| 1. |
- Liu, Yawei, et al.
(författare)
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Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE.
- 2006
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 12:5, s. 518-525
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Tidskriftsartikel (refereegranskat)abstract
- Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1–TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+TGF-beta1+CTLA-4+FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.
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| 2. |
- Engel, Jörgen, 1942, et al.
(författare)
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Neonatal herpes simplex virus type 1 brain infection affects the development of sensorimotor gating in rats.
- 2000
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Ingår i: Brain research. - 0006-8993. ; 863:1-2, s. 233-40
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Tidskriftsartikel (refereegranskat)abstract
- The effect of neonatal brain infection of herpes simplex virus type 1 (HSV-1) on the development of sensorimotor function in the rat was investigated using an acoustic startle paradigm. Intracerebral inoculation of HSV-1 at day 2 after birth, but not at day 4, caused a significant delay in the development of prepulse inhibition of acoustic startle. A decrease in prepulse inhibition was shown at 37, 46 and 58 days of age in these rats compared to control rats. No evidence was obtained for other behavioural dysfunctions such as differences in sensorimotor reactivity, sensorimotor response habituation, spontaneous locomotor activity, rearing activity or stereotyped behaviour. Prepulse inhibition of acoustic startle is an accepted model of sensorimotor gating in the CNS, a function which has been shown diminished in schizophrenic persons. The present results suggest that early viral infections during a neurone-susceptible period may contribute to the development of this deficit.
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| 3. |
- Birnir, Bryndis, et al.
(författare)
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The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:31, s. 3169-3177
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Tidskriftsartikel (refereegranskat)abstract
- Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
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| 4. |
- Lindquist, Catarina, et al.
(författare)
-
Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice
- 2003
-
Ingår i: Molecular and Cellular Neuroscience. - 1044-7431 .- 1095-9327. ; 24:1, s. 250-257
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Tidskriftsartikel (refereegranskat)abstract
- Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 muM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 muM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 muM THIP plus 1 muM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 AM) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 5. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
-
Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 6. |
- Birnir, Bryndis, et al.
(författare)
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Bicuculline, pentobarbital and diazepam modulate spontaneous GABA(A) channels in rat hippocampal neurons
- 2000
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 131:4, s. 695-704
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Tidskriftsartikel (refereegranskat)abstract
- Spontaneously opening, chloride-selective channels that showed outward rectification were recorded in ripped-off patches from rat cultured hippocampal neurons and in cell-attached patches from rat hippocampal CA1 pyramidal neurons in slices. In both preparations, channels had multiple conductance states and the most common single-channel conductance varied. In the outside-out patches it ranged from 12 to 70 pS (Vp=40 mV) whereas in the cell-attached patches it ranged from 56 to 85 pS (-Vp=80 mV). Application of GABA to a patch showing spontaneous channel activity evoked a rapid, synchronous activation of channels. During prolonged exposure to either 5 or 100 microM GABA, the open probability of channels decreased. Application of GABA appeared to have no immediate effect on single-channel conductance. Exposure of the patches to 100 microM bicuculline caused a gradual decrease on the single-channel conductance of the spontaneous channels. The time for complete inhibition to take place was slower in the outside-out than in the cell-attached patches. Application of 100 microM pentobarbital or 1 microM diazepam caused 2 - 4 fold increase in the maximum channel conductance of low conductance (<40 pS) spontaneously active channels. The observation of spontaneously opening GABA(A) channels in cell-attached patches on neurons in slices suggests that they may have a role in neurons in vivo and could be an important site of action for some drugs such as benzodiazepines, barbiturates and general anaesthetics.
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| 7. |
- Blomgren, Klas, 1963, et al.
(författare)
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Pathological apoptosis in the developing brain
- 2007
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Ingår i: Apoptosis. - : Springer Science and Business Media LLC. - 1360-8185 .- 1573-675X. ; 12:5, s. 993-1010
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Forskningsöversikt (refereegranskat)abstract
- More than half of the initially-formed neurons are deleted in certain brain regions during normal development. This process, whereby cells are discretely removed without interfering with the further development of remaining cells, is called programmed cell death (PCD). The term apoptosis is used to describe certain morphological manifestations of PCD. Many of the effectors of this developmental cell death program are highly expressed in the developing brain, making it more susceptible to accidental activation of the death machinery, e.g. following hypoxia-ischemia or irradiation. Recent evidence suggests, however, that activation and regulation of cell death mechanisms under pathological conditions do not exactly mirror physiological, developmentally regulated PCD. It may be argued that the conditions after e.g. ischemia are not even compatible with the execution of PCD as we know it. Under pathological conditions cells are exposed to various stressors, including energy failure, oxidative stress and unbalanced ion fluxes. This results in parallel triggering and potential overshooting of several different cell death pathways, which then interact with one another and result in complex patterns of biochemical manifestations and cellular morphological features. These types of cell death are here called "pathological apoptosis," where classical hallmarks of PCD, like pyknosis, nuclear condensation and caspase-3 activation, are combined with non-PCD features of cell death. Here we review our current knowledge of the mechanisms involved, with special focus on the potential for therapeutic intervention tailored to the needs of the developing brain.
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| 8. |
- Cheng, Fang, et al.
