| 1. |
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| 2. |
- Carlsson, Per-Inge, et al.
(författare)
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The influence of genetic variation in oxidative stress genes on human noise susceptibility
- 2005
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Ingår i: Hearing Research. - 0378-5955 .- 1878-5891. ; 202:1-2, s. 87-96
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Tidskriftsartikel (refereegranskat)abstract
- Noise induced hearing loss (NIHL) is a complex disease caused by an interaction between genetic and environmental factors. Damage in the cochlea as a result of noise exposure appears to be mediated by reactive oxygen species (ROS). To investigate whether genetic variation in the human protective antioxidant system is associated with high or low susceptibility to NIHL, genetic polymorphisms derived from genes involved in the oxidative stress response were analysed in the 10% most susceptible and 10% most resistant extremes of 1200 Swedish noise-exposed workers. The genetic polymorphisms included 2 deletion polymorphisms for the GSTM1 and GSTT1 gene, and 14 SNPs derived from the CAT, SOD, GPX, GSR and GSTP1 genes. No significant differences were found between susceptible and resistant groups, providing no support for a major role of genetic variation of antioxidant enzymes in the susceptibility to NIHL.
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| 3. |
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| 4. |
- Konings, Annelies, et al.
(författare)
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Association between variations in CAT and noise-induced hearing loss in two independent noise-exposed populations
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:15, s. 1872-1883
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is an important occupational hazard that results from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied quite extensively, little is known about the genetic factors. On the basis of multiple studies, it was proposed that oxidative stress plays an important role in the development of NIHL. Here, we investigated whether variations (single nucleotide polymorphisms; SNPs) in the catalase gene (CAT), one of the genes involved in oxidative stress, influence noise susceptibility. Audiometric data from 1261 Swedish and 4500 Polish noise-exposed labourers were analysed. DNA samples were collected from the 10% most susceptible and the 10% most resistant individuals. Twelve SNPs were selected and genotyped. Subsequently, the interaction between noise exposure and genotypes and their effect on NIHL were analysed using logistic regression. Significant interactions were observed between noise exposure levels and genotypes of two SNPs for the Swedish population and of five SNPs for the Polish population. Two of these SNPs were significant in both populations. The interaction between predictor haplotypes and tagSNP haplotypes and noise exposure levels and their effect on NIHL were also analysed, resulting in several significant associations. In conclusion, this study identified significant associations between catalase SNPs and haplotypes and susceptibility to development of NIHL. These results indicate that catalase is a NIHL susceptibility gene, but that the effect of CAT polymorphisms can only be detected when noise exposure levels are taken into account.
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| 5. |
- Konings, Annelies, et al.
(författare)
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Variations in HSP70 genes associated with noise-induced hearing loss in two independent populations
- 2009
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 17:3, s. 329-35
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is one of the most important occupational health hazards. Millions of people worldwide are exposed daily to harmful levels of noise. NIHL is a complex disease resulting from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied extensively, little is known about the genetic factors. Heat-shock proteins (HSPs) are induced after exposure to severe noise. When first induced by exposure to moderate sound levels, they can protect the ear from damage from excessive noise exposure. This protection is highly variable between individuals. An association of HSP70 genes with NIHL has been described by Yang et al (2006) in a Chinese sample set of noise-exposed workers. In this study, three polymorphisms (rs1043618, rs1061581 and rs2227956) in HSP70-1, HSP70-2 and HSP70-hom, respectively, were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed subjects and analyzed. One SNP, rs2227956 in HSP70-hom, resulted in a significant association with NIHL in both sample sets. In addition, rs1043618 and rs1061581 were significant in the Swedish sample set. Analysis of the haplotypes composed of the three SNPs revealed significant associations between NIHL and haplotype GAC in both sample sets and with haplotype CGT in the Swedish sample set. In conclusion, this study replicated the association of HSP70 genes with NIHL in a second and third independent noise-exposed sample set, hereby adding to the evidence that HSP70 genes may be NIHL susceptibility genes.
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| 6. |
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| 7. |
- Van Laer, Lut, et al.
(författare)
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The contribution of genes involved in potassium-recyclingin the inner ear to noise-induced hearing loss
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:8, s. 786-795
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is one of the most important occupational diseases and, after presbyacusis, the most frequent cause of hearing loss. NIHL is a complex disease caused by an interaction between environmental and genetic factors. The various environmental factors involved in NIHL have been relatively extensively studied. On the other hand, little research has been performed on the genetic factors responsible for NIHL. To test whether the variation in genes involved in coupling of cells and potassium recycling in the inner ear might partly explain the variability in susceptibility to noise, we performed a case-control association study using 35 SNPs selected in 10 candidate genes on a total of 218 samples selected from a population of 1,261 Swedish male noise,exposed workers. We have obtained significant differences between susceptible and resistant individuals for the allele, genotype, and haplotype frequencies for three SNPs of the KCNEI gene, and for the allele frequencies for one SNP of KCNQ1 and one SNP of KCNQ4. Patch-clamp experiments in high K+-concentrations using a Chinese hamster ovary (CHO) cell model were performed to investigate the possibility that the KCNE1-p.85N variant (NT_011512.10:g.21483550G > A; NP_00210.2:p.Asp85Asn) was causative for high noise susceptibility. The normalized current density generated by KCNQ1/KCNE1-p.85N channels, thus containing the susceptibility variant, differed significantly from that from wild-type channels. Furthermore, the midpoint potential of KCNQ1/KCNE1-p.85N channels (i.e., the voltage at which 50% of the channels are open) differed from that of wild-type channels. Further genetic and physiological studies will be necessary to confirm these findings.
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| 8. |
- Ven, Arne, et al.
