Selectively expressed RNA molecules as a versatile tool for functionalized cell targeting.

Targeting of diseased cells is one of the most urgently needed prerequisites for a next generation of potent pharmaceuticals. Different approaches pursued fail mainly due to a lack of specific surface markers. Developing an RNA-based methodology, we can now ensure precise cell targeting combined with selective expression of effector proteins for therapy, diagnostics or cell steering.

Early Blood-Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice.

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice.

Transcranial Direct Current Stimulation Reverses Stroke-Induced Network Alterations in Mice.

Background: Beyond focal effects, stroke lesions impact the function of distributed networks. We here investigated (1) whether transcranial direct current stimulation (tDCS) alters the network changes induced by cerebral ischemia and (2) whether functional network parameters predict the therapeutic efficacy of tDCS in a mouse model of focal photothrombotic stroke.

Methods: Starting 3 days after stroke, cathodal tDCS (charge density=39.

Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration.

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery.

Background: Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity.

The gut microbiota modulates brain network connectivity under physiological conditions and after acute brain ischemia.

The gut microbiome has been implicated as a key regulator of brain function in health and disease. But the impact of gut microbiota on functional brain connectivity is unknown. We used resting-state functional magnetic resonance imaging in germ-free and normally colonized mice under naive conditions and after ischemic stroke.

Towards chronic deep brain stimulation in freely moving hemiparkinsonian rats: applicability and functionality of a fully implantable stimulation system.

This study aimed at investigating a novel fully implantable deep brain stimulation (DBS) system and its ability to modulate brain metabolism and behavior through subthalamic nucleus (STN) stimulation in a hemiparkinsonian rat model.Twelve male rats were unilaterally lesioned with 6-hydroxydopamine in the medial forebrain bundle and received a fully implantable DBS system aiming at the ipsilesional STN. Each rat underwent three cylinder tests to analyze front paw use: a PRE test before any surgical intervention, an OFF test after surgery but before stimulation onset and an ON test under DBS.

Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats.

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function.

Human Neural Stem Cell Induced Functional Network Stabilization After Cortical Stroke: A Longitudinal Resting-State fMRI Study in Mice.

Most stroke studies dealing with functional deficits and assessing stem cell therapy produce extensive hemispheric damage and can be seen as a model for severe clinical strokes. However, mild strokes have a better prospect for functional recovery. Recently, anatomic and behavioral changes have been reported for distal occlusion of the middle cerebral artery (MCA), generating a well-circumscribed and small cortical lesion, which can thus be proposed as mild to moderate cortical stroke.

Aging Reduces the Functional Brain Networks Strength-a Resting State fMRI Study of Healthy Mouse Brain.

Resting-state functional magnetic resonance imaging (rsfMRI) is increasingly used to unravel the functional neuronal networks in health and disease. In particular, this technique of simultaneously probing the whole brain has found high interest in monitoring brain wide effects of cerebral disease and in evaluating therapeutic strategies. Such studies, applied in preclinical experimental mouse models, often require long-term observations.

Processing Pipeline for Atlas-Based Imaging Data Analysis of Structural and Functional Mouse Brain MRI (AIDAmri).

Magnetic resonance imaging (MRI) is a key technology in multimodal animal studies of brain connectivity and disease pathology. MRI provides non-invasive, whole brain macroscopic images containing structural and functional information, thereby complementing invasive high-resolution microscopy and molecular techniques. Brain mapping, the correlation of corresponding regions between multiple brains in a standard brain atlas system, is widely used in human MRI.

Effects of subthalamic deep brain stimulation on striatal metabolic connectivity in a rat hemiparkinsonian model.

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular.

Cortical tissue loss and major structural reorganization as result of distal middle cerebral artery occlusion in the chronic phase of nude mice.

The stroke model of distal middle cerebral artery occlusion is considered a reliable stroke model with high reproducibility and low mortality rate. Thus, it is preferred for assessments of therapeutic strategies, in particular for neurorepair and regeneration studies. However, present literature has reported only on the lesion behavior and behavioral deficits during the acute and subacute phase of maximally three weeks.

Persistent Quantitative Vitality of Stem Cell Graft Is Necessary for Stabilization of Functional Brain Networks After Stroke.