(författare)
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Differences in the uptake and nuclear localization of anti-proliferative heparan sulfate between human lung fibroblasts and human lung carcinoma cells
- 2001
-
Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 83:4, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate inhibits the proliferation of normal human lung fibroblasts (HFL-1) but not of a human lung carcinoma cell-line (A549). in this study we investigated possible mechanisms and structural requirements by which anti proliferative heparan sulfates exerts its effects on binding, uptake and subcellular localisation. Both HFL-1 and A549 cells were incubated with I-125- or rhodamine-labeled L-iduronate-rich antiproliferative heparan sulfate species as well as L-iduronate-poor inactive ones. The anti proliferative heparan sulfate was bound to the cell surface on both HFL-1 and A549 cells, but to a lesser extent and with less affinity to A549 cells. Both cell types bound the anti proliferative heparan sulfate with one high- and with one low affinity site. The L-iduronate-poor heparan sulfate bound to a lesser extent and with less affinity to both cell types compared to the anti proliferative heparan sulfate. The antiproliferative heparan sulfate accumulated in the cytoplasm of HFL-1 cells after 24 h incubation, but after 72 h it was found evenly distributed in the nucleus. The time-scale for anti proliferative activity correlated with nuclear localization. In contrast, in A549 cells it was only found near the nuclear membrane. The inactive heparan sulfate was taken up in considerably smaller amounts compared to the antiproliferative heparan sulfate and could not be detected in the nucleus of either HFL-1 or A549 cells. Our data suggest that the anti proliferative activity of L-iduronate-rich heparan sulfate on normal fibroblasts may be due to direct effects on nuclear processes, such as gene transcription.
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| 9. |
- Eghbali, M, et al.
(författare)
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Pentobarbital modulates gamma-aminobutyric acid-activated single-channel conductance in rat cultured hippocampal neurons.
- 2000
-
Ingår i: Molecular Pharmacology. - 0026-895X .- 1521-0111. ; 58:3, s. 463-9
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effect of a range of pentobarbital concentrations on 0.5 microM gamma-aminobutyric acid (GABA)-activated channels (10 +/- 1 pS) in inside-out or outside-out patches from rat cultured hippocampal neurons. The conductance increased from 12 +/- 4 to 62 +/- 9 pS as the pentobarbital concentration was raised from 10 to 500 microM and the data could be fitted by a Hill-type equation. At 100 microM pentobarbital plus 0.5 microM GABA, the conductance seemed to reach a plateau. The pentobarbital EC(50)(0.5 microM GABA) value was 22 +/- 4 microM and n was 1.9 +/- 0.5. In 1 mM pentobarbital plus 0.5 microM GABA, the single-channel conductance decreased to 34 +/- 8 pS. This apparent inhibition of channel conductance was relieved by 1 microM diazepam. The channel conductance was 64 +/- 6 pS in the presence of all three drugs. The channels were open more in the presence of both GABA and pentobarbital than in the presence of either drug alone. Pentobarbital alone (100 microM) activated channels with conductance (30 +/- 2 pS) and kinetic properties distinct from those activated by either GABA alone or GABA plus pentobarbital. Whether pentobarbital induces new conformations or promotes conformations observed in the presence of GABA alone cannot be determined from our study, but the results clearly show that it is the combination of drugs present that determines the single-channel conductance and the kinetic properties of the receptors.
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| 10. |
- Zhu, Changlian, 1964, et al.
(författare)
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X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants.
- 2007
-
Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 26:12, s. 3402-10
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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| 11. |
- van West, Dirk, et al.
(författare)
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Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression
- 2006
-
Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 31:3, s. 620-627
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.
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| 12. |
- Gustafson, Deborah, 1966, et al.
(författare)
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Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women.
- 2007
-
Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 78:5, s. 461-4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Low levels of cerebrospinal fluid (CSF) beta-amyloid 1-42 (Abeta42) and high total tau (T-tau) are diagnostic for manifest Alzheimer's disease. It is not known, however, whether these biomarkers may be risk indicators for cognitive decline in otherwise healthy older people. METHODS: The longitudinal relationship between CSF markers, Abeta42 and T-tau, measured in 1992, and change in Mini-Mental State Examination (deltaMMSE) score between 1992 and 2002 were investigated in 55 women (aged 70-84 years, mean (SD) MMSE score = 28.3 (1.5)), who were participants in the Prospective Population Study of Women in Gothenburg, Sweden. These women did not have dementia when they experienced lumbar puncture in 1992-3. RESULTS: Over the 8-year follow-up period, deltaMMSE (range = +3 to -21 points) was correlated with Abeta42 (Spearman's r = 0.40, p = 0.002), such that lower levels of Abeta42 were related to greater decline. This was also observed after excluding 4 women who developed dementia between 1992 and 2002 (Spearman's r = 0.34, p = 0.019). A multivariate logistic regression model predicting a decline of > or = 5 points on the MMSE (observed in six women), or a risk of developing dementia over the 8-year follow-up period (observed in four women), including age, education, Abeta42 and T-tau as covariates, showed that Abeta42 was the sole predictor of significant cognitive decline or dementia (OR per 100 pg/ml Abeta42 = 2.24, 95% CI 1.19 to 4.22, p = 0.013). CONCLUSIONS: Low levels of CSF Abeta42 may predict cognitive decline among older women without dementia.
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| 13. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis.
