49 research outputs found

    Functional networks and network perturbations in rodents

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    Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed

    The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

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    In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species

    Systematic Review: Anesthetic Protocols and Management as Confounders in Rodent Blood Oxygen Level Dependent Functional Magnetic Resonance Imaging (BOLD fMRI)—Part B: Effects of Anesthetic Agents, Doses and Timing

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    In rodent models the use of functional magnetic resonance imaging (fMRI) under anesthesia is common. The anesthetic protocol might influence fMRI readouts either directly or via changes in physiological parameters. As long as those factors cannot be objectively quantified, the scientific validity of fMRI in rodents is impaired. In the present systematic review, literature analyzing in rats and mice the influence of anesthesia regimes and concurrent physiological functions on blood oxygen level dependent (BOLD) fMRI results was investigated. Studies from four databases that were searched were selected following pre-defined criteria. Two separate articles publish the results; the herewith presented article includes the analyses of 83 studies. Most studies found differences in BOLD fMRI readouts with different anesthesia drugs and dose rates, time points of imaging or when awake status was compared to anesthetized animals. To obtain scientifically valid, reproducible results from rodent fMRI studies, stable levels of anesthesia with agents suitable for the model under investigation as well as known and objectively quantifiable effects on readouts are, thus, mandatory. Further studies should establish dose ranges for standardized anesthetic protocols and determine time windows for imaging during which influence of anesthesia on readout is objectively quantifiable

    Fasting prevents medetomidine-induced hyperglycaemia and alterations of neurovascular coupling in the somatosensory cortex of the rat during noxious stimulation

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    Abstract Medetomidine and isoflurane are commonly used for general anaesthesia in fMRI studies, but they alter cerebral blood flow (CBF) regulation and neurovascular coupling (NVC). In addition, medetomidine induces hypoinsulinemia and hyperglycaemia, which also alter CBF regulation and NVC. Furthermore, sudden changes in arterial pressure induced by noxious stimulation may affect NVC differently under medetomidine and isoflurane anaesthesia, considering their different effects on vascular functions. The first objective of this study was to compare NVC under medetomidine and isoflurane anaesthesia during noxious stimulation. The second objective was to examine whether fasting may improve NVC by reducing medetomidine-induced hyperglycaemia. In male Wister rats, noxious electrical stimulation was applied to the sciatic nerve in fasted or non-fasted animals. CBF and local field potentials (LFP) were recorded in the somatosensory cortex to assess NVC (CBF/LFP ratio). The CBF/LFP ratio was increased by medetomidine compared with isoflurane (p = 0.004), but this effect was abolished by fasting (p = 0.8). Accordingly, medetomidine produced a threefold increase in blood glucose (p < 0.001), but this effect was also abolished by fasting (p = 0.3). This indicates that isoflurane and medetomidine anaesthesia alter NVC differently, but the undesirable glucose dependent effects of medetomidine on NVC can be prevented by fasting

    Physiological properties of mature adult-born neurons in the olfactory bulb of awake mice

