that was short‐lasting and coincided with the initial arteriolar constriction. Mice lacking AQP4 displayed volume changes of similar magnitude. CSD‐induced endfoot swelling and arteriolar constriction also occurred in awake mice, albeit with faster kinetics than in anesthetized mice. We conclude that swelling of astrocytic endfeet is a robust event in CSD. The early onset and magnitude of the endfoot swelling is such that it may significantly delay perivascular drainage of interstitial solutes in neurological conditions where CSD plays a pathophysiological role.

• Heuser, Kjell; Nome, Cecilie; Pettersen, Klas; Åbjørsbråten, Knut Sindre; Jensen, Vidar & Tang, Wannan [Vis alle 10 forfattere av denne artikkelen] (2018). Ca2+ signals in astrocytes facilitate spread of epileptiform activity. Cerebral Cortex. ISSN 1047-3211. 28(11), s. 4036–4048. doi: 10.1093/cercor/bhy196. Fulltekst i vitenarkiv
• Hasan-Olive, Md Mahdi; Enger, Rune; Hansson, Hans-Arne; Nagelhus, Erlend Arnulf & Eide, Per Kristian (2018). Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus. Glia. ISSN 0894-1491. 67(1), s. 91–100. doi: 10.1002/glia.23528.
• Enger, Rune (2017). Automated gold particle quantification of immunogold labeled micrographs. Journal of Neuroscience Methods. ISSN 0165-0270. 286, s. 31–37. doi: 10.1016/j.jneumeth.2017.05.018. Fulltekst i vitenarkiv
• Eidsvaag, Vigdis Andersen; Enger, Rune; Hansson, Hans-Arne; Eide, Per Kristian & Nagelhus, Erlend Arnulf (2017). Human and mouse cortical astrocytes differ in aquaporin-4 polarization toward microvessels. Glia. ISSN 0894-1491. 65(6), s. 964–973. doi: 10.1002/glia.23138. Fulltekst i vitenarkiv
• Enger, Rune; Dukefoss, Didrik Bakke; Tang, Wannan; Pettersen, Klas; Bjørnstad, Daniel Marelius & Helm, Paul Johannes [Vis alle 11 forfattere av denne artikkelen] (2016). Deletion of aquaporin-4 curtails extracellular glutamate elevation in cortical spreading depression in awake mice. Cerebral Cortex. ISSN 1047-3211. doi: 10.1093/cercor/bhw359.
• Enger, Rune; Tang, Wannan; Vindedal, Gry Fluge; Jensen, Vidar; Helm, Paul Johannes & Sprengel, Rolf [Vis alle 8 forfattere av denne artikkelen] (2015). Dynamics of ionic shifts in cortical spreading depression. Cerebral Cortex. ISSN 1047-3211. 25(11), s. 4469–4476. doi: 10.1093/cercor/bhv054. Vis sammendrag

  Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K(+) or glutamate have been proposed. Here we use extracellular direct current potential recordings, K(+)-sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca(2+) and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca(2+) carrying the cortical spreading depression wavefront and are in favor of interstitial K(+) diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression.

• Tang, Wannan; Szokol, Karolina; Jensen, Vidar; Enger, Rune; Trivedi, Chintan A. & Hvalby, Øyvind Christian dødsbo [Vis alle 10 forfattere av denne artikkelen] (2015). Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP. Journal of Neuroscience. ISSN 0270-6474. 35(7), s. 3016–3021. doi: 10.1523/JNEUROSCI.3319-14.2015. Vis sammendrag

  To date, it has been difficult to reveal physiological Ca(2+) events occurring within the fine astrocytic processes of mature animals. The objective of the study was to explore whether neuronal activity evokes astrocytic Ca(2+) signals at glutamatergic synapses of adult mice. We stimulated the Schaffer collateral/commissural fibers in acute hippocampal slices from adult mice transduced with the genetically encoded Ca(2+) indicator GCaMP5E driven by the glial fibrillary acidic protein promoter. Two-photon imaging revealed global stimulation-evoked astrocytic Ca(2+) signals with distinct latencies, rise rates, and amplitudes in fine processes and somata. Specifically, the Ca(2+) signals in the processes were faster and of higher amplitude than those in the somata. A combination of P2 purinergic and group I/II metabotropic glutamate receptor (mGluR) antagonists reduced the amplitude of the Ca(2+) transients by 30-40% in both astrocytic compartments. Blockage of the mGluRs alone only modestly reduced the magnitude of the stimulation-evoked Ca(2+) signals in processes and failed to affect the somatic Ca(2+) response. Local application of group I or I/II mGluR agonists or adenosine triphosphate (ATP) elicited global astrocytic Ca(2+) signals that mimicked the stimulation-evoked astrocytic Ca(2+) responses. We conclude that stimulation-evoked Ca(2+) signals in astrocytic processes at CA3-CA1 synapses of adult mice (1) differ from those in astrocytic somata and (2) are modulated by glutamate and ATP.

