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| 2. |
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| 3. |
- Blackwell, Kim T., et al.
(författare)
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Molecular mechanisms underlying striatal synaptic plasticity : relevance chronic alcohol consumption and seeking
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 49:6, s. 768-783
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Tidskriftsartikel (refereegranskat)abstract
- The striatum, the input structure of the basal ganglia, is a major site learning and memory for goal-directed actions and habit formation. iny projection neurons of the striatum integrate cortical, thalamic, d nigral inputs to learn associations, with cortico-striatal synaptic asticity as a learning mechanism. Signaling molecules implicated in naptic plasticity are altered in alcohol withdrawal, which may ntribute to overly strong learning and increased alcohol seeking and nsumption. To understand how interactions among signaling molecules oduce synaptic plasticity, we implemented a mechanistic model of gnaling pathways activated by dopamine D1 receptors, acetylcholine ceptors, and glutamate. We use our novel, computationally efficient mulator, NeuroRD, to simulate stochastic interactions both within and tween dendritic spines. Dopamine release during theta burst and 20-Hz imulation was extrapolated from fast-scan cyclic voltammetry data llected in mouse striatal slices. Our results show that the combined tivity of several key plasticity molecules correctly predicts the currence of either LTP, LTD, or no plasticity for numerous perimental protocols. To investigate spatial interactions, we imulate two spines, either adjacent or separated on a 20-mu m ndritic segment. Our results show that molecules underlying LTP hibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a atially diffuse elevation. We also implement changes in NMDA ceptors, adenylyl cyclase, and G protein signaling that have been asured following chronic alcohol treatment. Simulations under these nditions suggest that the molecular changes can predict changes in naptic plasticity, thereby accounting for some aspects of alcohol use sorder.
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| 4. |
- Bolzoni, Francesco, et al.
(författare)
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Ephaptic interactions between myelinated nerve fibres of rodent peripheral nerves
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 50:7, s. 3101-3107
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Tidskriftsartikel (refereegranskat)abstract
- We report evidence that ephaptic interactions may occur between intact mammalian myelinated nerve fibres and not only between demyelinated or damaged mammalian nerve fibres or nerve cells as analysed in previous studies. The ephaptic interactions were investigated between nerve fibres traversing the lumbar dorsal roots and between bundles of fibres in the sciatic nerve in anaesthetized rats in vivo. The interactions were estimated by comparing the excitability of nerve fibres originating from one of the hindlimb nerves (peroneal or sural) under control conditions and when the stimulation of these fibres was combined with stimulation of another nerve (tibial). An increase in nerve volleys recorded from group I muscle afferents in the peroneal nerve and of the fastest skin afferents in the sural nerve was used as a measure of the increase in the excitability. The excitability of these fibres was increased during a fraction of a millisecond, coinciding with the period of passage of nerve impulses evoked by the conditioning stimulation of the tibial nerve. The degree of the increase was comparable to the increases in the excitability evoked by 1–2min lasting fibre polarization. Ephaptic interactions were found to be more potent and with longer lasting after-effects within the dorsal roots than within the sciatic nerve. We postulate that ephaptic interactions may result in the synchronization of information forwarded via neighbouring afferent nerve fibres prior to their entry into the spinal cord and thereby securing the propagation of nerve impulses across branching points within the spinal grey matter. © 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
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| 5. |
- Böhme, Rebecca, et al.
(författare)
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Reversal learning strategy in adolescence is associated with prefrontal cortex activation
- 2017
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Ingår i: European Journal of Neuroscience. - : WILEY-BLACKWELL. - 0953-816X .- 1460-9568. ; 45:1, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- Adolescence is a critical maturation period for human cognitive control and executive function. In this study, a large sample of adolescents (n=85) performed a reversal learning task during functional magnetic resonance imaging. We analyzed behavioral data using a reinforcement learning model to provide individually fitted parameters and imaging data with regard to reward prediction errors (PE). Following a model-based approach, we formed two groups depending on whether individuals tended to update expectations predominantly for the chosen stimulus or also for the unchosen one. These groups significantly differed in their problem behavior score obtained using the child behavior checklist (CBCL) and in a measure of their developmental stage. Imaging results showed that dorsolateral striatal areas covaried with PE. Participants who relied less on learning based on task structure showed less prefrontal activation compared with participants who relied more on task structure. An exploratory analysis revealed that PE-related activity was associated with pubertal development in prefrontal areas, insula and anterior cingulate. These findings support the hypothesis that the prefrontal cortex is implicated in mediating flexible goal-directed behavioral control.