- 2009
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 15:4, s. 448-54
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cell and animal experiments have shown that beta-site APP-cleaving enzyme 1 (BACE1) may be involved in myelination. OBJECTIVE: Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS). METHODS: BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-beta (Abeta) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. Patients with systemic lupus erythematosus (SLE), 26 with and 41 without cerebral engagement, were also included to enable comparisons with regards to another autoimmune disease. A subset of patients with MS and controls underwent a second lumbar puncture after 10 years. RESULTS: MS patients had lower CSF BACE1 activity than controls (P = 0.03) and patients with cerebral SLE (P < 0.001). Patients with cerebral SLE had higher BACE1 activity than any other group (P < 0.05 for all comparisons). BACE1 activity correlated with the different amyloid markers in all study groups. BACE1 activity decreased over 10 years in the MS group (P = 0.039) and correlated weakly with clinical disease severity scores in an inverse manner. CONCLUSIONS: These results suggest an involvement of BACE1 in the MS disease process.
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| 14. |
- Sabirsh, A, et al.
(författare)
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Fluorescent leukotriene B-4: potential applications
- 2005
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Ingår i: Journal of Lipid Research. - 1539-7262 .- 0022-2275. ; 46:6, s. 1339-1346
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Tidskriftsartikel (refereegranskat)abstract
- Leukotriene B-4 (LTB4) is a potent lipid mediator of inflammation that acts primarily via a seven-transmembrane-spanning, G-protein-coupled receptor denoted BLT1. Here, we describe the synthesis and characterization of fluorescent analogs of LTB4 that are easy to produce, inexpensive, and without the disadvantages of a radioligand. Fluorescent LTB4 is useful for labeling LTB4 receptors for which no antibodies are available and for performing one-step fluorescence polarization assays conducive to high-throughput screening. We found that orange and green fluorescent LTB4 were full agonists that activated the LTB4 receptor BLT1 with EC50 values of 68 and 40 nM, respectively (4.5 nM for unmodified LTB4). Flow cytometric measurements and confocal imaging showed that fluorescent LTB4 colocalized with BLT1. Fluorescence polarization measurements showed that orange fluorescent LTB4 bound to BLT1 with a K-d of 66 nM and that this binding could be displaced by unlabeled LTB4 and other BLT1-specific ligands. Fluorescent LTB4 analogs were also able to displace tritiated LTB4. Orange fluorescent LTB4 binding to enhanced green fluorescent protein-tagged BLT1 could be observed using fluorescence resonance energy transfer. In addition to being a useful alternative to radiolabeled LTB4, the unique properties of fluorescently labeled LTB4 allow a variety of detection technologies to be used.
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| 15. |
- Zuberovic, Aida, et al.
(författare)
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Proteome profiling of human cerebrospinal fluid: exploring the potential of capillary electrophoresis with surface modified capillaries for analysis of complex biological samples.
- 2008
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Ingår i: European journal of mass spectrometry (Chichester, England). - : SAGE Publications. - 1469-0667 .- 1751-6838. ; 14:4, s. 249-60
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Tidskriftsartikel (refereegranskat)abstract
- A bottom-up proteomic approach, based on capillary electrophoresis (CE) in combination with matrix- assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-ToF/ToF MS), was used to analyze immunoaffinity depleted human cerebrospinal fluid (CSF) and compare it with a non-depleted sample. After enzymatic digestion and desalting, the tryptic peptides were separated by CE using PolyE-323 modified capillaries and fractionated off-line onto MALDI target plates for further analysis by MALDI-MS and MS/MS. The protein profile of the depleted sample was compared with non depleted CSF. Overall, 85 proteins were identified with 95% significance in both samples. The significance scores for proposed biomarkers, such as amyloid-like protein 1 precursor, could be increased up to 12 times after the depletion. Other proteins, often suggested to be related to neurodegenerative diseases, like amyloid beta A4 protein precursor, superoxide dismutase and apolipoprotein E precursor could only be found in the depleted CSF samples. The effect of a derivatization of tryptic peptides with 2- methoxy-4,5-dihydro-1H-imidazole reagent for protein identification with MS was also employed to increase the number of identified proteins and the sequence coverages. The results presented in this study illustrate the benefit of combining a sample pre-fractionation step and a label's ability to enhance the ionization efficiency with the potential of CE using PolyE-323 modified capillaries in the analysis of complex samples. The straight-forward approach that provides speed and simplicity resulting in high-resolution separations and low sample consumption represents an easily applicable separation technique that can serve as a complement to other currently existing analytical approaches needed in modern proteomic analysis of clinically relevant samples.
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| 16. |
- Bengtsson, Fredrik, et al.
(författare)
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Ketamine and xylazine depress sensory-evoked parallel fiber and climbing fiber responses.
- 2007
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 98:3, s. 705-1697
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The last few years have seen an increase in the variety of in vivo experiments used for studying cerebellar physiological mechanisms. A combination of ketamine and xylazine has become a particularly popular form of anesthesia. However, because nonanesthetized control conditions are lacking in these experiments, so far there has been no evaluation of the effects of these drugs on the physiological activity in the cerebellar neuronal network. In the present study, we used the mossy fiber, parallel fiber, and climbing fiber field potentials evoked in the nonanesthetized, decerebrated rat to serve as a control condition against which the effects of intravenous drug injections could be compared. All anesthetics were applied at doses required for normal maintenance of anesthesia. We found that ketamine substantially depressed the evoked N3 field potential, which is an indicator of the activity in the parallel fiber synapses (-40%), and nearly completely abolished evoked climbing fiber field potentials (-90%). Xylazine severely depressed the N3 field (-75%) and completely abolished the climbing fiber field (-100%). In a combination commonly used for general anesthesia (20:1), ketamine-xylazine injections also severely depressed the N3 field (-75%) and nearly completely abolished the climbing fiber field (-90%). We also observed that lowered body and surface temperatures (<34 degrees C) resulted in a substantial depression of the N3 field (-50%). These results urge for some caution in the interpretations of studies on cerebellar network physiology performed in animals anesthetized with these drugs
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| 17. |
- Björkqvist, Maria, et al.