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    In the adult brain, new cells are added to existing neural networks throughout life (adult neurogenesis). In mammals, the continuous addition of adult-born cells (ABCs) has been observed in the olfactory bulb and hippocampus. In the olfactory bulb, these ABCs are believed to be involved in many olfactory functions, as for instance odor detection, odor discrimination, and olfactory learning. The major goal of this work was to test whether mature ABCs in awake animals have unique features that distinguish them from resident cells. Our results demonstrate that mature ABCs differ from resident cells in (1) odor-response properties, (2) modulation by K/X anesthesia, and (3) innervation by serotonergic fibers or responsiveness to activation of serotonin receptors. Larger Ca2+ signals in mature ABCs in response to odor application might be relevant in the context of activity-dependent plasticity as a basis of olfactory learning, the function suggested for mature ABCs. The observation that serotonergic inputs might innervate specifically mature ABCs indicates that mature ABCs could exert a specific function via serotonin, such as sensory gain control in dependence of the brain state of the animal.Im adulten Gehirn werden während des gesamten Lebens neugeborene Nervenzellen in bestehende neuronale Netzwerke hinzugefügt (adulte Neurogenese). In Säugetieren wurde die kontinuierliche Einwanderung von adult-geborenen Nervenzellen in Riechkolben und Hippocampus nachgewiesen. Im Riechkolben wird angenommen, dass die adult-geborene Zellen an vielen Funktionen des Riechsystems beteiligt sind, unter anderem Geruchsdetektion, Geruchsdiskriminierung und olfaktorisches Lernen. Das Hauptziel dieser Arbeit war in wachen Tieren zu testen, ob reife adult-geborene Zellen im Riechkolben physiologische Merkmale haben, die sie von residenten Zellen unterscheiden. Unsere Ergebnisse zeigen, dass sich reife adult-geborene Zellen von residenten Zellen in (1) Duftstoff-evozierter Aktivität, (2) Modulation durch Ketamin/Xylazin-Anästhesie und in (3) serotonerger Innervierung oder ihrer Empfindlichkeit auf die Aktivierung von Serotoninrezeptoren unterscheiden. Größere Ca2+-Signale bei Duftstoffapplikation in adult-geborenen Zellen könnten mit aktivitätsabhängiger Plastizität als Grundlage für olfaktorisches Lernen im Zusammenhang stehen. Die Beobachtung, dass serotonerge Nervenfasern eventuell ausschliesslich reife adult-geborene Zellen innervieren, zeigt, dass diese eine über Serotonin vermittelte Funktion ausüben könnten, wie z. B. die Filterung von sensorischen Reizen in Abhängigkeit vom Gehirnzustand

    Generation of a whole-brain hemodynamic response function and sex-specific differences in cerebral processing of mechano-sensation in mice detected by BOLD fMRI

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    BOLD fMRI has become a prevalent method to study cerebral sensory processing in rodent disease models, including pain and mechanical hypersensitivity. fMRI data analysis is frequently combined with a general-linear-model (GLM) -based analysis, which uses the convolution of a hemodynamic response function (HRF) with the stimulus paradigm. However, several studies indicated that the HRF differs across species, sexes, brain structures, and experimental factors, including stimulation modalities or anesthesia, and hence might strongly affect the outcome of BOLD analyzes. While considerable work has been done in humans and rats to understand the HRF, much less is known in mice. As a prerequisite to investigate mechano-sensory processing and BOLD fMRI data in male and female mice, we (1) designed a rotating stimulator that allows application of two different mechanical modalities, including innocuous von Frey and noxious pinprick stimuli and (2) determined and statistically compared HRFs across 30 brain structures and experimental conditions, including sex and, stimulus modalities. We found that mechanical stimulation lead to brain-wide BOLD signal changes thereby allowing extraction of HRFs from multiple brain structures. However, we did not find differences in HRFs across all brain structures and experimental conditions. Hence, we computed a whole-brain mouse HRF, which is based on 88 functional scans from 30 mice. A comparison of this mouse-specific HRF with our previously reported rat-derived HRF showed significantly slower kinetics in mice. Finally, we detected pronounced differences in cerebral BOLD activation between male and female mice with mechanical stimulation, thereby exposing divergent processing of noxious and innocuous stimuli in both sexes

    The alpha2C-adrenoceptor as a neuropsychiatric drug tar-get - PET studies in human subjects

