| 1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 2. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 3. |
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| 4. |
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| 5. |
- Kempermann, G., et al.
(författare)
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Human Adult Neurogenesis: Evidence and Remaining Questions
- 2018
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 23:1, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.
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| 6. |
- Bigdeli, TB, et al.
(författare)
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Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry
- 2020
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 25:10, s. 2455-2467
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.
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| 7. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- The steps involved in the grafting of mesencephalic and septal embryonic tissue in the form of dissociated cell suspensions are described in detail. This includes dissection of the donor embryos, incubation in trypsin, mechanical dissociation, and stereotaxic injection into the brains of adult recipient rats. Some of the technical problems and limitations are discussed.
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| 8. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cells implanted in different brain sites
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 9-18
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Tidskriftsartikel (refereegranskat)abstract
- Dissociated dopamine-rich cell suspensions were prepared from the ventral mesencephalon of rat embryos and injected in one or several sites in striatal and non-striatal regions in the dopaminergically denervated brain of adult rats. While the grafts survived well in all sites, the dopamine fibre outgrowth was markedly different depending on whether the grafts occurred in an area normally innervated by the mesencephalic dopamine neurones (i.e. neostriatum or nc. accumbens) or in areas not normally innervated by these neurones (i.e. parietal cortex, lateral hypothalamus or substantia nigra). Moreover, in grafts placed at different sites along the trajectory of the nigrostriatal pathway the outgrowing fibres remained confined to the graft, and there was little evidence that the implanted neurones could elongate their axons along the pathway of the nigrostriatal tract to reach the striatum from a distance. Thus, the intracerebral suspension grafts provided efficient reinnervation of a denervated target only when placed in the immediate vicinity of the target area. The results of multiple graft placements indicate that a relatively complete restoration of a lost innervation should be possible to achieve in large areas of the brain, such as the striatal complex, with the suspension grafting technique.
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| 9. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippccampus reinnervated by septal suspension implants
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 59-66
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Tidskriftsartikel (refereegranskat)abstract
- The time-course and magnitude of fibre outgrowth from septal suspension grafts injected into the previously denervated hippocampal formation was monitored by measurements of choline acetyltransferase (ChAT), and the activity of the grafted neurons was assessed by measurements of [14C]acetylcholine (ACh) synthesis from [14C]glucose in vitro. Graft-derived ChAT activity was barely detectable 10 days after grafting, but increased sharply between 10 days and 1 month in the areas of the hippocampus located close to the septal implants. By 6 months ChAT activity was restored to near normal levels in all segments of the previously denervated hippocampus. The overall hippocampal [14C]ACh synthesis was also restored to normal levels in the grafted animals, and estimates of the ACh turnover rate suggested that the transmitter machinery of the newly established "septo-hippocampal" connections operated at a rate similar to that of the intrinsic septohippocampal pathway. The intrahippocampal septal suspension grafts, similar to the intrastriatal nigral grafts, thus seem to be capable of maintaining function at a relatively "physiological" level despite their abnormal positions.
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| 10. |
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| 11. |
- Horne, B D, et al.
(författare)
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Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
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| 12. |
- Lenzini, P., et al.
(författare)
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Integration of genetic, clinical, and INR data to refine warfarin dosing
- 2010
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 87:5, s. 572-578
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Tidskriftsartikel (refereegranskat)abstract
- Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
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| 13. |
- Schmidt, R H, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. III. Activaty of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 19-28
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Tidskriftsartikel (refereegranskat)abstract
- The activity of intrastriatal grafts of nigral cell suspensions has been monitored biochemically, using radioenzymatic assays of dopamine, its major acidic metabolite, DOPAC, and DOPA accumulation after DOPA-decarboxylase inhibition. Implants of 4-9 microliter of nigral cell suspension restored striatal DA levels by an average of 13-18%, with the highest individual values reaching about 50% of control. DOPAC was restored from about 5% in the lesioned controls to about 20% of normal in the grafted animals. The DOPAC: DA ratios and the DOPA accumulation measures indicated that the grafted DA neurons were spontaneously active and that the transmitter turnover rate was on the average some 50-100% higher than the intact intrinsic nigrostriatal DA neurones. These results thus provide evidence that the intrastriatal nigral suspension grafts are capable of restoring dopaminergic neurotransmission in the previously denervated striatum.
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| 14. |
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| 15. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VI. Survival and growth of intrahippocampal implants of septal cell suspensions
- 1983
-
Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- The survival and growth of intrahippocampal septal suspension grafts were investigated by acetylcholine esterase (AChE) histochemistry in animals with lesions of the intrinsic septohippocampal cholinergic pathways. AChE was demonstrable in the grafts after the first postoperative week, and AChE-positive fibres were seen to extend into the host hippocampus by 3 weeks. Rapid fibre outgrowth occurred between 3 weeks and 3 months after grafting, and continued at a slower rate thereafter. By 6 months a fairly complete reinnervation of the initially denervated hippocampus was achieved in most specimens, and this persisted at 14 months, the longest postoperative time analysed. A comparison between the development of the AChE-positive neurones in the suspension grafts with that seen during ontogeny in situ suggested that the grafted neurones lagged behind normal development by at least 1 week. Similar to our previous observations on septal grafts implanted as solid tissue pieces, the pattern of the newly-formed AChE-positive innervation in the host hippocampal formation, established from the septal suspension grafts, was remarkably similar to that of the normal AChE-positive septal innervation. This pattern became established as soon as the graft-derived fibres first grew in, suggesting that the ingrowing axons extended and ramified preferentially into those hippocampal subfields which normally receive an AChE-positive innervation from the septal-diagonal band area.