(författare)
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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
- 2008
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
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| 18. |
- Garwicz, Martin, et al.
(författare)
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A unifying model for timing of walking onset in humans and other mammals
- 2009
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:51, s. 21889-21893
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Tidskriftsartikel (refereegranskat)abstract
- The onset of walking is a fundamental milestone in motor development of humans and other mammals, yet little is known about what factors determine its timing. Hoofed animals start walking within hours after birth, rodents and small carnivores require days or weeks, and nonhuman primates take months and humans approximately a year to achieve this locomotor skill. Here we show that a key to the explanation for these differences is that time to the onset of walking counts from conception and not from birth, indicating that mechanisms underlying motor development constitute a functional continuum from pre- to postnatal life. In a multiple-regression model encompassing 24 species representative of 11 extant orders of placental mammals that habitually walk on the ground, including humans, adult brain mass accounted for 94% of variance in time to walking onset postconception. A dichotomous variable reflecting species differences in functional limb anatomy accounted for another 3.8% of variance. The model predicted the timing of walking onset in humans with high accuracy, showing that this milestone in human motor development occurs no later than expected given the mass of the adult human brain, which in turn reflects the duration of its ontogenetic development. The timing of motor development appears to be highly conserved in mammalian evolution as the ancestors of some of the species in the sample presented here diverged in phylogenesis as long as 100 million years ago. Fundamental patterns of early human life history may therefore have evolved before the evolution of primates.
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| 19. |
- Jensen, Jimmy, et al.
(författare)
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Direct activation of the ventral striatum in anticipation of aversive stimuli.
- 2003
-
Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 40:6, s. 1251-1257
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Tidskriftsartikel (refereegranskat)abstract
- The brain "reward" system, centered on the limbic ventral striatum, plays a critical role in the response to pleasure and pain. The ventral striatum is activated in animal and human studies during anticipation of appetitive/pleasurable events, but its role in aversive/painful events is less clear. Here we present data from three human fMRI studies based on aversive conditioning using unpleasant cutaneous electrical stimulation and show that the ventral striatum is reliably activated. This activation is observed during anticipation and is not a consequence of relief after the aversive event. Further, the ventral striatum is activated in anticipation regardless of whether there is an opportunity to avoid the aversive stimulus or not. Our data suggest that the ventral striatum, a crucial element of the brain "reward" system, is directly activated in anticipation of aversive stimuli.
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| 20. |
- Jensen, Jimmy, et al.
(författare)
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Neurocognitive and psychopathological correlates of self-monitoring ability in schizophrenia.
- 2004
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer. - 0940-1334 .- 1433-8491. ; 254:5, s. 312-317
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study reported by our group one salient finding was that many patients with schizophrenia appeared to be unable to judge their own quality of life (QoL) and that this inability was associated with negative symptoms. The association between negative symptoms, poor self-monitoring capacity and lack of insight might be explained by a common underlying factor, i.e. neurocognitive impairment. Fifty schizophrenic patients were examined by symptom ratings and a comprehensive neuropsychological test battery. The cognitive performance of the patients was very poor. The major findings of the present study were the association between clinically rated Lack of judgement (PANSS G12) and 1) a set of standard performance and executive indices of the computerised tests, and 2) difference scores between objective performance/strategies and self-ratings of the same attributes. There appears to be a substantial contribution of cognitive and executive problems to the poor judgement and lack of insight of schizophrenic patients, and these problems can to some extent be assessed objectively.
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| 21. |
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| 22. |
- Jensen, Jimmy, et al.
(författare)
-
Separate brain regions code for salience vs. valence during reward prediction in humans.
- 2007
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Ingår i: Human Brain Mapping. - 1065-9471 .- 1097-0193. ; 28:4, s. 294-302
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Tidskriftsartikel (refereegranskat)abstract
- Predicting rewards and avoiding aversive conditions is essential for survival. Recent studies using computational models of reward prediction implicate the ventral striatum in appetitive rewards. Whether the same system mediates an organism's response to aversive conditions is unclear. We examined the question using fMRI blood oxygen level-dependent measurements while healthy volunteers were conditioned using appetitive and aversive stimuli. The temporal difference learning algorithm was used to estimate reward prediction error. Activations in the ventral striatum were robustly correlated with prediction error, regardless of the valence of the stimuli, suggesting that the ventral striatum processes salience prediction error. In contrast, the orbitofrontal cortex and anterior insula coded for the differential valence of appetitive/aversive stimuli. Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions.
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| 23. |
- Jensen, Jimmy, et al.
(författare)
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The formation of abnormal associations in schizophrenia : neural and behavioral evidence.
- 2008
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Ingår i: Neuropsychopharmacology. - 0893-133X .- 1740-634X. ; 33:3, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS-). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS-) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.
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| 24. |
- Kotarsky, Knut, et al.
(författare)
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Progress in methodology improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors.
- 2003
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Ingår i: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:6, s. 249-258
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Forskningsöversikt (refereegranskat)abstract
- Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as "orphan" receptors. A pre-requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence-based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE® (high-throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE® system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
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| 25. |
- Lindqvist, Andreas, et al.
(författare)
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Decreased UCP2 mRNA expression in rat stomach following vagotomy: novel role for UCP2 as free radical scavenger in the stomach?