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| 6. |
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| 7. |
- Chemnitz, Anette, et al.
(författare)
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Normalized activation in the somatosensory cortex 30 years following nerve repair in children- an fMRI study.
- 2015
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 42:4, s. 2022-2027
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Tidskriftsartikel (refereegranskat)abstract
- The clinical outcome following a peripheral nerve injury in the upper extremity is generally better in young children than in teenagers and in adults, but the mechanism behind this difference is unknown. In twenty-eight patients with a complete median nerve injury sustained at the ages of 1-13 years (n=13) and 14-20 years (n=15), the cortical activation during tactile finger stimulation of the injured and healthy hands was monitored at a median time since injury of 28 years using functional magnetic resonance imaging (fMRI) at 3 Tesla. The results from the fMRI were compared with the clinical outcome and electroneurography. The cortical activation pattern following sensory stimulation of the median nerve innervated fingers was dependent on the patient's age at injury. Those injured at a young age (1-13 years) had an activation pattern similar to that of healthy controls. Furthermore, they showed a clinical outcome significantly superior (p=0.001) to the outcome in subjects injured at a later age, however, electroneurographical parameters did not differ between the groups. In subjects injured at age 14-20 years, a more extended activation of the contralateral hemisphere was seen in general. Interestingly, these patients also displayed changes in the ipsilateral hemisphere where a reduced inhibition of somatosensory areas was seen. This loss of ipsilateral inhibition correlated to increasing age at injury as well as to poor recovery of sensory functions in the hand. In conclusion, cerebral changes in both brain hemispheres may explain differences in clinical outcome following a median nerve injury in childhood or adolescence. This article is protected by copyright. All rights reserved.
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| 8. |
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| 9. |
- Ekmark-Lewén, Sara, et al.
(författare)
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Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
- 2016
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 43:8, s. 1016-1033
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Tidskriftsartikel (refereegranskat)abstract
- Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1 has not been established in TAI. An IL-1-neutralizing or a control antibody was administered intraperitoneally at 30min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n=41) were compared with sham-injured controls (n=20) and untreated, naive mice (n=9). The anti-IL-1 antibody reached the target brain regions in adequate therapeutic concentrations (up to similar to 30g/brain tissue) at 24h post-injury in both cFPI (n=5) and sham-injured (n=3) mice, with lower concentrations at 72h post-injury (up to similar to 18g/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9days post-injury, and the Morris water maze (MWM) at 14-21days post-injury. Following TAI, the IL-1-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1 is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.
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| 10. |
- Gomez-Alvarez, Marcelo, et al.
(författare)
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Temporal information in tones, broadband noise, and natural vocalizations is conveyed by differential spiking responses in the superior paraolivary nucleus
- 2018
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Ingår i: European Journal of Neuroscience. - : Wiley-VCH Verlagsgesellschaft. - 0953-816X .- 1460-9568. ; 48:4, s. 2030-2049
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Tidskriftsartikel (refereegranskat)abstract
- Communication sounds across all mammals consist of multiple frequencies repeated in sequence. The onset and offset of vocalizations are potentially important cues for recognizing distinct units, such as phonemes and syllables, which are needed to perceive meaningful communication. The superior paraolivary nucleus (SPON) in the auditory brainstem has been implicated in the processing of rhythmic sounds. Here, we compared how best frequency tones (BFTs), broadband noise (BBN), and natural mouse calls elicit onset and offset spiking in the mouse SPON. The results demonstrate that onset spiking typically occurs in response to BBN, but not. BFT stimulation, while spiking at the sound offset occurs for both stimulus types. This effect of stimulus bandwidth on spiking is consistent with two of the established inputs to the SPON from the octopus cells (onset spiking) and medial nucleus of the trapezoid body (offset spiking). Natural mouse calls elicit two main spiking peaks. The first spiking peak, which is weak or absent with BFT stimulation, occurs most consistently during the call envelope, while the second spiking peak occurs at the call offset. This suggests that the combined spiking activity in the SPON elicited by vocalizations reflects the entire envelope, that is, the coarse amplitude waveform. Since the output from the SPON is purely inhibitory, it is speculated that, at the level of the inferior colliculus, the broadly tuned first peak may improve the signal-to-noise ratio of the subsequent, more call frequency-specific peak. Thus, the SPON may provide a dual inhibition mechanism for tracking phonetic boundaries in social-vocal communication.