(författare)
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Phosphorus addition increased carbon partitioning to autotrophic respiration but not to biomass production in an experiment with Zea mays
- 2020
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Ingår i: Plant, Cell and Environment. - : Wiley. - 0140-7791 .- 1365-3040. ; 43:9, s. 2054-2065
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Tidskriftsartikel (refereegranskat)abstract
- Plant carbon (C) partitioning—the relative use of photosynthates for biomass production, respiration, and other plant functions—is a key but poorly understood ecosystem process. In an experiment with Zea mays, with or without arbuscular mycorrhizal fungi (AMF), we investigated the effect of phosphorus (P) fertilization and AMF on plant C partitioning. Based on earlier studies, we expected C partitioning to biomass production (i.e., biomass production efficiency; BPE) to increase with increasing P addition due to reduced C partitioning to AMF. However, although plant growth was clearly stimulated by P addition, BPE did not increase. Instead, C partitioning to autotrophic respiration increased. These results contrasted with our expectations and with a previous experiment in the same set-up where P addition increased BPE while no effect on autotropic respiration was found. The comparison of both experiments suggests a key role for AMF in explaining these contrasts. Whereas in the previous experiment substantial C partitioning to AMF reduced BPE under low P, in the current experiment, C partitioning to AMF was too low to directly influence BPE. Our results illustrate the complex influence of nutrient availability and mycorrhizal symbiosis on plant C partitioning.
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| 9. |
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| 10. |
- Bulovaite, Edita, et al.
(författare)
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A brain atlas of synapse protein lifetime across the mouse lifespan
- 2022
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 110:24, s. 4057-
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
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| 11. |
- Carlsson, Per Inge, et al.
(författare)
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The influence of genetic factors, smoking and cardiovascular disease on human noise susceptibility
- 2007
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Ingår i: Audiological Medicine. - : Informa UK Limited. - 1651-386X .- 1651-3835. ; 5:2, s. 82-91
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Tidskriftsartikel (refereegranskat)abstract
- Noise has a metabolic and mechanical effect on the inner ear and may therefore interfere with gap junction channels, thus disrupting the interaction between cells in the cochlea. Studies have shown that carriers of connexin mutations in genes involved in HI may have some disturbance in auditory function and may be more susceptible to damage caused by, e.g. noises. Furthermore, hair cell damage in the cochlea as a result of noise exposure can also be mediated by reactive oxygen species. Smoking in combination with elevated diastolic blood pressure and presence of the Raynaud's disease (white finger disease) seems to aggravate noise induced hearing loss (NIHL). In the present study we investigated whether interaction between connexin mutations (C26 and C30) alone, or in combination with genetic variability in the cochlear antioxidant system (GSTM1 deletion, GSTT1 deletion), could explain differences in human noise susceptibility. Furthermore, smoking habits and cardiovascular factors (hypertension, heart disease and white finger diseases) were correlated with noise susceptibility and interactions between genetic factors. Smoking and cardiovascular factors were analysed and correlated with the differences in noise susceptibility found in a Swedish noise-exposed population. The results revealed that smoking alone seems to increase noise susceptibility, and that null-genotypes for the GSTM1 gene in the protective antioxidant system, who smoke/have ever smoked had an additional risk for NIHL compared to those who do not smoke/have never smoked.
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| 12. |
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| 13. |
- Cervenka, Simon, et al.
(författare)
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PET Studies of D2-Receptor Binding in Striatal and Extrastriatal Brain Regions : Biochemical Support In Vivo for Separate Dopaminergic Systems in Humans
- 2010
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 64:6, s. 478-485
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Tidskriftsartikel (refereegranskat)abstract
- Most molecular imaging studies of the dopamine (DA) system performed to date have focused on the striatum, a region receiving dense dopaminergic innervation. In clinical research on the DA D2-receptor, striatal binding has often been regarded as an index of global DA function, based on the underlying assumption of common regulatory mechanisms for receptor expression across brain regions. Recent data has challenged this view, suggesting differences in genetic regulation between striatal and extrastriatal brain regions. The relationship between binding levels in brain regions has, however, not been directly examined in the same sample. In this study, we searched for interregional correlations between DA D2-receptor availability as determined with Positron Emission Tomography in 16 control subjects. The radioligands [C-11]raclopride and [C-11]FLB 457 were used for measurements of D2-receptor binding in striatal and extrastriatal regions, respectively. No correlation was observed between D2-receptor availability in striatum and any of the extrastriatal regions, as assessed using both region of interest- and voxel-based analyses. Instead, the pattern of correlations was consistent with the model of separate dopaminergic systems as has been originally observed in rodents. These preliminary results encourage approaches searching for individual patterns of receptor binding across the whole brain volume in clinical studies on the dopamine system.
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| 14. |
- Cizeron, Mélissa, et al.
(författare)
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A brain-wide atlas of synapses across the mouse lifespan
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6501, s. 270-275
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Tidskriftsartikel (refereegranskat)abstract
- Synapses connect neurons together to form the circuits of the brain, and their molecular composition controls innate and learned behavior. We analyzed the molecular and morphological diversity of 5 billion excitatory synapses at single-synapse resolution across the mouse brain from birth to old age. A continuum of changes alters synapse composition in all brain regions across the life span. Expansion in synapse diversity produces differentiation of brain regions until early adulthood, and compositional changes cause dedifferentiation in old age. The spatiotemporal synaptome architecture of the brain potentially accounts for life-span transitions in intellectual ability, memory, and susceptibility to behavioral disorders.
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| 15. |
- Dickson, C. T., et al.
(författare)
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Properties and role of I-h in the pacing of subthreshold oscillations in entorhinal cortex layer II neurons
- 2000
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 83:5, s. 2562-2579
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Forskningsöversikt (refereegranskat)abstract
- Various subsets of brain neurons express a hyperpolarization-activated inward current (I-h) that has been shown to be instrumental in pacing oscillatory activity at both a single-cell and a network level. A characteristic feature of the stellate cells (SCs) of entorhinal cortex (EC) layer II, those neurons giving rise to the main component of the perforant path input to the hippocampal formation, is their ability to generate persistent, Na+-dependent rhythmic subthreshold membrane potential oscillations, which are thought to be instrumental in implementing theta rhythmicity in the entorhinal-hippocampal network. The SCs also display a robust time-dependent inward rectification in the hyperpolarizing direction that may contribute to the generation of these oscillations. We performed whole cell recordings of SCs in in vitro slices to investigate the specific biophysical and pharmacological properties of the current underlying this inward rectification and to clarify its potential role in the genesis of the subthreshold oscillations. In voltage-clamp conditions, hyperpolarizing voltage steps evoked a slow, noninactivating inward current, which also deactivated slowly on depolarization. This current was identified as I-h because it was resistant to extracellular Ba2+, sensitive to Cs+, completely and selectively abolished by ZD7288, and carried by both Na+ and K+ ions. I-h in the SCs had an activation threshold and reversal potential at approximately -45 and -20 mV, respectively. Its half-activation voltage was -77 mV. Importantly, bath perfusion with ZD7288, but not Ba2+ gradually and completely abolished the subthreshold oscillations, thus directly implicating I-h in their generation. Using experimentally derived biophysical parameters for I-h and the low-threshold persistent Na+ current (I-NaP) present in the SCs, a simplified model of these neurons was constructed and their subthreshold electroresponsiveness simulated. This indicated that the interplay between I-NaP and I-h can sustain persistent subthreshold oscillations in SCs. I-NaP and I-h operate in a push-pull fashion where the delay in the activation/deactivation of I-h gives rise to the oscillatory process.