- 2004
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Ingår i: Nutritional Neuroscience. - : Informa UK Limited. - 1476-8305 .- 1028-415X. ; 7:4, s. 217-222
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Tidskriftsartikel (refereegranskat)abstract
- Uncoupling protein 2 (UCP2) is a protein, located in the inner mitochondrial membrane, which dissipates the proton gradient of this membrane and uncouples respiration from oxidative phosphorylation. We found, by in situ hybridisation, UCP2 mRNA to be located in the proliferating zone of the mucous neck cells in the fundus part of the rat stomach. We also found that UCP2 expression in fundus was significantly decreased after seven days of vagotomy. Furthermore, we found manganese-containing superoxide dismutase (SOD2), in fundus, to be down-regulated in a way similar to UCP2. The amount of ATP was significantly decreased following vagotomy. It is concluded that UCP2 in the gastro-intestinal tract is regulated through vagal innervation and suggested to act as a free radical scavenger.
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| 26. |
- Menon, Mahesh, et al.
(författare)
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Temporal difference modeling of the blood-oxygen level dependent response during aversive conditioning in humans : effects of dopaminergic modulation.
- 2007
-
Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 62:7, s. 765-772
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum.METHODS: Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS-, respectively).RESULTS: Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions.CONCLUSIONS: Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.
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| 27. |
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| 28. |
- Ousdal, O T, et al.
(författare)
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The human amygdala is involved in general behavioral relevance detection : evidence from an event-related functional magnetic resonance imaging Go-NoGo task.
- 2008
-
Ingår i: Neuroscience. - 0306-4522 .- 1873-7544. ; 156:3, s. 450-455
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Tidskriftsartikel (refereegranskat)abstract
- The amygdala is classically regarded as a detector of potential threat and as a critical component of the neural circuitry mediating conditioned fear responses. However, it has been reported that the human amygdala responds to multiple expressions of emotions as well as emotionally neutral stimuli of a novel, uncertain or ambiguous nature. Thus, it has been proposed that the function of the amygdala may be of a more general art, i.e. as a detector of behaviorally relevant stimuli [Sander D, Grafman J, Zalla T (2003) The human amygdala: an evolved system for relevance detection. Rev Neurosci 14:303-316]. To investigate this putative function of the amygdala, we used event related functional magnetic resonance imaging (fMRI) and a modified Go-NoGo task composed of behaviorally relevant and irrelevant letter and number stimuli. Analyses revealed bilateral amygdala activation in response to letter stimuli that were behaviorally relevant as compared with letters with less behavioral relevance. Similar results were obtained for relatively infrequent NoGo relevant stimuli as compared with more frequent Go stimuli. Our findings support a role for the human amygdala in general detection of behaviorally relevant stimuli.
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| 29. |
- Sigvartsen, Niels Petter, et al.
(författare)
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Temporal difference modelling of aversive conditioning and extinction : An fMRI study
- 2009
-
Ingår i: Front. Neur. Conference Abstract.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The prediction error (PE) signal from temporal difference (TD) models have been shown to correlate with activity in specific brain regions in both human and animals during conditioning tasks. One of the key regions involved is the ventral striatum (VS). The purpose of this study was to investigate how the TD model predicted VS activations during aversive conditioning and extinction. Functional Magnetic Resonance Imaging (fMRI) Blood-Oxygen Level Dependent (BOLD) data were acquired on a 1.5 T GE Signa scanner. Thirty-three healthy subjects completed a 33% partially reinforced classical conditioning paradigm using coloured circles as the conditioned stimulus (CS) and aversive cutaneous electrical stimulation (CES) as the unconditioned stimulus (US). After a short break a second scanning session was performed where the subjects were divided into three groups (N=11 in each group): 1) a control group that repeated the paradigm; 2) an extinction group that repeated the paradigm with the CES turned off without their knowledge; and 3) an intervention group that were told that the CES would be turned off before they repeated the paradigm. Thus, in the second session the extinction and intervention groups saw the CS but without US. A modified TD algorithm was used to generate a salience PE signal vector which was used as a regressor in the fMRI analyses. Pre-processing and analyses of data were done using SPM5. Final analysis of the first session and preliminary analysis of the control and extinction groups from the second session are reported here. Analysis of the first session included all 33 subjects and PE activations bilaterally in the VS, anterior insula and anterior cingulate were obtained. Analyses from the second session showed that activations were predicted by salience PE bilaterally in the VS and the anterior insula in the control group while the extinction group recruited the VS and the ventro-medial PFC. The findings from the first session and the control group in the second session replicated previous studies. However, the results of the second session in the extinction group extend that fMRI BOLD behave according to salience PE to a more general level in aversive learning ranging from acquisition to maintenance to extinction of associations.