Stem cell treatment after stroke has demonstrated substantial outcome improvement. However, monitoring of stem cell fate is still challenging and not routinely performed, yet important to quantify the role of the implanted stem cells on lesion improvement; in several studies even mortality of the graft has been reported. Resting state functional magnetic resonance imaging (rs-fMRI) is a highly sensitive imaging modality to monitor the brain-wide functional network alterations of many brain diseases .

Functional networks are impaired by elevated tau-protein but reversible in a regulatable Alzheimer's disease mouse model.

Background: Aggregation of tau proteins is a distinct hallmark of tauopathies and has been a focus of research and clinical trials for Alzheimer's Disease. Recent reports have pointed towards a toxic effect of soluble or oligomeric tau in the spreading of tau pathology in Alzheimer's disease. Here we investigated the effects of expressing human tau repeat domain (tauRD) with pro- or anti-aggregant mutations in regulatable transgenic mouse models of Alzheimer's Disease on the functional neuronal networks and the structural connectivity strength.

Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain.

Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft However, an assessment of the long-term functional and structural improvement is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation.

Whole-brain 3D mapping of human neural transplant innervation.

While transplantation represents a key tool for assessing in vivo functionality of neural stem cells and their suitability for neural repair, little is known about the integration of grafted neurons into the host brain circuitry. Rabies virus-based retrograde tracing has developed into a powerful approach for visualizing synaptically connected neurons. Here, we combine this technique with light sheet fluorescence microscopy (LSFM) to visualize transplanted cells and connected host neurons in whole-mouse brain preparations.

The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats.

Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus ("prepulse") attenuates the motor response ("startle reaction") to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation.

MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia.

microRNA-124 (miR-124), the most abundant miRNA of the CNS, was recently shown to modulate the polarization of activated microglia and infiltrating macrophages towards the anti-inflammatory M2 phenotype and protect neurons in various ways after brain disease. In ischemic stroke, microglia and macrophages of a detrimental and persistent pro-inflammatory M1 phenotype have been shown to aggravate the secondary injury. Thus, shifting the polarization of microglia/macrophages into the beneficial, anti-inflammatory M2-like phenotype is considered neuroprotective after stroke onset.

Morphological maturation of the mouse brain: An in vivo MRI and histology investigation.

With the wide access to studies of selected gene expressions in transgenic animals, mice have become the dominant species as cerebral disease models. Many of these studies are performed on animals of not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain maturation requires at least three months in rats, there is a clear need to discern the corresponding minimal animal age to provide an "adult brain" in mice in order to avoid modulation of disease progression/therapy studies by ongoing developmental changes.

In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke.

Background And Purpose: In vivo imaging of inflammatory processes is a valuable tool in stroke research. We here investigated the combination of two imaging modalities in the chronic phase after cerebral ischemia: magnetic resonance imaging (MRI) using intravenously applied ultra small supraparamagnetic iron oxide particles (USPIO), and positron emission tomography (PET) with the tracer [(11)C]PK11195.

Methods: Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by the macrosphere model and monitored by MRI and PET for 28 or 56 days, followed by immunohistochemical endpoint analysis.

Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks.

Human neural stem cells (hNSCs) hold great promise for the treatment of neurological diseases. Considerable progress has been made to induce neural differentiation in the cell culture in vitro and upon transplantation in vivo [2] in order to explore restoration of damaged neuronal circuits. However, in vivo conventional strategies are limited to post mortem analysis.

Transcranial direct current stimulation promotes the mobility of engrafted NSCs in the rat brain.

Transcranial direct current stimulation (tDCS) is used in numerous clinical studies and considered an effective and versatile add-on therapy in neurorehabilitation. To date, however, the underlying neurobiological mechanisms remain elusive. In a rat model of tDCS, we recently observed a polarity-dependent accumulation of endogenous neural stem cells (NSCs) in the stimulated cortex.

Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats.

Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications.

Vascular changes after stroke in the rat: a longitudinal study using optimized magnetic resonance imaging.

During stroke, the reduction of blood flow leads to undersupply of oxygen and nutrients and, finally, to cell death, but also to upregulation of pro-angiogenic molecules and vascular remodeling. However, the temporal profile of vascular changes after stroke is still poorly understood. Here, we optimized steady-state contrast-enhanced magnetic resonance imaging (SSCE MRI) and followed the dynamic changes in vascular architecture for up to 4 weeks after transient middle cerebral artery occlusion (MCAO) in rats.