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| 16. |
- Egorov, A. V., et al.
(författare)
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Graded persistent activity in entorhinal cortex neurons
- 2002
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 420:6912, s. 173-178
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Tidskriftsartikel (refereegranskat)abstract
- Working memory represents the ability of the brain to hold externally or internally driven information for relatively short periods of time(1,2). Persistent neuronal activity is the elementary process underlying working memory but its cellular basis remains unknown. The most widely accepted hypothesis is that persistent activity is based on synaptic reverberations in recurrent circuits. The entorhinal cortex in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operations are essential(2). Here we show that individual neurons from layer V of the entorhinal cortex-which link the hippocampus to extensive cortical regions(3)-respond to consecutive stimuli with graded changes in firing frequency that remain stable after each stimulus presentation. In addition, the sustained levels of firing frequency can be either increased or decreased in an input-specific manner. This firing behaviour displays robustness to distractors; it is linked to cholinergic muscarinic receptor activation, and relies on activity-dependent changes of a Ca2+-sensitive cationic current. Such an intrinsic neuronal ability to generate graded persistent activity constitutes an elementary mechanism for working memory.
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| 17. |
- Ekeberg, Örjan, et al.
(författare)
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Computational Brain Science at CST, CSC, KTH
- 2016
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mission and Vision - Computational Brain Science Lab at CST, CSC, KTHThe scientific mission of the Computational Brain Science Lab at CSC is to be at the forefront of mathematical modelling, quantitative analysis and mechanistic understanding of brain function. We perform research on (i) computational modelling of biological brain function and on (ii) developing theory, algorithms and software for building computer systems that can perform brain-like functions. Our research answers scientific questions and develops methods in these fields. We integrate results from our science-driven brain research into our work on brain-like algorithms and likewise use theoretical results about artificial brain-like functions as hypotheses for biological brain research.Our research on biological brain function includes sensory perception (vision, hearing, olfaction, pain), cognition (action selection, memory, learning) and motor control at different levels of biological detail (molecular, cellular, network) and mathematical/functional description. Methods development for investigating biological brain function and its dynamics as well as dysfunction comprises biomechanical simulation engines for locomotion and voice, machine learning methods for analysing functional brain images, craniofacial morphology and neuronal multi-scale simulations. Projects are conducted in close collaborations with Karolinska Institutet and Karolinska Hospital in Sweden as well as other laboratories in Europe, U.S., Japan and India.Our research on brain-like computing concerns methods development for perceptual systems that extract information from sensory signals (images, video and audio), analysis of functional brain images and EEG data, learning for autonomous agents as well as development of computational architectures (both software and hardware) for neural information processing. Our brain-inspired approach to computing also applies more generically to other computer science problems such as pattern recognition, data analysis and intelligent systems. Recent industrial collaborations include analysis of patient brain data with MentisCura and the startup company 13 Lab bought by Facebook.Our long term vision is to contribute to (i) deeper understanding of the computational mechanisms underlying biological brain function and (ii) better theories, methods and algorithms for perceptual and intelligent systems that perform artificial brain-like functions by (iii) performing interdisciplinary and cross-fertilizing research on both biological and artificial brain-like functions. On one hand, biological brains provide existence proofs for guiding our research on artificial perceptual and intelligent systems. On the other hand, applying Richard Feynman’s famous statement ”What I cannot create I do not understand” to brain science implies that we can only claim to fully understand the computational mechanisms underlying biological brain function if we can build and implement corresponding computational mechanisms on a computerized system that performs similar brain-like functions.
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| 18. |
- Eriksson, David, et al.
(författare)
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Effects of short-term synaptic plasticity in a local microcircuit on cell firing
- 2003
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 52-54, s. 7-12
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Tidskriftsartikel (refereegranskat)abstract
- Effects of short-term synaptic plasticity on cell firing properties in a microcircuit formed by a reciprocally connected pyramidal cell and FSN interneuron in layer 2/3 of neocortex were analyzed in a biophysical model. Induction of synaptic depression by backpropagating dendritic action potentials was replicated, as well as the resulting time dependent depression of IPSP amplitudes. Results indicate that the effect of the depression becomes significant above 30 Hz input frequency. The magnitude of the effect depends on the time constant of the dendritic calcium regulating the depression. The frequency range depends on the time constant of the IPSP.
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| 19. |
- Fransén, Erik A.
(författare)
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Mechanisms of Graded Persistent Activity : Implications for Epilepsy
- 2008
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Ingår i: Computational Neuroscience in Epilepsy. - : Elsevier. - 9780123736499 ; , s. 215-231
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- One major topic in epilepsy is factors contributing to neuronal excitability. This chapter considers depolarizing sources from cationic currents. These ion channels of the TRP-type are permeable to Na, K and sometimes Ca, and show a slow time dynamics. They can therefore provide the dendrites with integrative properties over seconds and perhaps even minutes. This makes them powerful as integrators of synaptic input. Further, their activation depends to a large degree on intracellular calcium. They may therefore during seizures become strongly activated and thereby further contribute to epileptogenic activity directly by depolarization and indirectly by their calcium permeability. Cationic currents are widely distributed throughout the nervous system, including cortical, cerebellar and subcortical neurons. This chapter describes the work in entorhinal cortex and, specifically, the plateau firing characteristics found in pyramidal cells of layer V. These cells show persistent action potential firing at plateaus, which may last over ten minutes. Intriguingly, these plateaus are graded in that input, synaptic or by current injection, can shift them up and down in frequency. After the original finding, graded plateaus have been found also in perirhinal cortex and amygdala. Functionally, cationic neuronal integrator capacity has been shown to be involved in sensory-motor integration. Finally, anticonvulsants like lamotrigine and phenytoin have been found to reduce depolarizations involving cationic currents. Cation currents may therefore be targets in treatments of epilepsy.