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| 30. |
- Tehranian, Roya, 1969-
(författare)
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On inflammatory cytokines and β-amyloid peptides in acute and chronic neurodegeneration
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insults to the brain as well as neurodegenerative diseases are known to elicit inflammatory responses. Inflammation in the brain can on one hand initiate processes that are harmful to the injured tissue and exacerbate the damage, leading to neuronal degeneration and glial activation, and on the other hand activate processes that may be necessary for repair mechanisms and regeneration. Among the mediators of inflammatory response in the brain are the inflammatory cytokines. The most studied are interleukin-1 (IL)-1, IL-6 and tumor necrosis factor-alfa (TNF- ). Although the expression of these cytokines is low under normal conditions in the brain, it can be rapidly induced in response to injury.This thesis is focused on the role of IL-1 family of proteins, namely the agonists IL-1 and and the endogenous IL-1 receptor antagonist (IL-1ra), and IL-6, in different experimental models of neurodegeneration. In order to study the role of IL-1 family of proteins during inflammation in an excitotoxic model of brain injury, adult rats were injected systemically with kainic acid, a glutamate analogue known to evoke seizures and neuronal cell loss in the rat brain. Using the combined technique of reverse-transcriptase coupled to PCR (RT-PCR) and in situ hybridization histochemistry, an upregulation of microglial mRNA expression of IL-1 and IL-1ra was found in brain areas with neuronal degeneration, such as the hippocampus and amygdala. IL-1ra mRNA was induced at later time point than IL-1 mRNA and was identified as the transcript coding for the secreted isoform of IL-1ra. This suggets that upregulation of these cytokines is a part of an inflammtory response associated with neurodegeneration and that the effect of IL-1 may be regulated by the expression of IL-1ra in this model. In order to study the role played by IL-1 in inflammation associated with traumatic brain injury (TBI), an experimental model was inflicted on transgenic mice. Heterozygous overexpression of the human secreted isoform of IL-1ra in the brain decreased the induction of IL-1 and IL-6 after injury. Using a neurological severity score (NSS), which mainly reflects motor recovery, we found that these animals recovered faster as compared to their non-transgenic littermates.Furthermore, the proinflammatory cytokine expression was studied by RT-PCR in a mouse model of Alzheimer's disease (AD). The Tg2576 mice strain overexpress -amyloid (A ) precursor protein with the "Swedish" mutation linked to familiar AD and exhibits some of the neuropathology associated with AD, such as the deposition of insoluble extracellular amyloid fibrils (amyloid plaques) in specific brain regions. Analysis of expression of cytokines in the brain of Tg2576 mice revealed an early induction of IL-6 in the hippocampus and cerebral cortex that precedes the formation of amyloid plaques. This finding is interesting since in AD brain IL-6 is detected in microglia in the vicinity of diffuse plaques (non-fibrillar). Thus, the result from this study suggests that increased IL-6 expression may be an early event in AD inflammation.The main constituent of amyloid plaques in the AD brain is the A peptide. The synthetic peptide A (25-35), a neurotoxic fragment of the full-length A peptide was studied for its ability to activate glial cells in culture and induce cytokine expression, as well as for its influence on G-protein coupled signalling in rat brain tissue. A (25-35) treatment of mixed astroglial cultures resulted in marked induction of IL-6 mRNA as studied by RT-PCR. Together with the results from the Tg2576 mice these results suggest a role for IL-6 in AD pathogenesis.Alteration in cellular signal transduction has also been reported in AD brain. A (25-35) was shown to stimulate the enzymatic activities of GTPase and adenylate cyclase in membrane preparations from rat hippocampus and cerebral cortex, which are particularly affected regions in AD brain. Using Pertussis toxin treated membranes, the stimulatory effect on GTPase activity was totally abolished, suggesting that Gi/Go type of G-proteins mediated the effect of the A peptide.
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| 31. |
- Welander-Vatn, Audun S, et al.
(författare)
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No altered dorsal anterior cingulate activation in bipolar II disorder patients during a Go/No-go task : an fMRI study.
- 2009
-
Ingår i: Bipolar Disorders. - 1398-5647 .- 1399-5618. ; 11:3, s. 270-279
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: It has been reported that one of the core features in patients with bipolar disorder II (BD II) is increased impulsivity. The aim of this study was to investigate whether patients with BD II showed decreased activation in the dorsal anterior cingulate cortex (dACC) as compared to healthy controls when performing a task sensitive to impulsivity.METHODS: Twenty-seven BD II patients and 28 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Eleven of the patients were unmedicated, and possible group differences between medicated and unmedicated patients were also assessed. Results: The groups did not differ in behavioral performance on the Go/No-go task. Both BD II subjects and healthy controls demonstrated dACC activity during the task, and analyses revealed no statistically significant group differences. Medicated and unmedicated patients also did not differ in the degree of fMRI activation.CONCLUSIONS: These findings do not support the hypothesis of abnormal dACC activity during a Go/No-go task in BD II patients.
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| 32. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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Reversible synaptic depression in developing rat CA3-CA1 synapses explained by a novel cycle of AMPA silencing-unsilencing
- 2007
-
Ingår i: JOURNAL OF NEUROPHYSIOLOGY. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 98:5, s. 2604-2611
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Tidskriftsartikel (refereegranskat)abstract
- In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.
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| 33. |
- Andersson, Christin, et al.
(författare)
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Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
- 2008
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:10, s. 1466-1473
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression. OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline. METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up. CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.
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| 34. |
- Birnir, Bryndis, et al.
(författare)
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GABA concentration sets the conductance of delayed GABAA channels in outside-out patches from rat hippocampal neurons.
