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  1. Article ; Online: Low oxygen in inspired air causes severe cerebrocortical hypoxia and cell death in the cerebral cortex of awake rats.

    Barakat, Rawan M / Turcani, Marian / Al-Khaledi, Ghanim / Kilarkaje, Narayana / Al-Sarraf, Hameed / Sayed, Zeinab / Redzic, Zoran

    Neuroscience letters

    2023  Volume 818, Page(s) 137515

    Abstract: Type 1 respiratory failure (T1RF) is associated with secondary acute brain injury (sABI). The underlying mechanisms of sABI could include injury to brain cells mediated either by hypoxia or by lung injury-triggered inflammation. To elucidate to what ... ...

    Abstract Type 1 respiratory failure (T1RF) is associated with secondary acute brain injury (sABI). The underlying mechanisms of sABI could include injury to brain cells mediated either by hypoxia or by lung injury-triggered inflammation. To elucidate to what extent T1RF causes hypoxia and a consequent hypoxic injury in the brain in the absence of lung injury, we exposed healthy, conscious Sprague-Dawley rats to 48 h long low partial pressure of O
    MeSH term(s) Rats ; Animals ; Oxygen/metabolism ; Lung Injury/metabolism ; Wakefulness ; Rats, Sprague-Dawley ; Oxygen Consumption/physiology ; Hypoxia/metabolism ; Cerebral Cortex/metabolism ; Cell Death ; Lactates
    Chemical Substances Oxygen (S88TT14065) ; Lactates
    Language English
    Publishing date 2023-10-20
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 194929-9
    ISSN 1872-7972 ; 0304-3940
    ISSN (online) 1872-7972
    ISSN 0304-3940
    DOI 10.1016/j.neulet.2023.137515
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  2. Article ; Online: Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences.

    Redzic, Zoran

    Fluids and barriers of the CNS

    2011  Volume 8, Issue 1, Page(s) 3

    Abstract: Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly ... ...

    Abstract Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells.
    Language English
    Publishing date 2011-01-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118 ; 2045-8118
    ISSN (online) 2045-8118
    ISSN 2045-8118
    DOI 10.1186/2045-8118-8-3
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  3. Article: Studies on the human choroid plexus in vitro.

    Redzic, Zoran B

    Fluids and barriers of the CNS

    2013  Volume 10, Issue 1, Page(s) 10

    Abstract: The role of human choroid plexus (CP) epithelium in the transport of solutes between the blood and the cerebrospinal fluid and/or in secretion processes may be studied by employing several experimental approaches. There are a number of in vitro ... ...

    Abstract The role of human choroid plexus (CP) epithelium in the transport of solutes between the blood and the cerebrospinal fluid and/or in secretion processes may be studied by employing several experimental approaches. There are a number of in vitro techniques for human CP epithelium (CPE) and all have limitations that do not exclude them a priori, but that should be carefully taken into consideration. Developmental and morphological studies have been largely performed on human choroid plexus samples of either embryonic or post-mortem origin. Functional uptake studies may be performed on pathologically unaltered CP samples obtained during surgical removal of choroid plexus tumors. This approach can be used to explore transport processes mainly across the apical side of the CPE, but cannot be used to study vectorial transport across the CPE. Also, these samples have limited viability. A monolayer of CPE in culture, grown on permeable supports, provides the best available tool to study transport processes or polarized secretion by the CP, but thus far only limited attempts to culture these cells have been published and they mainly include data from neoplastic CPE. A study that used a human papilloma-derived cell line in culture showed that it forms a monolayer with barrier properties, although the cells express pleomorphic and neoplastic features and lack contact inhibition. Other cell cultures express some CPE markers but do not develop tight junctions/barrier properties. This article reviews the main characteristics and limitations of available in vitro methods to study human CPE, which could help researchers choose an appropriate experimental approach for a particular study.
    Language English
    Publishing date 2013-02-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118
    ISSN 2045-8118
    DOI 10.1186/2045-8118-10-10
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  4. Article ; Online: Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers

    Redzic Zoran

    Fluids and Barriers of the CNS, Vol 8, Iss 1, p

    similarities and differences

    2011  Volume 3

    Abstract: Abstract Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly ...