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| 11. |
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| 12. |
- Hendy, Ashlee M, et al.
(författare)
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Investigating the effects of muscle contraction and conditioning stimulus intensity on short-interval intracortical inhibition.
- 2019
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Ingår i: European Journal of Neuroscience. - : John Wiley & Sons. - 0953-816X .- 1460-9568. ; 50:7, s. 3133-3140
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Tidskriftsartikel (refereegranskat)abstract
- A reduction in short-interval intracortical inhibition (SICI) has been shown to accompany acute or chronic resistance exercise; however, little is known about how SICI is modulated under different contraction intensities. Therefore, the purpose of this study was to assess the effect of muscle contraction and conditioning stimulus intensity on the modulation of SICI. Single- and paired-pulse transcranial magnetic stimulation was applied to the primary motor cortex (M1), and motor evoked potentials (MEPs) were recorded from the biceps brachii in 16 adults (10M/6F). A conditioning-test stimulus paradigm (3 ms inter-stimulus intervals) was delivered during 10%, 20%, 40% and 75% of maximal voluntary isometric contraction (MVIC). At each force level, conditioning stimulus intensities of 60%, 70% and 80% of active motor threshold (AMT) were tested. Single-pulse MEPs were expressed as a proportion of the maximal muscle compound action potential, while SICI was quantified as a ratio of the unconditioned MEP. MEP amplitude increased with force output, with the greatest increase at 75% of MVIC. A reduction in SICI was observed from 40% to 75% of MVIC, but not 10%-40% of MVIC. There was no significant interaction between conditioning stimulus intensity and force level. The conditioning stimulus intensity (60%, 70% or 80% of AMT) did not alter the modulation of SICI. SICI was reduced at 75% of MVIC compared with the lower force outputs, and the magnitude of SICI in individual participants at different force outputs was not related. The findings suggest that strong muscle contractions are accompanied by less inhibition, which may have implications for neuroplasticity in exercise interventions.
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| 13. |
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| 14. |
- Kilpatrick, L. A., et al.
(författare)
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Cross sex hormone treatment is linked with a reversal of cerebral patterns associated with gender dysphoria to the baseline of cisgender controls
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 50:8, s. 3269-3281
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Tidskriftsartikel (refereegranskat)abstract
- Transgender persons experience incongruence between their gender identity and birth-assigned sex. The resulting gender dysphoria (GD), is frequently treated with cross-sex hormones. However, very little is known about how this treatment affects the brain of individuals with GD, nor do we know the neurobiology of GD. We recently suggested that disconnection of fronto-parietal networks involved in own-body self-referential processing could be a plausible mechanism, and that the anatomical correlate could be a thickening of the mesial prefrontal and precuneus cortex, which is unrelated to sex. Here, we investigate how cross-sex hormone treatment affects cerebral tissue in persons with GD, and how potential changes are related to self-body perception. Longitudinal MRI measurements of cortical thickness (Cth) were carried out in 40 transgender men (TrM), 24 transgender women (TrW) and 19 controls. Cth increased in the mesial temporal and insular cortices with testosterone treatment in TrM, whereas anti-androgen and oestrogen treatment in TrW caused widespread cortical thinning. However, after correction for treatment-related changes in total grey and white matter volumes (increase with testosterone; decrease with anti-androgen and oestrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs. controls) – regions showing greater pre-treatment Cth than in controls. The own body – self congruence ratings increased with treatment, and correlated with a left parietal cortical thinning. These data confirm our hypothesis that GD may be associated with specific anatomical features in own-body/self-processing circuits that reverse to the pattern of cisgender controls after cross-sex hormone treatment. © 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
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| 15. |
- Koivisto, Mika, et al.