- 2001
-
Ingår i: Journal of Membrane Biology. - 0022-2631 .- 1432-1424. ; 181:3, s. 171-83
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Tidskriftsartikel (refereegranskat)abstract
- GABAA channels were activated by GABA in outside-out patches from rat cultured hippocampal neurons. They were blocked by bicuculline and potentiated by diazepam. In 109 of 190 outside-out patches, no channels were active before exposure to GABA (silent patches). The other 81 patches showed spontaneous channel activity. In patches containing spontaneous channel activity, rapid application of GABA rapidly activated channels. In 93 of the silent patches, channels could be activated by GABA but only after a delay that was sometimes as long as 10 minutes. The maximum channel conductance of the channels activated after a delay increased with GABA concentration from less than 10 pS (0.5 microm GABA) to more than 100 pS (10 mm GABA). Fitting the data with a Hill-type equation gave an EC50 value of 33 microm and a Hill coefficient of 0.6. The channels showed outward rectification and were chloride selective. In the presence of 1 microm diazepam, the GABA EC50 decreased to 0.2 microm but the maximum conductance was unchanged. Diazepam decreased the average latency for channel opening. Bicuculline, a GABA antagonist, caused a concentration-dependent decrease in channel conductance. In channels activated with 100 microm GABA the bicuculline IC50 was 19 microm. The effect of GABA on channel conductance shows that the role of the ligand in GABAA receptor channel function is more complex than previously thought.
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| 35. |
- Birnir, Bryndis, et al.
(författare)
-
Spontaneously opening GABA(A) channels in CA1 pyramidal neurones of rat hippocampus.
- 2000
-
Ingår i: Journal of Membrane Biology. - 0022-2631 .- 1432-1424. ; 174:1, s. 21-9
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Tidskriftsartikel (refereegranskat)abstract
- Spontaneous, single channel, chloride currents were recorded in 48% of cell-attached patches on neurones in the CA1 region of rat hippocampal slices. In some patches, there was more than 1 channel active. They showed outward rectification: both channel conductance and open probability were greater at depolarized than at hyperpolarized potentials. Channels activated by gamma-aminobutyric acid (GABA) in silent patches on the same neurones had similar conductance and outward rectification. The spontaneous currents were inhibited by bicuculline and potentiated by diazepam. It was concluded that the spontaneously opening channels were constitutively active, nonsynaptic GABA(A) channels. Such spontaneously opening GABA(A) channels may provide a tonic inhibitory mechanism in these cells and perhaps in other cells that have GABA(A) receptors although not having a GABA(A) synaptic input. They may also be a target for clinically useful drugs such as the benzodiazepines.
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| 36. |
- Birznieks, Ingvars, et al.
(författare)
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Encoding of direction of fingertip forces by human tactile afferents
- 2001
-
Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 21:20, s. 8222-8237
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Tidskriftsartikel (refereegranskat)abstract
- In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.
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| 37. |
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| 38. |
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| 39. |
- de Frias, Cindy M, et al.
(författare)
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Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults.
- 2005
-
Ingår i: Journal of cognitive neuroscience. - Cambridge : MIT Press - Journals. - 0898-929X .- 1530-8898. ; 17:7, s. 1018-25
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Tidskriftsartikel (refereegranskat)abstract
- The catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition (executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions (verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial (block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele (with higher enzyme activity) compared with carriers of the Met/Met genotype (with low enzyme activity) performed worse on executive functioning and visuospatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age x COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults.
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| 40. |
- Dimberg, Ulf, et al.
(författare)
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Facial reactions to happy and angry facial expressions: Evidence for right hemisphere dominance
- 2000
-
Ingår i: Psychophysiology. - : CAMBRIDGE UNIV PRESS. - 0048-5772 .- 1469-8986. ; 37:5, s. 693-696
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Tidskriftsartikel (refereegranskat)abstract
- Previous research on asymmetric effects of emotional expression and brain-hemispheric asymmetry has supported opposing theories of hemispheric dominance in the control of emotional reactions. In the present study, 32 subjects were exposed to pictures of happy and angry facial stimuli while facial electromyographic (EMG) activity from the zygomatic major and the corrugator supercilii muscle regions was detected from the left and right sides of the face. The subjects reacted spontaneously and rapidly with larger zygomatic EMG activity to happy facial stimuli and larger corrugator EMG activity to angry stimuli. These distinct reactions were significantly larger on the left side of the face. It is concluded that the present results support the hypothesis that the right brain hemisphere is predominantly involved in the control of spontaneously evoked emotional reactions.
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| 41. |
- Eghbali, Mansoureh, et al.
(författare)
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Conductance of GABAA channels activated by pentobarbitone in hippocampal neurons from newborn rats.
- 2003
-
Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 552:Pt 1, s. 13-22
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Tidskriftsartikel (refereegranskat)abstract
- Neurons were obtained from the CA1 region of the hippocampus of newborn rats and maintained in culture. Channels were activated by pentobarbitone in cell-attached, inside-out or outside-out patches, normally by applying pentobarbitone in flowing bath solution. Currents were outwardly rectifying and blocked by bicuculline, properties of GABAA channels in these cells. Maximum channel conductance increased as pentobarbitone concentration was increased to 500 microM but conductance then decreased as pentobarbitone concentration was raised further. The best fit of a Hill-type equation to the relationship between maximum channel conductance and pentobarbitone concentration (up to 500 microM) gave an EC50 of 41 microM, a maximum conductance of 36 pS and a Hill coefficient of 1.6. Bicuculline decreased the maximum conductance of the channels activated by pentobarbitone, with an IC50 of 224 microM. Diazepam increased channel conductance, with a maximum effect being obtained with 1 microM diazepam. Diazepam (1 microM) decreased the EC50 of the pentobarbitone effect on channel conductance from 41 microM to 7.2 microM and increased maximum conductance to 72 pS. We conclude that GABAA channel conductance is related to the concentration of the allosteric agonist pentobarbitone.
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| 42. |
- Eghbali, Mansoureh, et al.
(författare)
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Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons.