    Abstract Abstract Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells.
    Keywords Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 612
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The Role of Activated Microglia and Resident Macrophages in the Neurovascular Unit during Cerebral Ischemia: Is the Jury Still Out?

    Barakat, Rawan / Redzic, Zoran

    Medical principles and practice : international journal of the Kuwait University, Health Science Centre

    2016  Volume 25 Suppl 1, Page(s) 3–14

    Abstract: Paracrine signaling in the neurovascular unit (NVU) is aimed to adjust the supply of oxygen and nutrients to metabolic demands of the brain in a feed-forward manner. Cerebral ischemia (CI) severely disrupts this homeostatic mechanism and also causes ... ...

    Abstract Paracrine signaling in the neurovascular unit (NVU) is aimed to adjust the supply of oxygen and nutrients to metabolic demands of the brain in a feed-forward manner. Cerebral ischemia (CI) severely disrupts this homeostatic mechanism and also causes activation of microglia and resident macrophages in the brain. Contradictory data exist on the time pattern of microglial activation and polarization during CI, on molecular mechanisms that trigger them and on effects of microglia-derived cytokines on brain cells. It appears that conditions that occur during transient ischemia or in the penumbra of focal ischemia in vivo or equivalent conditions in vitro trigger polarization of resting microglia/macrophages into the M2 phenotype, which mainly exerts anti-inflammatory and protective effects in the brain, while prolonged ischemia with abundant necrosis promotes microglial polarization into the M1 phenotype. During the later stages of recovery, microglia that polarized initially into the M2 phenotype can shift into the M1 phenotype. Thus, it appears that cells with both phenotypes are present in the affected area, but their relative amount changes in time and probably depends on the proximity to the ischemic core. It was assumed that cells with the M1 phenotype exert detrimental effects on neurons and contribute to the blood-brain barrier opening. Several M1 phenotype-specific cytokines exert protective effects on astrocytes, which could be important for reactive gliosis occurring after ischemia. Thus, whether or not suppression of microglial activity after CI is beneficial for neurological outcome still remains unclear and current evidence suggests that no simple answer could be given to this question.
    MeSH term(s) Brain Ischemia/metabolism ; Brain Ischemia/pathology ; Humans ; Macrophage Activation/physiology ; Macrophages/metabolism ; Microglia/metabolism ; Microglia/pathology
    Language English
    Publishing date 2016
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 645108-1
    ISSN 1423-0151 ; 1011-7571
    ISSN (online) 1423-0151
    ISSN 1011-7571
    DOI 10.1159/000435858
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    Zs.A 2486: Show issues Location:
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  6. Article: Differential cytokine expression by brain microglia/macrophages in primary culture after oxygen glucose deprivation and their protective effects on astrocytes during anoxia.

    Barakat, Rawan / Redzic, Zoran

    Fluids and barriers of the CNS

    2015  Volume 12, Page(s) 6

    Abstract: Background: Activation of microglia/macrophages following cerebral ischemia may be beneficial or detrimental for the survival of brain cells, an ambiguity in effects that has been explained by findings that ischemia can induce transformation of resting ... ...

    Abstract Background: Activation of microglia/macrophages following cerebral ischemia may be beneficial or detrimental for the survival of brain cells, an ambiguity in effects that has been explained by findings that ischemia can induce transformation of resting monocytes/macrophages into two different inflammation-related phenotypes, termed M1 and M2. The extent to which this differentiation depends on paracrine signaling from other brain cells is not clear. This study explored if oxygen glucose deprivation (OGD) can trigger expression of phenotype-specific markers in rat microglia/macrophages in primary culture, in absence/low abundance of other brain cells. Time pattern of these changes was assessed and compared to time-pattern that has been revealed in vivo previously. Effects of phenotype-specific cytokines on viability of astrocytes in primary culture during anoxia were also explored.
    Methods: Primary cultures of rat microglia/macrophages were exposed to 2h OGD and then incubated further under normal conditions; this was considered as a recovery period. Expression of mRNA for specific markers and secretion of phenotype-specific cytokines were explored at different time points by real time PCR and ELISA, respectively. Effects of cytokines that were secreted by microglia in primary culture after OGD on viability of astrocytes were determined.
    Results: Expression and secretion of M2 phenotype-specific markers and/or cytokines after OGD increased early after OGD and then decreased in the later stages of the recovery period. Expression and secretion of M1 phenotype-specific markers and cytokines did not show a common time pattern, but there was a tendency for an increase during the recovery period. All M1 phenotype-specific and two out of the three tested M2 phenotype-specific cytokines revealed protective effects on astrocytes during near-anoxia by a marked reduction of apoptosis.
    Conclusions: Time-pattern of expression/secretion of phenotype-specific markers suggested that polarization of the brain microglia/macrophages in vitro to M2 and M1 phenotypes were largely independent and likely dependent on signaling from other brain cells, respectively. Time-pattern of polarization to the M2 phenotype partially resembled time-pattern that has been seen in vivo. Effects of M1 phenotype-specific cytokines on primary culture of astrocytes were protective, thus largely opposite to effects that have been observed in vivo.
    Language English
    Publishing date 2015
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118
    ISSN 2045-8118
    DOI 10.1186/s12987-015-0002-1
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  7. Article ; Online: Studies on the human choroid plexus in vitro