(författare)
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Subjective visual awareness emerges prior to P3
- 2016
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Ingår i: European Journal of Neuroscience. - : Wiley-Blackwell. - 0953-816X .- 1460-9568. ; 43:12, s. 1601-1611
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Tidskriftsartikel (refereegranskat)abstract
- Studies on the neural basis of visual awareness, the subjective experience of seeing, have found several potential neural corre- lates of visual awareness. Some of them may not directly correlate with awareness but with post-perceptual processes, such as reporting one’s awareness of the stimulus. We dissociated potential electrophysiological correlates of visual awareness from those occurring during response selection and thus co-occurring with post-perceptual processing. The participants performed two GO-NOGO conditions. In the aware-GO condition they responded with a key press when they were aware of the stimulus and withheld responding when they were unaware of it. In the unaware-GO condition they withheld responding when they were aware and responded when they were not aware of the stimulus. Thus, event-related potentials could be measured to aware and una- ware trials when responding was required and when not required. The results revealed that the N200 amplitude (180–280 ms) over the occipital and posterior temporal cortex was enhanced in aware trials as compared with trials without awareness. This effect (visual awareness negativity, VAN) did not depend on responding. The amplitude of P3 (350–450 ms) also was enhanced in aware trials as compared with unaware trials. In addition, the amplitudes in the P3 time window depended on responding: they were greater when awareness was mapped to GO-response than when not, suggesting that P3 reflects post-perceptual process- ing, that is, it occurs after awareness has emerged. These findings support theories of visual awareness that assume a relatively early onset of visual awareness before P3.
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| 16. |
- Landeck, Natalie, et al.
(författare)
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Toxic effects of human and rodent variants of alpha-synuclein in vivo
- 2017
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 45:4, s. 536-547
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions. To date, the precise mechanisms leading to aggregation of asyn in the brain is not well-understood. Previous studies in yeast, drosophila, and transgenic mice suggested that a non-A beta component depleted version of human asyn [h-asyn(D70-83)] or human beta-synuclein (h-bsyn), naturally lacking this centrally located hydrophobic region, are less prone to form aggregates in vitro and are expected to be less toxic compared to h-asyn in vivo, although not all experimental studies unequivocally support the latter view. To address this outstanding issue, we directly compared the neurotoxicity of human asyn against that of h-asyn(D70-83), h-bsyn as well as rat asyn using an adeno-associated viral vector to express these proteins in a dose-response study where the vector load was varied over two orders of magnitude. By quantifying the neurodegeneration of rat substantia nigra dopamine neurons here we show that h-asyn, h-bsyn, and h-asyn(D70-83) display comparable neurotoxicity across the vector doses tested. On the other hand, rat asyn and GFP control vectors displayed a different profile, where no detectable neurodegeneration was seen except at the highest vector titer. Thus, the two main conclusions of our study are that (i) deletion of the central hydrophobic region in h-asyn is not sufficient to alter its neurotoxic properties and (ii) expression of the widely used GFP control protein can cause measurable neurodegeneration at high titers.
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| 17. |
- Lassalle, A., et al.
(författare)
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Effect of visual stimuli of pain on empathy brain network in people with and without Autism Spectrum Disorder
- 2018
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 48:6, s. 2333-2342
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some-but not all-previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD.
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| 18. |
- Lindström, Johan, 1984, et al.
(författare)
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Cerebrospinal fluid viral load and biomarkers of neuronal and glial cells in Ramsay Hunt syndrome.
- 2016
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Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 44:11, s. 2944-2949
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Tidskriftsartikel (refereegranskat)abstract
- Reactivation of varicella zoster virus (VZV) can manifest with facial palsy diagnosed as Ramsay Hunt Syndrome (RHS) or Ramsay Hunt Syndrome zoster sine herpete (RHS-ZSH). These syndromes are associated with poor prognosis despite treatment with antivirals and corticosteroids. Concentrations of biomarkers such as neurofilament protein (NFL), S-100β protein and glial fibrillary acidic protein (GFAp) have previously been measured in cerebrospinal fluid (CSF) to assess neuronal damage and glial pathology. We employed immunochemical methods to measure concentrations of NFL, S-100β protein and GFAp in CSF from patients with RHS (n=15) and RHS-ZSH (n=13) diagnosed by detection of VZV DNA in the CSF by quantitative PCR, and compared with a control group (n=52). The biomarker concentrations were correlated with CSF viral load and outcome measured by House-Brackmann score. NFL and GFAp concentrations were increased compared with controls (P=0.008 and P=0.04), while S-100β levels were decreased. This pattern was more pronounced in patients with RHS compared to the patients with RHS-ZSH (NS and P=0.028). The amount of viral DNA in CSF correlated with increased GFAp (P=0.003) and NFL (P=0.006). No correlations were found between biomarker concentrations and patient outcome. Patients with facial palsy caused by VZV had biochemical signs of neuronal damage and astrogliosis. High amounts of viral DNA may be associated with the degree of damage on neuronal and astroglial cells. Prospective studies are warranted to elucidate the association of elevated biomarkers in the CSF and outcome assessed by more sensitive tests.
