| 1. |
- Björefeldt, Andreas, 1982, et al.
(författare)
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Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies.
- 2018
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Ingår i: Frontiers in neural circuits. - : Frontiers Media SA. - 1662-5110. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) occupies the brain's ventricles and subarachnoid space and, together with the interstitial fluid (ISF), forms a continuous fluidic network that bathes all cells of the central nervous system (CNS). As such, the CSF is well positioned to actively distribute neuromodulators to neural circuitsin vivovia volume transmission. Recentin vitroexperimental work in brain slices and neuronal cultures has shown that human CSF indeed contains neuromodulators that strongly influence neuronal activity. Here we briefly summarize these new findings and discuss their potential relevance to neural circuits in health and disease.
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| 2. |
- Henningson, Måns, 1964, et al.
(författare)
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Analysis and Modeling of Subthreshold Neural Multi-Electrode Array Data by Statistical Field Theory
- 2017
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Ingår i: Frontiers in Computational Neuroscience. - : Frontiers Media SA. - 1662-5188. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Multi-electrode arrays (MEA) are increasingly used to investigate spontaneous neuronal network activity. The recorded signals comprise several distinct components: Apart from artefacts without biological significance, one can distinguish between spikes (action potentials) and subthreshold fluctuations (local fields potentials). Here we aim to develop a theoretical model that allows for a compact and robust characterization of subthreshold fluctuations in terms of a Gaussian statistical field theory in two spatial and one temporal dimension. What is usually referred to as the driving noise in the context of statistical physics is here interpreted as a representation of the neural activity. Spatial and temporal correlations of this activity give valuable information about the connectivity in the neural tissue. We apply our methods on a dataset obtained from MEA-measurements in an acute hippocampal brain slice from a rat. Our main finding is that the empirical correlation functions indeed obey the logarithmic behaviour that is a general feature of theoretical models of this kind. We also find a clear correlation between the activity and the occurence of spikes. Another important insight is the importance of correcly separating out certain artefacts from the data before proceeding with the analysis.
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| 3. |
- Illes, Sebastian
(författare)
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More than a drainage fluid: the role of CSF in signaling in the brain and other effects on brain tissue
- 2017
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Ingår i: Cerebrospinal Fluid in Neurologic Disorders. Handbook of Clinical Neurology. - : Elsevier. - 0072-9752. - 9780128042793 ; , s. 33-46
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Current progress in neuroscience demonstrates that the brain is not an isolated organ and is influenced by the systemic environment and extracerebral processes within the body. In view of this new concept, blood and cerebrospinal fluid (CSF) are important body fluids linking extracerebral and intracerebral processes. For decades, substantial evidence has been accumulated indicating that CSF modulates brain states and influences behavior as well as cognition. This chapter provides an overview of how CSF directly modulates the function of different types of brain cells, such as neurons, neural stem cells, and CSF-contacting cells. Alterations in CSF content occur in most pathologic central nervous system (CNS) conditions. In a classic view, the function of CSF is to drain waste products and detrimental factors derived from diseased brain parenchyma. This chapter presents examples for how intra- and extracerebral pathologic processes lead to alterations in the CSF content. Current knowledge about how pathologically altered CSF influences the functionality of brain cells will be presented. Thereby, it becomes evident that CSF has more than a drainage function and has a causal role for the etiology and pathogenesis of different CNS diseases. © 2017 Elsevier B.V.
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| 4. |
- Ishima, T., et al.
(författare)
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Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder
- 2021
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327. ; 290, s. 61-64
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Tidskriftsartikel (refereegranskat)abstract
- Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age-and sex-matched controls. Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. Limitations: Sample sizes are relatively low. Conclusions: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.
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| 5. |
- Izsak, Julia, et al.
(författare)
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Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.
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| 6. |
- Izsak, Julia, et al.
(författare)
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Human Cerebrospinal Fluid Promotes Neuronal Circuit Maturation of Human Induced Pluripotent Stem Cell-Derived 3D Neural Aggregates
- 2020
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 14:6, s. 1044-1059
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Tidskriftsartikel (refereegranskat)abstract
- Human induced pluripotent stem cell (hiPSC)-derived in vitro neural and organoid models resemble fetal, rather than adult brain properties, indicating that currently applied cultivation media and supplements are insufficient to achieve neural maturation beyond the fetal stage. In vivo, cerebrospinal fluid molecules are regulating the transition of the immature fetal human brain into a mature adult brain. By culturing hiPSC-3D neural aggregates in human cerebrospinal fluid (hCSF) obtained from healthy adult individuals, we demonstrate that hCSF rapidly triggers neurogenesis, gliogenesis, synapse formation, neurite outgrowth, suppresses proliferation of residing neural stem cells, and results in the formation of synchronously active neuronal circuits in vitro within 3 days. Thus, a physiologically relevant and adult brain-like milieu triggers maturation of hiPSC-3D neural aggregates into highly functional neuronal circuits in vitro. The approach presented here opens a new avenue to identify novel physiological factors for the improvement of hiPSC neural in vitro models.
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| 7. |
- Izsak, Julia, et al.
(författare)
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Robust generation of person-specific, synchronously active neuronal networks using purely isogenic human iPSC-3D neural aggregate cultures
- 2019
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal in vitro models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample. Moreover, we demonstrate the robust ability of those neurons to create a highly synchronously active neuronal network within 3 weeks in vitro, without additionally applied astrocytes. The fusion of MEA-technology with functional neuronal circuits solely obtained from one individual's cells represent isogenic person-specific human neuronal sensor chips that pave the way for specific personalized in vitro neuronal networks as well as neurological and neuropsychiatric disease modeling.
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| 8. |
- Izsak, Julia, et al.
(författare)
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TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Persistent neural stem cell (NSC) proliferation is, among others, a hallmark of immaturity in human induced pluripotent stem cell (hiPSC)-based neural models. TGF-β1 is known to regulate NSCs in vivo during embryonic development in rodents. Here we examined the role of TGF-β1 as a potential candidate to promote in vitro differentiation of hiPSCs-derived NSCs and maturation of neuronal progenies. We present that TGF-β1 is specifically present in early phases of human fetal brain development. We applied confocal imaging and electrophysiological assessment in hiPSC-NSC and 3D neural in vitro models and demonstrate that TGF-β1 is a signaling protein, which specifically suppresses proliferation, enhances neuronal and glial differentiation, without effecting neuronal maturation. Moreover, we demonstrate that TGF-β1 is equally efficient in enhancing neuronal differentiation of human NSCs as an artificial synthetic small molecule. The presented approach provides a proof-of-concept to replace artificial small molecules with more physiological signaling factors, which paves the way to improve the physiological relevance of human neural developmental in vitro models.
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| 9. |
- Perez-Alcazar, Marta, et al.
(författare)
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Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro
- 2016
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling.
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| 10. |
- Vizlin-Hodzic, Dzeneta, et al.
(författare)
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Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P = 2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P = 3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN, and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the CNS. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter, and cytoskeletal signalling occurs during early foetal brain development of BD I patients.
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