    Redzic Zoran B

    Fluids and Barriers of the CNS, Vol 10, Iss 1, p

    2013  Volume 10

    Abstract: Abstract The role of human choroid plexus (CP) epithelium in the transport of solutes between the blood and the cerebrospinal fluid and/or in secretion processes may be studied by employing several experimental approaches. There are a number of in vitro ... ...

    Abstract Abstract The role of human choroid plexus (CP) epithelium in the transport of solutes between the blood and the cerebrospinal fluid and/or in secretion processes may be studied by employing several experimental approaches. There are a number of in vitro techniques for human CP epithelium (CPE) and all have limitations that do not exclude them a priori , but that should be carefully taken into consideration. Developmental and morphological studies have been largely performed on human choroid plexus samples of either embryonic or post-mortem origin. Functional uptake studies may be performed on pathologically unaltered CP samples obtained during surgical removal of choroid plexus tumors. This approach can be used to explore transport processes mainly across the apical side of the CPE, but cannot be used to study vectorial transport across the CPE. Also, these samples have limited viability. A monolayer of CPE in culture, grown on permeable supports, provides the best available tool to study transport processes or polarized secretion by the CP, but thus far only limited attempts to culture these cells have been published and they mainly include data from neoplastic CPE. A study that used a human papilloma-derived cell line in culture showed that it forms a monolayer with barrier properties, although the cells express pleomorphic and neoplastic features and lack contact inhibition. Other cell cultures express some CPE markers but do not develop tight junctions/barrier properties. This article reviews the main characteristics and limitations of available in vitro methods to study human CPE, which could help researchers choose an appropriate experimental approach for a particular study.
    Keywords Human choroid plexus ; Cerebrospinal fluid ; Blood-cerebrospinal fluid barrier ; Choroid plexus papilloma ; Choroid plexus carcinoma ; Primary culture ; Choroid plexus epithelium ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 500
    Language English
    Publishing date 2013-02-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Quantitative Determination of Cellular-and Neurite Motility Speed in Dense Cell Cultures.

    Henkel, Andreas W / Al-Abdullah, Lulwa A A D / Al-Qallaf, Mohammed S / Redzic, Zoran B

    Frontiers in neuroinformatics

    2019  Volume 13, Page(s) 15

    Abstract: Mobility quantification of single cells and cellular processes in dense cultures is a challenge, because single cell tracking is impossible. We developed a software for cell structure segmentation and implemented 2 algorithms to measure motility speed. ... ...

    Abstract Mobility quantification of single cells and cellular processes in dense cultures is a challenge, because single cell tracking is impossible. We developed a software for cell structure segmentation and implemented 2 algorithms to measure motility speed. Complex algorithms were tested to separate cells and cellular components, an important prerequisite for the acquisition of meaningful motility data. Plasma membrane segmentation was performed to measure membrane contraction dynamics and organelle trafficking. The discriminative performance and sensitivity of the algorithms were tested on different cell types and calibrated on computer-simulated cells to obtain absolute values for cellular velocity. Both motility algorithms had advantages in different experimental setups, depending on the complexity of the cellular movement. The correlation algorithm (COPRAMove) performed best under most tested conditions and appeared less sensitive to variable cell densities, brightness and focus changes than the differentiation algorithm (DiffMove). In summary, our software can be used successfully to analyze and quantify cellular and subcellular movements in dense cell cultures.
    Language English
    Publishing date 2019-03-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452979-5
    ISSN 1662-5196
    ISSN 1662-5196
    DOI 10.3389/fninf.2019.00015
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  9. Article ; Online: Effects of erythropoietin on astrocytes and brain endothelial cells in primary culture during anoxia depend on simultaneous signaling by other cytokines and on duration of anoxia.