- 2003
-
Ingår i: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 468:2, s. 75-82
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Tidskriftsartikel (refereegranskat)abstract
- Channels were activated, in ripped-off patches from rat-cultured hippocampal neurons, by propofol alone, propofol plus 0.5 microM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 microM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 microM) to about 60 pS (500 microM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 microM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 microM and a Hill coefficient of 1.1. Addition of 0.5 microM GABA shifted the propofol EC50 value to 10 microM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 microM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABAA channels conductance.
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| 43. |
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| 44. |
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| 45. |
- Fuxe, K., et al.
(författare)
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Intramembrane receptor-receptor interactions: a novel principle in molecular medicine
- 2007
-
Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 114:1, s. 49-75
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Tidskriftsartikel (refereegranskat)abstract
- In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.
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| 46. |
- Gerdle, Björn, 1953-, et al.
(författare)
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Firing rate and conduction velocity of single motor units in the trapezius muscle in fibromyalgia patients and healthy controls
- 2008
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Ingår i: Journal of Electromyography & Kinesiology. - : Elsevier. - 1050-6411 .- 1873-5711. ; 18:5, s. 707-716
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia is a common chronic pain condition in the population (2-4%), which often is associated with prominent negative consequences with respect to participation in daily activities. There are several reports in the literature concerning the effects of acute experimental pain on motor control. However, a more heterogeneous picture exists in the literature with respect to whether chronic pain conditions affect motor control. This study compares firing rate and conduction velocity (CV) of single motor units (MUs) in the trapezius muscle of fibromyalgia patients (FM) and healthy controls (CON). Multi-channel surface electromyography was used to estimate both MU firing rate and CV because this technique allows simultaneous estimation of both these variables and the measurements are easy and non-invasive. In this study, 29 FM and 30 CON subjects participated and performed isometric shoulder elevations using weights up to 4 kg. No significant differences in the firing rate of MUs in the trapezius muscle were found between the FM and CON groups (95% confidence interval was -1.9 and 1.3 pulses per second). There were no significant differences in CV between the groups at 1 and 2 kg load. However, the FM group had significantly higher CV in contractions without external load (p=0.004). We were unable to confirm the pain-adaptation model since no differences in firing rate between the two groups were found. CV was significantly higher in FM than in healthy controls; this might be due to alterations in histopathology and microcirculation.
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| 47. |
- Gezelius, Henrik, 1977-
(författare)
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Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spinal neurons are important in several aspects motor control. For example, the neurons essential for locomotor movements reside in the ventral spinal cord. In this thesis, different motor control functions are being related to neuronal populations defined by their common expression of a gene. First, a targeted disruption of the gene for vesicular glutamate transporter 2 (Vglut2/ Slc17a6) is described. The mutant animals die at birth because of their inability to breathe. The neuronal network in the brainstem, responsible for inspiration, was shown to become non-functional by the targeted deletion of Vglut2. To our surprise, it was still possible to induce rhythmic activity with normal left/right alternation in spinal cords isolated from VGLUT2-null embryos. Inconsistent reports of Vglut1 expression in the spinal cord made us re-evaluate the Vglut1 and Vglut2 expressions. While Vglut2 expression was widespread in the spinal cord, Vglut1 expression was restricted to a few cells dorsal to the central canal. Taken together, the data suggest that, glutamatergic signaling is mandatory to drive the bilateral breathing, but not needed for coordination of basal alternating spinal locomotor rhythm. Next, a screen for genes with restricted ventral expression was made. Some of the genes found could be connected to the characteristics of specific neuronal cell populations. For example, fast motor neurons were shown to express the genes Calca and Chodl. Further, we found the Chrna2 expression selectively in putative Renshaw cells. It seems likely that the gene product, the alpha2 subunit of the nicotinergic receptor, could be linked to the unique connection of motor neurons to Renshaw cells. We used the Chrna2 promoter to drive expression of Cre recombinase in a transgenic mouse. The Cre activity was present in most neurons labeled with Renshaw cell markers, which should make it a useful tool for functional studies of this population. The studies presented here show how the genes expressed in subsets of neurons can be used to target populations of neurons for functional studies of neuronal systems.
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| 48. |
- Grip, Helena, et al.
(författare)
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Classification of Neck Movement Patterns Related to Whiplash-Associated Disorders Using Neural Networks
- 2003
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Ingår i: IEEE transactions on information technology in biomedicine. - : IEEE. - 1089-7771 .- 1558-0032. ; 7:4, s. 412-418
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a new method for classification of neck movement patterns related to Whiplash-associated disorders (WAD) using a resilient backpropagation neural network (BPNN). WAD are a common diagnosis after neck trauma, typically caused by rear-end car accidents. Since physical injuries seldom are found with present imaging techniques, the diagnosis can be difficult to make. The active range of the neck is often visually inspected in patients with neck pain, but this is a subjective measure, and a more objective decision support system, that gives a reliable and more detailed analysis of neck movement pattern, is needed. The objective of this study was to evaluate the predictive ability of a BPNN, using neck movement variables as input. Three-dimensional (3-D) neck movement data from 59 subjects with WAD and 56 control subjects were collected with a ProReflex system. Rotation angle and angle velocity were calculated using the instantaneous helical axis method and motion variables were extracted. A principal component analysis was performed in order to reduce data and improve the BPNN performance. BPNNs with six hidden nodes had a predictivity of 0.89, a sensitivity of 0.90 and a specificity of 0.88, which are very promising results. This shows that neck movement analysis combined with a neural network could build the basis of a decision support system for classifying suspected WAD, even though further evaluation of the method is needed.
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| 49. |
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| 50. |
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