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| 20. |
- Fransén, Erik, 1962-, et al.
(författare)
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A model of cortical associative memory based on a horizontal network of connected columns
- 1998
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Ingår i: Network. - BRISTOL : IOP PUBLISHING. - 0954-898X .- 1361-6536. ; 9:2, s. 235-264
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Tidskriftsartikel (refereegranskat)abstract
- An attractor network model of cortical associative memory functions has been constructed and simulated. By replacing the single cell as the functional unit by multiple cells in cortical columns connected by long-range fibers, the model is improved in terms of correspondence with cortical connectivity. The connectivity is improved, since the original dense and symmetric connectivity of a standard recurrent network becomes sparse and asymmetric at the cell-to-cell level. Our simulations show that this kind of network, with model neurons of the Hodgkin-Huxley type arranged in columns, can operate as an associative memory in much the same way as previous models having simpler connectivity. The network shows attractor-like behaviour and performs the standard assembly operations despite differences in the dynamics introduced by the more detailed cell model and network structure. Furthermore, the model has become sufficiently detailed to allow evaluation against electrophysiological and anatomical observations. For instance, cell activities comply with experimental findings and reaction times are within biological and psychological ranges. By introducing a scaling model we demonstrate that a network approaching experimentally reported neuron numbers and synaptic distributions also could work like the model studied here.
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| 21. |
- Fransén, Erik, 1962-
(författare)
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A synapse which can switch from inhibitory to excitatory and back
- 2005
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 65, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- Co-release of transmitters has recently been observed at synapse terminals and can even be a combination such as glutamate and GABA. A second recent experimental finding is a short-term synaptic plasticity, which depends on postsynaptic depolarization releasing a dendritic transmitter, which affects presynaptic release probability. In this work we are investigating the functional consequences for a synapse if it had both co-release and conditioning depression. If initially the GABA component is larger than the glutamate component, the synapse has an inhibitory net effect. However, if the postsynaptic cell is conditioned, the GABA component will be suppressed yielding an excitatory synapse.
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| 22. |
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| 23. |
- Fransén, Erik, 1962-
(författare)
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Coexistence of synchronized oscillatory and desynchronized rate activity in cortical networks
- 2003
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; apr-52, s. 763-769
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Tidskriftsartikel (refereegranskat)abstract
- The basis of MRI and PET experiments is the finding that neuronal cell firing levels are modulated in a task dependent manner. Results from EEG and MEG experiments on the other hand point to the importance of synchrony, e.g. the peak frequency may depend on the difficulty of the task. In most models only one of these activity modes of firing is desirable or possible to produce. In this work we show how a cortical microcircuit can produce either synchronized or desynchronized firing, and how this solves problems of present day rate and synchronization models.
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| 24. |
- Fransén, Erik, 1962-, et al.
(författare)
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Computational modeling of activity dependent velocity changes in peripheral C-fibers
- 2011
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Konferensbidrag (refereegranskat)abstract
- Initiation and propagation of action potentials along unmyelinated C-fibers are the first steps of the pain pathway. Propagation velocity and its fiber class-specific activity-dependent slowing (ADS) is intimately linked to fibre excitability. In chronic pain patients, ADS alterations have been suggested to reflect increased excitability, possibly underlying clinical pain. Due to their small diameter, peripheral axons of nociceptors in patients are not accessible for intraaxonal recordings of their ion channel properties. We have therefore constructed a model of a C-fibre to study the relationship between ion channel composition and velocity changes as well as excitability. Ion channels are modeled from data of DRG somata using a Hodgkin-Huxley formalism (Na currents: TTX-sensitive, Nav1.8, Nav1.9, K currents: Kdr, A-type, Kv7.3, non-specific cationic: HCN). Moreover, ion pumps (Na/K-ATPase) and concentrations of intra and extraaxonal sodium and potassium are also included. The geometry and temperature of the fibre represents a section of the superficial branch and the deeper parent and is represented by a multicompartmental structure where each compartment contains passive as well as ion channel and pump elements. Using parameter estimation techniques, we optimized ion channel and pump expression pattern such that basic electrophysiological characteristics of the action potential and its velocity matched the experimental data. Moreover, we have also replicated activity dependent slowing. In ongoing work, we extend optimization to also include recovery cycles. The model will be used to study hypothesis of the relationship between individual ion channel subtypes and axonal excitability related to pain, generating independent information on impact of selective neuronal targets.
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| 25. |
- Fransén, Erik, 1962-, et al.
(författare)
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Differences in action potential propagation in mechanosensitive and insensitive C-nociceptors - a modeling approach
- 2012
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Konferensbidrag (refereegranskat)abstract
- C-fibers, unmyelinated afferent axons, convey information from the periphery of the nervous system to the spinal cord. They transmit signals originating from noxious stimulation evoking the sensations of itch and pain in the central nervous system. Different classes of C-fibers are characterized by functional, morphological and biochemical characteristics. In pain studies, a classification into mechano-insensitive (CMi) and mechano responsive fibers (CM) has proven useful as changes in proportions and response characteristics of these fibers have been observed in neuropathy patients (Weidner et al. 1999, 2000; Orstavik 2003, 2010). In this study, using computational modeling of a C-fiber, we have studied the possible contribution of different ion channel subtypes (Na-TTXs, Nav1.8, Nav1.9, Kdr, KA, KM, K(Na), h) as well as the Na/K-ATPase pump to conductive properties of C-fibers. In particular we investigated mechanisms that could generate the fiber-specific differences between CM and CMi fibers with regard to activity dependent slowing (ADS) and recovery cycles (RC). In our study we represent the axon by three cylindrical sections, one representing the peripheral thin end (branch, 2.5 cm), one the central part (parent, 10 cm) and a conical section between these (0.5 cm). In total 730 compartments are used. Temperature is set to 32 degrees C in branch and 37 degrees in parent sections. We represent variable ion concentrations of Na and K intra axonally, periaxonally and extracellularly, from which reversal potentials are calculated. We use ion channel models based on Hodgkin Huxley formalism. An ion pump (Na/K-ATPase) is included. We find that TTX-sensitive Na and Nav1.8 have the strongest influence on action potential conduction velocity as is expected since these are the major components of the rising phase of the action potential. Preliminary observations indicate that a small subset of Na and K currents play a key role in determining differences in activity dependent velocity changes (ADS) in the two fiber classes. We plan to also study contributions from morphological characteristics (superficial branch lengths) to activity dependent differences between the fiber classes (Schmidt et al. 2002). We further intend to investigate candidate ion channels which could play a role in changing the functional characteristics of a CMi fiber to that of a CM fiber. Our studies may provide insights into ionic changes underlying changes in the excitability of C-fibers associated with pain.