    Al-Sarraf, Hameed / Malatiali, Slava / Al-Awadi, Mariam / Redzic, Zoran

    Neurochemistry international

    2017  Volume 113, Page(s) 34–45

    Abstract: Studies on animals revealed neuroprotective effects of exogenously applied erythropoietin (EPO) during cerebral ischemia/hypoxia. Yet, application of exogenous EPO in stroke patients often lead to haemorrhagic transformation. To clarify potential ... ...

    Abstract Studies on animals revealed neuroprotective effects of exogenously applied erythropoietin (EPO) during cerebral ischemia/hypoxia. Yet, application of exogenous EPO in stroke patients often lead to haemorrhagic transformation. To clarify potential mechanism of this adverse effect we explored effects of EPO on viabilities of astrocytes and brain endothelial cells (BECs) in primary culture during anoxia of various durations, in the presence or absence of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), which are cytokines that are also released from the neurovascular unit during hypoxia. Anoxia (2-48 h) exerted marginal effects on BECs' viability and significant reductions in viability of astrocytes. Astrocyte-conditioned medium did not exert effects and exerted detrimental effects on BECs during 2 h and 24 h anoxia, respectively. This was partially reversed by inhibition of Janus kinase (Jak)2/signal transducer and activator of transcription (STAT)5 activation. Addition of rat recombinant EPO (rrEPO) during 2 h-6h anoxia was protective for astrocytes, but had no effect on BECs. Addition of rrEPO significantly reduced viability of BECs and astrocytes after 48 h anoxia and after 24 h-48 h anoxia, respectively, which was attenuated by inhibition of Jak2/STAT5 activation. Simultaneous addition of rrEPO and VEGFA (1-165) caused marginal effects on BECs, but a highly significant protective effects on astrocytes during 24-48 h anoxia, which were attenuated by inhibition of Jak2/STAT5 activation. Simultaneous addition of EPO, VEGFA 1-165 and Ang1 exerted protective effects on BECs during 24 h-48 h anoxia, which were attenuated by addition of soluble Tie2 receptor. These data revealed that EPO could exert protective, but also injurious effects on BECs and astrocytes during anoxia, which depended on the duration of anoxia and on simultaneous signaling by VEGF and Ang1. If these injurious effects occur in stroke patients, they could enhance vascular damage and haemorrhagic transformation.
    MeSH term(s) Animals ; Astrocytes/drug effects ; Astrocytes/metabolism ; Brain/drug effects ; Brain/metabolism ; Cell Hypoxia/drug effects ; Cell Hypoxia/physiology ; Cell Survival/drug effects ; Cell Survival/physiology ; Cells, Cultured ; Cytokines/metabolism ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Erythropoietin/adverse effects ; Erythropoietin/pharmacology ; Female ; Male ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Time Factors
    Chemical Substances Cytokines ; Erythropoietin (11096-26-7)
    Language English
    Publishing date 2017-11-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 283190-9
    ISSN 1872-9754 ; 0197-0186
    ISSN (online) 1872-9754
    ISSN 0197-0186
    DOI 10.1016/j.neuint.2017.11.014
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    Zs.A 1610: Show issues Location:
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  10. Article: Viability and Contractility of Rat Brain Pericytes in Conditions That Mimic Stroke; an

    Heyba, Mohammed / Al-Abdullah, Lulwa / Henkel, Andreas W / Sayed, Zeinab / Malatiali, Slava A / Redzic, Zoran B

    Frontiers in neuroscience

    2019  Volume 13, Page(s) 1306

    Abstract: Reopening of the cerebral artery after occlusion often results in "no-reflow" that has been attributed to the death and contraction ( ...

    Abstract Reopening of the cerebral artery after occlusion often results in "no-reflow" that has been attributed to the death and contraction (
    Language English
    Publishing date 2019-12-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2019.01306
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