• Szokol, Karolina; Heuser, Kjell; Tang, Wannan; Jensen, Vidar; Enger, Rune & Bedner, Peter [Vis alle 10 forfattere av denne artikkelen] (2015). Augmentation of Ca<sup>2+</sup> signaling in astrocytic endfeet in the latent phase of temporal lobe epilepsy. Frontiers in Cellular Neuroscience. ISSN 1662-5102. 9. doi: 10.3389/fncel.2015.00049. Fulltekst i vitenarkiv Vis sammendrag

  Astrocytic endfeet are specialized cell compartments whose important homeostatic roles depend on their enrichment of water and ion channels anchored by the dystrophin associated protein complex (DAPC). This protein complex is known to disassemble in patients with mesial temporal lobe epilepsy and in the latent phase of experimental epilepsies. The mechanistic underpinning of this disassembly is an obvious target of future therapies, but remains unresolved. Here we show in a kainate model of temporal lobe epilepsy that astrocytic endfeet display an enhanced stimulation-evoked Ca(2+) signal that outlast the Ca(2+) signal in the cell bodies. While the amplitude of this Ca(2+) signal is reduced following group I/II metabotropic receptor (mGluR) blockade, the duration is sustained. Based on previous studies it has been hypothesized that the molecular disassembly in astrocytic endfeet is caused by dystrophin cleavage mediated by Ca(2+) dependent proteases. Using a newly developed genetically encoded Ca(2+) sensor, the present study bolsters this hypothesis by demonstrating long-lasting, enhanced stimulation-evoked Ca(2+) signals in astrocytic endfeet.

• Enger, Rune; Gundersen, Georg Andreas; Haj-Yasein, Nadia Nabil; Eilert-Olsen, Martine; Thoren, Anna & Vindedal, Gry Fluge [Vis alle 11 forfattere av denne artikkelen] (2012). Molecular scaffolds underpinning macroglial polarization: An analysis of retinal Muller cells and brain astrocytes in mouse. Glia. ISSN 0894-1491. 60(12), s. 2018–2026. doi: 10.1002/glia.22416. Vis sammendrag

  Key roles of macroglia are inextricably coupled to specialized membrane domains. The perivascular endfoot membrane has drawn particular attention, as this domain contains a unique complement of aquaporin‐4 (AQP4) and other channel proteins that distinguishes it from perisynaptic membranes. Recent studies indicate that the polarization of macroglia is lost in a number of diseases, including temporal lobe epilepsy and Alzheimer's disease. A better understanding is required of the molecular underpinning of astroglial polarization, particularly when it comes to the significance of the dystrophin associated protein complex (DAPC). Here, we employ immunofluorescence and immunogold cytochemistry to analyze the molecular scaffolding in perivascular endfeet in macroglia of retina and three regions of brain (cortex, dentate gyrus, and cerebellum), using AQP4 as a marker. Compared with brain astrocytes, Müller cells (a class of retinal macroglia) exhibit lower densities of the scaffold proteins dystrophin and α‐syntrophin (a DAPC protein), but higher levels of AQP4. In agreement, depletion of dystrophin or α‐syntrophin—while causing a dramatic loss of AQP4 from endfoot membranes of brain astrocytes—had only modest or insignificant effect, respectively, on the AQP4 pool in endfoot membranes of Müller cells. In addition, while polarization of brain macroglia was less affected by dystrophin depletion than by targeted deletion of α‐syntrophin, the reverse was true for retinal macroglia. These data indicate that the molecular scaffolding in perivascular endfeet is more complex than previously assumed and that macroglia are heterogeneous with respect to the mechanisms that dictate their polarization.

• Eilert-Olsen, Martine; Haj Yasein, Nadia Nabil; Vindedal, Gry Fluge; Enger, Rune; Gundersen, Georg Andreas & Hoddevik, Eystein Hellstrøm [Vis alle 14 forfattere av denne artikkelen] (2012). Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia. ISSN 0894-1491. 60(3), s. 432–440. doi: 10.1002/glia.22277.
• Thrane, Alexander Stanley; Rappold, Philip M; Fujita, Takumi; Torres, Arnulfo; Bekar, Lane K & Takano, Takahiro [Vis alle 17 forfattere av denne artikkelen] (2011). Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proceedings of the National Academy of Sciences of the United States of America. ISSN 0027-8424. 108(2), s. 846–851. doi: 10.1073/pnas.1015217108.
• Nase, Gabriele; Helm, Paul Johannes; Enger, Rune & Ottersen, Ole Petter (2008). Water entry into astrocytes during brain edema formation. Glia. ISSN 0894-1491. 56, s. 895–902. doi: 10.1002/glia.20664.

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• Naik, Aditi; Jensen, Vidar; Bakketun, Cecilie Bugge; Enger, Rune; Hrabetova, Sabina & Hrabe, Jan (2024). Author Correction: BubbleDrive, a low-volume incubation chamber for acute brain slices (Scientific Reports, (2023), 13, 1, (20005), 10.1038/s41598-023-45949-9). Scientific Reports. ISSN 2045-2322. 14(1). doi: 10.1038/s41598-024-52441-5.
• Boccara, Charlotte N; Hu, Hua; Enger, Rune & Bojarskaite, Laura (2020). Hvorfor sover vi?

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