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| 26. |
- Fransén, Erik, 1962-, et al.
(författare)
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Entorhinal neuronal activity during delayed matching tasks may depend upon muscarinic-induced non-specific cation current I(CANM)
- 2001
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Ingår i: Neurocomputing. - 0925-2312 .- 1872-8286. ; 38, s. 601-606
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Tidskriftsartikel (refereegranskat)abstract
- Biophysical compartmental models of stellate, pyramidal-like and interneurons in layer II of the rat entorhinal cortex were used to explore cellular and synaptic components involved in neuronal responses to stimuli in a delayed match to sample (DMS) task. Simulations demonstrate that the muscarinic receptor-induced non-specific cation current, I(CANM), could contribute to these phenomena. Facilitation of I(CANM) by calcium influx during spikes induced by the sample stimulus can cause enhanced responses for matches as well as delay activity. In a network, lateral inhibition can produce match suppression, and in conjunction with stimulus selective/non-selective cells produce non-match enhancement and suppression.
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| 27. |
- Fransén, Erik, et al.
(författare)
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Evaluation of model scalability in parallel neural simulators
- 2005
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Konferensbidrag (refereegranskat)abstract
- A long standing belief in neuroscience has been that the brain and specifically the neocortex obtains its computational power by massive parallelism. Albeit conceptually appealing, this notion that effective processing requires large networks has not been possible to test in detailed simulations. In one project, we intend to study the generation of theta activity in the entorhinal-hippocampal system. Several simulation studies indicate that frequency and synchronization of the oscillation generated may depend on density of connectivity and/or geometry of connections. In a second project, we are studying how a model of early visual processing scales towards realistic sizes. To effectively evaluate the model, it must be scaled up to sizes where processing demands from the input given are sufficiently high, and where network size is made sufficiently large to process this information.We have in preliminary studies tested two parallel simulators. One is a version of pGENESIS supporting MPI from University of Sunderland, UK. The other is Split, a software produced in our own laboratory. Both have been tested on an Itanium2 cluster. Tests include variable number of processors and scaling number of neurons/compartments or number of synapses. In these simulations, average spike frequency in the network is also varied. The aim is to identify main bottle-necks. For instance, we foresee the need to parallelize the construction/layout of synapses.
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| 28. |
- Fransén, Erik, 1962-
(författare)
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Functional role of Entorhinal cortex in working memory and information processing of the medial temporal lobe
- 2004
-
Ingår i: 2004 IEEE INTERNATIONAL JOINT CONFERENCE ON NEURAL NETWORKS, VOLS 1-4, PROCEEDINGS. ; , s. 621-624
-
Konferensbidrag (refereegranskat)abstract
- Our learning and memory system has the challenge to work in a world where items to learn are dispersed in space and time. From the information extracted by the perceptual systems, the learning system must select and combine information. Both these operations may require a temporary storage where significance and correlations may be assessed. This work builds on the common hypothesis that hippocampus and subicular, entorhinal and parahippocampal/postrhinal areas are essential for these functions. We bring up two examples of models, one modeling in vivo and in vitro data from entorhinal cortex layer II of delay match-to-sample working memory experiments, and one modeling slice data from layer V showing cellular "integrator-like" intrinsically generated stable graded levels of spiking activity. In both cases we discuss how cationic currents might be involved and relate their kinetics and pharmacology to behavioral and cellular experimental results.
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| 29. |
- Fransén, Erik, 1962-
(författare)
-
Functional role of entorhinal cortex in working memory processing
- 2005
-
Ingår i: Neural Networks. - : Elsevier BV. - 0893-6080 .- 1879-2782. ; 18:9, s. 1141-1149
-
Tidskriftsartikel (refereegranskat)abstract
- Our learning and memory system has the challenge to work in a world where items to learn are dispersed in space and time. From the information extracted by the perceptual systems, the learning system must select and combine information. Both these operations may require a temporary storage where significance and correlations could be assessed. This work builds on the common hypothesis that hippocampus and subicular, entorhinal and parahippocampal/postrhinal areas are essential for the above-mentioned functions. We bring up two examples of models: the first one is modeling of in vivo and in vitro data from entorhinal cortex layer 11 of delayed match-to-sample working memory experiments, the second one studying mechanisms in theta rhythmicity in EC. In both cases, we discuss how cationic currents might be involved and relate their kinetics and pharmacology to behavioral and cellular experimental results.
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| 30. |
- Fransén, Erik
(författare)
-
Ionic Mechanisms in Peripheral Pain
- 2014
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Ingår i: Computational Neuroscience. - : Elsevier. ; , s. 23-51
-
Bokkapitel (refereegranskat)abstract
- Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs.
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| 31. |
- Fransén, Erik, 1962-, et al.
(författare)
-
Ionic mechanisms in the generation of subthreshold oscillations and action potential clustering in entorhinal layer II stellate neurons
- 2004
-
Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 14:3, s. 368-384
-
Tidskriftsartikel (refereegranskat)abstract
- A multi compartmental biophysical model of entorhinal cortex layer II stellate cells was developed to analyze the ionic basis of physiological properties, such as subthreshold membrane potential oscillations, action potential clustering, and the medium afterhyperpolarization. In particular, the simulation illustrates the interaction of the persistent sodium current (I-NaP) and the hyperpolarization activated inward current (I-h) in the generation of subthreshold membrane potential oscillations. The potential role of I-h in contributing to the medium hyperpolarization (mAHP) and rebound spiking was studied. The role of I-h and the slow calcium-activated potassium current I-K(AHP) in action potential clustering was also studied. Representations of I-h and I-NaP were developed with parameters based on voltage-clamp data from whole-cell patch and single channel recordings of stellate cells (Dickson et A, J Neurophysiol 83:2562-2579, 2000; Magistretti and Alonso, J Gen Physiol 114:491-509, 1999; Magistretti et al., J Physiol 521:629-636, 1999a; J Neurosci 19:7334-7341, 1999b). These currents interacted to generate robust subthreshold membrane potentials with amplitude and frequency corresponding to data observed in the whole cell patch recordings. The model was also able to account for effects of pharmacological manipulations, including blockade of I-h with ZD7288, partial blockade with cesium, and the influence of barium on oscillations. In a model with a wider range of currents, the transition from oscillations to single spiking, to spike clustering, and finally tonic firing could be replicated. In agreement with experiment, blockade of calcium channels in the model strongly reduced clustering. In the voltage interval during which no data are available, the model predicts that the slow component of I-h does not follow the fast component down to very short time constants. The model also predicts that the fast component of I-h is responsible for the involvement in the generation of subthreshold oscillations, and the slow component dominates in the generation of spike clusters.