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    Positron emission tomography imaging has both academic and applied uses in revealing the distribution and density of different molecular targets in the central nervous system. Following the significant progress made with the dopamine D2 receptor, advances have been made in developing PET tracers to allow analysis of receptor occupancy of many other receptor types as well as evaluating changes in endogenous synaptic transmitter concentrations of transmitters e.g. serotonin and noradrenaline. Noradrenergic receptors are divided into α1-, α2- and β-adrenoceptor subfamilies, in humans each of which is composed of three receptor subtypes. The α2-adrenoceptors have an important presynaptic auto-inhibitory function on noradrenaline release but they also have postsynaptic roles in modulating the release of other neurotransmitters, such as serotonin and dopamine. One of the subtypes, the α2C-adrenoceptor, has been detected at distinct locations in the central nervous system, most notably the dorsal striatum. Several serious neurological conditions causing dementia, Alzheimer’s disease and Parkinson’s disease have been linked to disturbed noradrenergic signaling. Furthermore, altered noradrenergic signaling has also been implicated in conditions like ADHD, depression, anxiety and schizophrenia. In order to benefit future research into these central nervous system disorders as well as being useful in the clinical development of drugs affecting brain noradrenergic neurotransmission, validation work of a novel tracer for positron emission tomography studies in humans was performed. Altogether 85 PET imaging experiments were performed during four separate clinical trials. The repeatability of [11C]ORM-13070 binding was tested in healthy individuals, followed by a study to evaluate the dose-dependent displacement of [11C]ORM-13070 from α2C-adrenoceptors by a competing ligand, and the final two studies examined the sensitivity of [11C]ORM-13070 binding to reflect changes in endogenous noradrenaline levels. The repeatability of [11C]ORM-13070 binding was very high. The binding properties of the tracer allowed for a reliable estimation of α2C-AR occupancy by using the reference tissue ratio method with low test-retest variability. [11C]ORM-13070 was dose-dependently displaced from its specific binding sites by the subtype-nonselective α2-adrenoceptor antagonist atipamezole, and thus it proved suitable for use in clinical drug development of novel α2C-adrenoceptor ligands e.g. to determine the best doses and dosing intervals for clinical trials. Convincing experimental evidence was gained to support the suitability of [11C]ORM-13070 for detecting an increase in endogenous synaptic noradrenaline in the human brain. Tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, although statistical significance was not reached. Thus, the investigation was unable to fully validate [11C]ORM-13070 for the detection of pharmacologically evoked reductions in noradrenaline levels.Siirretty Doriast

    Watching the Healing Brain: Multimodal and Non-invasive Imaging of Regenerative Processes after Experimental Cerebral Ischemia

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    Stroke is a severe disease of the brain, which leads to cell death and loss of function. Neuroprotective therapy to prevent neuronal loss has not been effective in human stroke patients. Therefore, new therapeutic strategies are needed. Spontaneous recovery can be observed in some patients. However, the basis of this phenomenon is not completely understood yet. Several endogenous regenerative processes have been observed following cerebral ischemia, which may be the reason for functional recovery and can be used as a basis for new therapeutic strategies. Shortly after the insult, endothelial cells start to proliferate and eventually lead to revascularization of ischemic brain tissue (angiogenesis). Furthermore, resident neural progenitor cells increase their proliferative activity, migrate towards the ischemic tissue and even differentiate into new neurons (neurogenesis). Detailed knowledge about the molecular mechanisms and interactions between angiogenesis and neurogenesis in response to stroke is needed in order to reveal new therapeutic targets. This PhD thesis established novel non-invasive imaging strategies to followed post-stroke angiogenesis and neurogenesis with particular regard to their dynamic temporal profiles. Bioluminescence imaging and magnetic resonance imaging were chosen for this purpose. The vascular endothelial growth factor receptor 2 was used as a molecular marker for angiogenesis, and for the first time the molecular basis of post-stroke vascular remodelling was observed non-invasively with bioluminescence imaging in an angiogenesis-specific reporter mouse. Structural changes of the vascular system were monitored with a magnetic resonance imaging strategy. Initial pronounced decrease of vessel density in ischemic tissue was followed by vessel density normalization. Non-invasive observation of endogenous neurogenesis is limited by the small number of neural progenitor cells within the adult brain. This work established the first bioluminescence protocol optimized for highly sensitive bioluminescence imaging of neurogenesis in a neurogenesis-specific reporter mouse. For the first time, increased proliferation of neural progenitor cells after stroke was observed with bioluminescence imaging. As post-stroke angiogenesis and neurogenesis may lead to regeneration of brain function, this PhD thesis established the first functional magnetic resonance imaging protocol for the specific application in mice. First investigations of brain function after stroke were performed and future studies will have the opportunity to follow functional recovery in transgenic mouse models. All methods used in this thesis bear the exceptional potential to be combined into a multimodal approach. Screening for new therapeutic targets within the brain endogenous regenerative capacity will be possible non-invasively. Furthermore, the effect of new therapies on angiogenesis, neurogenesis or functional recovery can be quickly tested

    Functional network study on the wild type and DISC1 transgenic mice

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