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| 19. |
- Makela, Johanna, et al.
(författare)
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Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mediates neuroprotection against excitotoxic brain injury in transgenic mice : role of mitochondria and X-linked inhibitor of apoptosis protein
- 2016
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Ingår i: European Journal of Neuroscience. - : WILEY. - 0953-816X .- 1460-9568. ; 43:5, s. 626-639
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Tidskriftsartikel (refereegranskat)abstract
- Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1 in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1 in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1 transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1 transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48h in wild-type mice but significantly less so in PGC-1 transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1 overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1 transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1 overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP.
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| 20. |
- Parmar, Malin, et al.
(författare)
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Cell-based therapy for Parkinson's disease : A journey through decades toward the light side of the Force
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 49:4, s. 463-471
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Tidskriftsartikel (refereegranskat)abstract
- This review describes the history, development, and evolution of cell-based replacement therapy for Parkinson's disease (PD), from the first pioneering trials with fetal ventral midbrain progenitors to future trials using stem cells as well as reprogrammed cells. In the spirit of Tom Isaacs, the review takes parallels to the storyline of Star Wars, including the temptations from the dark side and the continuous fight for the light side of the Force. It is subdivided into headings based on the original movies, spanning from A New Hope to the Last Jedi.
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| 21. |
- Patra, Kalicharan, et al.
(författare)
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A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.
- 2015
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 41:3, s. 316-327
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Tidskriftsartikel (refereegranskat)abstract
- The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.
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| 22. |
- Paul, Gesine, et al.
(författare)
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Trophic factors for Parkinson's disease : Where are we and where do we go from here?
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 49:4, s. 440-452
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Tidskriftsartikel (refereegranskat)abstract
- Perhaps the most important unmet clinical need in Parkinson's disease (PD) is the development of a therapy that can slow or halt disease progression. Extensive preclinical research has provided evidence for the neurorestorative properties of several growth factors, yet only a few have been evaluated in clinical studies. Attempts to achieve neuroprotection by addressing cell-autonomous mechanisms and targeting dopaminergic neurons have been disappointing. Four different trophic factors have so far entered clinical trials in PD: glial cell line-derived growth factor, its close structural and functional analog neurturin, platelet-derived growth factor and cerebral dopaminergic neurotrophic factor. This article reviews the pre-clinical evidence for the neuroprotective and neurorestorative actions of these growth factors and discusses limitations of preclinical models, which may hamper successful translation to the clinic. We summarize the previous and ongoing clinical trials using growth factors in PD and emphasize the caveats in clinical trial design that may prevent the further development and registration of potentially neuroprotective and neurorestorative treatments for individuals suffering from PD.
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| 23. |
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| 24. |
- Perry, Sharn, et al.
(författare)
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Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents I-h and I-SK
- 2015
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 41:7, s. 887-898
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Tidskriftsartikel (refereegranskat)abstract
- Renshaw cells in the spinal cord ventral horn regulate motoneuron output through recurrent inhibition. Renshaw cells can be identified in vitro using anatomical and cellular criteria; however, their functional role in locomotion remains poorly defined because of the difficulty of functionally isolating Renshaw cells from surrounding motor circuits. Here we aimed to investigate whether the cholinergic nicotinic receptor alpha2 (Chrna2) can be used to identify Renshaw cells (RCs2) in the mouse spinal cord. Immunohistochemistry and electrophysiological characterization of passive and active RCs2 properties confirmed that neurons genetically marked by the Chrna2-Cre mouse line together with a fluorescent reporter mouse line are Renshaw cells. Whole-cell patch-clamp recordings revealed that RCs2 constitute an electrophysiologically stereotyped population with a resting membrane potential of -50.5 +/- 0.4mV and an input resistance of 233.1 +/- 11M. We identified a ZD7288-sensitive hyperpolarization-activated cation current (I-h) in all RCs2, contributing to membrane repolarization but not to the resting membrane potential in neonatal mice. Additionally, we found RCs2 to express small calcium-activated potassium currents (I-SK) that, when blocked by apamin, resulted in a complete attenuation of the afterhyperpolarisation potential, increasing cellular firing frequency. We conclude that RCs2 can be genetically targeted through their selective Chrna2 expression and that they display currents known to modulate rebound excitation and firing frequency. The genetic identification of Renshaw cells and their electrophysiological profile is required for genetic and pharmacological manipulation as well as computational simulations with the aim to understand their functional role.
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| 25. |
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