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| 32. |
- Fransén, Erik, 1962-, et al.
(författare)
-
Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons
- 2006
-
Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 49:5, s. 735-746
-
Tidskriftsartikel (refereegranskat)abstract
- Working memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. However, both high and low Ca2+ levels alter firing rates. Specifically, increases in persistent firing rate are triggered only during high levels of calcium, while decreases in rate occur in the presence of low levels of calcium. The model is consistent with detailed experimental observations and provides a mechanism for maintenance of memory-related activity in individual neurons.
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| 33. |
- Fransén, Erik, 1962-
(författare)
-
Neural response profile design : Reducing epileptogenic activity by modifying neuron responses to synchronized input using novel potassium channels obtained by parameter search optimization
- 2007
-
Ingår i: Neurocomputing. - AMSTERDAM : ELSEVIER SCIENCE. - 0925-2312 .- 1872-8286. ; 70:10-12, s. 1630-1634
-
Tidskriftsartikel (refereegranskat)abstract
- Neurons obtain their dynamical electrical characteristics by a set of ion channels. These properties may not only affect the function of the neuron and the local network it forms part of, but it may also eventually affect behavior. We were interested to study whether epileptogenic activity could be reduced by adding an ion channel. In this work, we used computational search techniques to optimize ion channel properties for the goal of modifying neural response characteristics. Our results show that this type of parameter search is possible and reasonably efficient. Successful searches were generated using the direct method PRAXIS, and by systematic searches in low-dimensional sub-spaces. We also report on unsuccessful searches using a simplex-type method, a gradient-based method, and attempts to reduce goal function evaluation time. Importantly, using this search strategy, our study has shown that it is possible to change a neuron's characteristics selectively with regard to response to degree of synchronicity in synaptic input.
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| 34. |
- Fransen, Erik, et al.
(författare)
-
Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective : A European Population-based Multicenter Study
- 2008
-
Ingår i: Journal of the Association for Research in Otolaryngology. - : Springer. - 1525-3961 .- 1438-7573. ; 9:3, s. 264-276
-
Tidskriftsartikel (refereegranskat)abstract
- A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high
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| 35. |
- Fransén, Erik, 1962-, et al.
(författare)
-
Role of A-type potassium currents in excitability, network synchronicity, and epilepsy
- 2010
-
Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 20:7, s. 877-887
-
Tidskriftsartikel (refereegranskat)abstract
- A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K-A). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K-A lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K-A by synaptic inputs of different levels of synchronicity. We find that K-A participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K-A suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K-A can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K-A might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. We also suggest that compounds changing K-A-kinetics may be used to pharmacologically improve epileptic status.
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| 36. |
- Fransén, Erik, 1962-, et al.
(författare)
-
Simulations of the role of the muscarinic-activated calcium-sensitive nonspecific cation current I-NCM in entorhinal neuronal activity during delayed matching tasks
- 2002
-
Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 22:3, s. 1081-1097
-
Tidskriftsartikel (refereegranskat)abstract
- Entorhinal lesions impair performance in delayed matching tasks, and blockade of muscarinic cholinergic receptors also impairs performance in these tasks. Physiological data demonstrate that muscarinic cholinergic receptor stimulation activates intrinsic cellular currents in entorhinal neurons that could underlie the role of entorhinal cortex in performance of these tasks. Here we use a network biophysical simulation of the entorhinal cortex to demonstrate the potential role of this cellular mechanism in the behavioral tasks. Simulations demonstrate how the muscarinic-activated calcium-sensitive nonspecific cation current I-NCM could provide a cellular mechanism for features of the neuronal activity observed during performance of delayed matching tasks. In particular, I-NCM could underlie (1) the maintenance of sustained spiking activity during the delay period, (2) the enhancement of spiking activity during the matching period relative to the sample period, and (3) the resistance of sustained activity to distractors. Simulation of a larger entorhinal network with connectivity chosen randomly within constraints on number, distribution, and weight demonstrates appearance of other phenomena observed in unit recordings from awake animals, including match suppression, non-match enhancement, and non-match suppression.
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| 37. |
- Fransén, Nelly, et al.
(författare)
-
Changes in the mucoadhesion of powder formulations after drug application investigated with a simplified method
- 2008
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 97:9, s. 3855-3864
-
Tidskriftsartikel (refereegranskat)abstract
- The residence time in the nasal cavity can be prolonged by dry particles that absorb water and subsequently increase the viscosity of the mucus layer. A novel nasal drug delivery system based on interactive mixtures has previously been developed, where fine particles of the active component are adhered to the surface of mucoadhesive carrier particles by dry mixing. The surface coverage may alter the original mucoadhesiveness of the carrier particles and to investigate this, a simplified tensile strength method was developed and evaluated. Reliable results were obtained with a plastic coated absorbent paper covered by a mucin solution as a substitution for porcine nasal mucosa and should also be applicable to other dry particle systems. The method showed that the swelling of sodium starch glycolate particles was slightly delayed, corresponding to the degree of hydrophobic surface coverage. Carrier particles of partly pregelatinized maize starch were not influenced by the addition of a hydrophobic substance, probably because of the rough particle shape that inhibited a complete surface coverage. It was concluded that the surface coverage of carrier particles in interactive mixtures only could cause a short delay in water absorption that should not affect their mucoadhesive characteristics in vivo.
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| 38. |
- Fransén, Nelly, et al.
(författare)
-
Clinical study shows improved absorption of desmopressin with novel formulation
- 2009
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 26:7, s. 1618-1625
-
Tidskriftsartikel (refereegranskat)abstract
- To create improved pharmaceutical formulations for nasal and sublingual administration of desmopressin and investigate their pharmacokinetic profiles in comparison with a commercial nasal liquid spray and finally to evaluate the volunteers' opinions on the different dosage forms. Both formulations were based on the characteristics of interactive mixtures. The nasal powder spray was produced by a rotary evaporator technique with sodium starch glycolate as carrier material and the sublingual tablet by direct compression after dry mixing with mannitol as carrier. The clinical study was an open-label, randomised cross-over pharmacokinetic study in healthy volunteers. The nasal powder formulation gave a threefold increase in the absorption, unaltered time to maximum plasma concentration and a tendency to lower variability in the amount absorbed compared with the liquid spray. The powder was reported to be more irritating than the liquid but was still well accepted by the volunteers. The tablet did not improve the uptake of desmopressin, likely because of a poor disintegration sublingually. The nasal powder formulation is a promising new dosage form for the delivery of desmopressin and other compounds. The sublingual tablet has a beneficial means of production and may be further developed by decreasing its disintegration time.
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| 39. |
- Fransén, Nelly, et al.
(författare)
-
Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery
- 2007
-
Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 67:2, s. 370-376
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether mucoadhesive interactive mixtures can be created using carrier particles in a size range appropriate for nasal administration, i.e. 10–50 μm. We also used theoretical models to investigate if homogeneity measurements can be used to evaluate the formation of interactive mixtures containing carrier particles in this size range. Sodium starch glycolate (SSG) was used as carrier material and sodium salicylate (SS) as the model fine-particulate drug. The size ranges of SSG particles and amounts of SS were varied to find the smallest carrier particle size and highest amount of drug that still resulted in an interactive mixture. Visual inspection of the mixtures by scanning electron microscopy showed that interactive mixtures could be formed with carrier particles as small as 30 μm and containing up to 4% (w/w) of SS. Comparisons with theoretical models highlighted the difficulties of using homogeneity measurements to determine if interactive mixtures were formed. The measured coefficients of variation (CV) for the amount of drug in the samples were low and inferior mixtures were associated with only a slight increase. It was thus concluded that mucoadhesive interactive mixtures can be created in an appropriate size range for nasal administration, but that visual inspection of these mixtures is initially necessary to confirm the formation of an interactive mixture.
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| 40. |
- Fransén, Nelly, et al.
(författare)
-
Physicochemical interactions between drugs and superdisintegrants
- 2008
-
Ingår i: Journal of Pharmacy and Pharmacology (JPP). - 0022-3573 .- 2042-7158. ; 60:12, s. 1583-9
-
Tidskriftsartikel (refereegranskat)abstract
- We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules.
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| 41. |
- Fransén, Nelly, 1978-
(författare)
-
Studies on a Novel Powder Formulation for Nasal Drug Delivery
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Nasal administration has potential for the treatment of indications requiring a fast onset of effect or for drugs with low oral bioavailability. Liquid nasal sprays are relatively common, but can be associated with suboptimal absorption from the nasal cavity; this thesis shows that nasal absorption can be significantly enhanced with a dry powder formulation. It was shown that interactive mixtures, consisting of fine drug particles adhered to the surface of mucoadhesive carrier particles, could be created in a particle size suitable for nasal administration. Sodium starch glycolate (SSG), a common tablet excipient, was used as carrier material. In vitro evaluation of the formulation indicated that the mucoadhesion of the carrier was unlikely to be affected by the addition of a drug. The powder formulation did not improve the in vitro transfer of dihydroergotamine across porcine nasal mucosa compared with a liquid formulation; however, the results were associated with methodological shortcomings. The binding of model substances to SSG and three other excipients was evaluated. Ion exchange interactions were for example detected between SSG and cationic drugs, but these interactions were most extensive at low salt concentrations and should unlikely affect in vivo bioavailability at physiological salt concentrations. Absorption of the peptide drug desmopressin from the SSG nasal formulation, from a novel sublingual tablet formulation and from a commercial nasal liquid spray was evaluated in a clinical trial. While no improvement over the liquid spray was seen with the sublingual tablet, plasma concentrations after the nasal powder formulation were three times higher than those after the liquid spray. All formulations were well accepted by the volunteers. The use of currently available mucoadhesive carrier particles in interactive mixtures offers potential for a new method of producing nasal powder formulations that should also be applicable to large scale production.
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| 42. |
- Fransén, Nelly, et al.
(författare)
-
The in vitro transport of dihydroergotamine across porcine nasal respiratory and olfactory mucosa and the effect of a novel powder formulation
- 2007
-
Ingår i: Journal of Drug Delivery Science and Technology. - 1773-2247. ; 17:4, s. 267-271
-
Tidskriftsartikel (refereegranskat)abstract
- The objective was to investigate the transport of dihydroergotamine (DHE) across porcine nasal respiratory and olfactory mucosa and to evaluate the absorption enhancing effect of a novel dry powder formulation compared with a reference solution with the horizontal Ussing chamber method. The powder formulation was obtained by mixing micronized DHE particles and mucoadhesive carrier particles (sodium starch glycolate) to create an interactive mixture. The horizontal Ussing chamber method was chosen as the in vitro model since it provides the opportunity to apply a dry powder formulation and compare the transport across the two types of nasal mucosa. A histological evaluation confirmed that the mucosa had been correctly isolated. The results showed no significant difference in the absorption from the powder formulation compared with the reference solution, but the transport of DHE was significantly higher across olfactory mucosa than across respiratory mucosa. This may be explained by facilitated transport through paracellular transfer along the olfactory nerve cells.
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| 43. |
- Giocomo, Lisa M., et al.
(författare)
-
Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing
- 2007
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 315:5819, s. 1719-1722
-
Tidskriftsartikel (refereegranskat)abstract
- Grid cells in layer II of rat entorhinal cortex fire to spatial locations in a repeating hexagonal grid, with smaller spacing between grid fields for neurons in more dorsal anatomical locations. Data from in vitro whole-cell patch recordings showed differences in frequency of subthreshold membrane potential oscillations in entorhinal neurons that correspond to different positions along the dorsal-to-ventral axis, supporting a model of physiological mechanisms for grid cell responses.
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| 44. |
- Grant, Seth G. N., et al.
(författare)
-
The Synapse Diversity Dilemma : Molecular Heterogeneity Confounds Studies of Synapse Function
- 2020
-
Ingår i: Frontiers in Synaptic Neuroscience. - : Frontiers Research Foundation. - 1663-3563. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Recent studies have shown an unexpectedly high degree of synapse diversity arising from molecular and morphological differences among individual synapses. Diverse synapse types are spatially distributed within individual dendrites, between different neurons, and across and between brain regions, producing the synaptome architecture of the brain. The spatial organization of synapse heterogeneity is important because the physiological activation of heterogeneous excitatory synapses produces a non-uniform spatial output of synaptic potentials, which confounds the interpretation of measurements obtained from population-averaging electrodes, optrodes and biochemical methods that lack single-synapse resolution. Population-averaging measurements cannot distinguish between changes in the composition of populations of synapses and changing synaptic physiology. Here we consider the implications of synapse diversity and its organization into synaptome architecture for studies of synapse physiology, plasticity, development and behavior, and for the interpretation of phenotypes arising from pharmacological and genetic perturbations. We conclude that prevailing models based on population-averaging measurements need reconsideration and that single-synapse resolution physiological recording methods are required to confirm or refute the major synaptic models of behavior.
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| 45. |
- Hasselmo, Michael E., et al.
(författare)
-
A phase code for memory could arise from circuit mechanisms in entorhinal cortex
- 2009
-
Ingår i: Neural Networks. - : PERGAMON-ELSEVIER. - 0893-6080 .- 1879-2782. ; 22:8, s. 1129-1138
-
Tidskriftsartikel (refereegranskat)abstract
- Neurophysiological data reveals intrinsic cellular properties that suggest how entorhinal cortical neurons could code memory by the phase of their firing. Potential cellular mechanisms for this phase coding in models of entorhinal function are reviewed. This mechanism for phase coding provides a substrate for modeling the responses of entorhinal grid cells, as well as the replay of neural spiking activity during waking and sleep. Efforts to implement these abstract models in more detailed biophysical compartmental simulations raise specific issues that could be addressed in larger scale population models incorporating mechanisms of inhibition.
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| 46. |
- Hasselmo, M. E., et al.
(författare)
-
Computational modeling of entorhinal cortex
- 2000
-
Ingår i: PARAHIPPOCAMPAL REGION. - NEW YORK : New York Academy of Sciences. - 1573312630 ; , s. 418-446
-
Konferensbidrag (refereegranskat)abstract
- Computational modeling provides a means for linking the physiological and anatomical characteristics of entorhinal cortex at a cellular level to the functional role of this region in behavior. We have developed detailed simulations of entorhinal cortical neurons and networks, with an emphasis on the role of acetylcholine in entorhinal cortical function. Computational modeling suggests that when acetylcholine levels are high, this sets appropriate dynamics for the storage of stimuli during performance of delayed matching tasks. In particular, acetylcholine activates a calcium-sensitive nonspecific cation current which provides an intrinsic cellular mechanism which could maintain neuronal activity across a delay period. Simulations demonstrate how this phenomena could underlie entorhinal cortex delay activity as described in previous unit recordings. Acetylcholine also induces theta rhythm oscillations which may be appropriate for timing of afferent input to be encoded in hippocampus and for extraction of individual stored sequences from multiple stored sequences. Lower levels of acetylcholine may allow sharp wave dynamics which can reactivate associations encoded in hippocampus and drive the formation of additional traces in hippocampus and entorhinal cortex during consolidation.
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| 47. |
- Hendrickx, Jan-Jaap, et al.
(författare)
-
Familial aggregation of pure tone hearing thresholds in an aging European population
- 2013
-
Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 34:5, s. 838-844
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated.STUDY DESIGN: Multicenter survey in 8 European centers.SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study.RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies.DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.
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| 48. |
- Hendrickx, Jan-Jaap, et al.
(författare)
-
Familial aggregation of tinnitus : a European multicentre study
- 2007
-
Ingår i: B-ENT. - Louvain, Belgium : Societe Royale Belge d'Oto - Rhino - Laryngologie et de Chirurgie Cervico - Faciale. - 0001-6497. ; 3:Suppl 7, s. 51-60
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION AND AIM:Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects.METHODS:In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member.RESULTS:All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15.CONCLUSION:The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.
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| 49. |
- Hornung, Maximilian, et al.
(författare)
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Detection of Ischemic Infarct Core in Non-contrast Computed Tomography
- 2020
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Ingår i: Machine Learning in Medical Imaging. - Cham : Springer Nature. ; , s. 260-269
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Konferensbidrag (refereegranskat)abstract
- Fast diagnosis is of critical importance for stroke treatment. In clinical routine, a non-contrast computed tomography scan (NCCT) is typically acquired immediately to determine whether the stroke is ischemic or hemorrhagic and plan therapy accordingly. In case of ischemia, early signs of infarction may appear due to increased water uptake. These signs may be subtle, especially if observed only shortly after symptom onset, but hold the potential to provide a crucial first assessment of the location and extent of the infarction. In this paper, we train a deep neural network to predict the infarct core from NCCT in an image-to-image fashion. To facilitate exploitation of anatomic correspondences, learning is carried out in the standardized coordinate system of a brain atlas to which all images are deformably registered. Apart from binary infarct core masks, perfusion maps such as cerebral blood volume and flow are employed as additional training targets to enrich the physiologic information available to the model. This extension is demonstrated to substantially improve the predictions of our model, which is trained on a data set consisting of 141 cases. It achieves a higher volumetric overlap (statistically significant,) of the predicted core with the reference mask as well as a better localization, although significance could not be shown for the latter. Agreement with human and automatic assessment of affected ASPECTS regions is likewise improved, measured as an increase of the area under the receiver operating characteristic curve from 72.7% to 75.1% and 71.9% to 83.5%, respectively.
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- Huyghe, Jeroen R, et al.
(författare)
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A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies
- 2011
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Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 19:3, s. 347-352
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Tidskriftsartikel (refereegranskat)abstract
- The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F-ST statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F-ST was smallest for the comparison with the Russians (F-ST=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.
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