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| 16. |
- Brundin, P, et al.
(författare)
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Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons
- 1985
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Ingår i: Experimental Brain Research. - 0014-4819. ; 60:1, s. 8-204
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Tidskriftsartikel (refereegranskat)abstract
- The survival and function of cross-species (mouse-to-rat) grafts of fetal mesencephalic dopamine (DA) neurons, implanted as a cell suspension in the striatum of rats with lesions of the mesostriatal DA system, have been studied in animals with and without immunosuppression induced by Cyclosporin A (CyA). At 6 weeks after grafting 3 out of 7 non-CyA treated animals showed some degree of graft survival and variable functional compensation. In those three animals an average of 92 DA neurons per graft was counted. In the grafted animals treated with daily CyA injections, all grafts survived and produced partial or complete functional compensation, and they had an average of 557 DA neurons per graft. It is concluded that intracerebral graft survival and function can be greatly improved by CyA treatment and that the immunological protection of neural transplants in the brain is only partial.
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| 17. |
- Clarke, D J, et al.
(författare)
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Synaptogenesis of grafted cholinergic neurons
- 1987
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 495:1, s. 268-282
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Tidskriftsartikel (refereegranskat)
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| 18. |
- Eriksson, Peter S, 1959, et al.
(författare)
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Neurogenesis in the adult human hippocampus
- 1998
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Ingår i: Nat Med. - 1078-8956. ; 4:11, s. 1313-7
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Tidskriftsartikel (refereegranskat)abstract
- The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.
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| 19. |
- Gage, F H, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VIII. Cell survival and axonal outgrcwth of dcpaminergic and cholinergic cells in the aged brain.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 67-75
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal cell suspensions prepared from the ventral mesencephalon and the septal-diagonal band area of rat embryos were implanted into the depth of the intact neostriatum or hippocampus of 21-23 month old female rats. Graft survival, assessed 3-4 months after grafting, was comparable to that seen in our previous studies of young adult recipients. Fibre outgrowth into the host brain was evaluated in animals which were subjected to lesions of the intrinsic nigrostriatal or septohippocampal system 6-10 days before killing. Dense dopamine fibre outgrowth was seen within a zone of up to about 1 mm radius around the nigral implants, and dense growth of acetylcholine esterase (AChE) positive fibres occurred up to about 2 mm away from the septal implants. The overall magnitude of fibre outgrowth was less than that generally seen in previously denervated targets in young adult recipients, but it appeared to be as extensive as in young recipients when the grafts are placed in non-denervated targets. The distribution of the AChE-positive fibres from the septal implants in the host hippocampus suggested that the pattern found in the non-denervated target of the aged recipients was more diffuse, and partly different, from normal, and that age-dependent synapse loss in intrinsic connections may influence the patterning of the graft-derived innervation.
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| 20. |
- Kuhn, Hans-Georg, 1961, et al.
(författare)
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Adult Hippocampal Neurogenesis: A Coming-of-Age Story
- 2018
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 38:49, s. 10401-10410
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Tidskriftsartikel (refereegranskat)abstract
- What has become standard textbook knowledge over the last decade was a hotly debated matter a decade earlier: the proposition that new neurons are generated in the adult mammalian CNS. The early discovery by Altman and colleagues in the 1960s was vulnerable to criticism due to the lack of technical strategies for unequivocal demonstration, quantification, and physiological analysis of newly generated neurons in adult brain tissue. After several technological advancements had been made in the field, we published a paper in 1996 describing the generation of new neurons in the adult rat brain and the decline of hippocampal neurogenesis during aging. The paper coincided with the publication of several other studies that together established neurogenesis as a cellular mechanism in the adult mammalian brain. In this Progressions article, which is by no means a comprehensive review, we recount our personal view of the initial setting that led to our study and we discuss some of its implications and developments that followed. We also address questions that remain regarding the regulation and function of neurogenesis in the adult mammalian brain, in particular the existence of neurogenesis in the adult human brain.
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| 21. |
- Limdi, Nita A., et al.
(författare)
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Warfarin pharmacogenetics : a single VKORC1 polymorphism is predictive of dose across three racial groups
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:18, s. 3827-3834
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Tidskriftsartikel (refereegranskat)abstract
- Warfarin dosing algorithms incorporating CYP2C9 and VKORC1-1639G>A improve dose prediction compared to algorithms based solely on clinical and demographic factors. However these algorithms better capture dose variability among Whites compared to Asians or Blacks. Herein we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1-1639G>A among Asians (n=1103), Blacks (n=670) and Whites (n=3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 SNPs and haplotypes on warfarin dose employed both univariate and multivariable linear regression. VKORC1-1639G>A and 1173C>T individually explained the greatest variance in dose in all three racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among Whites as compared to Blacks and Asians. Differences in the percent variance in dose explained by VKORC1 across race was largely accounted for by the frequency of the -1639 A (or 1173 T) allele. Thus, clinicians should recognize that although at a population level, the contribution of VKORC1 towards dose requirements is higher in Whites compared to non-whites; genotype predicts similar dose requirements across racial groups.
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| 22. |
- Nilsson, O G, et al.
(författare)
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Anticholinergic sensitivity in the aging rat septohippocampal system as assessed in a spatial memory task
- 1993
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Ingår i: Neurobiology of Aging. - 0197-4580. ; 14:5, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- The effects of central cholinergic blockade on spatial memory were tested in aged and basal forebrain-lesioned rats using the Morris Water Maze. In Experiment 1, aged rats (18-21 months old) were characterized as behaviorally impaired or nonimpaired based on water maze performance prior to an atropine sulfate challenge. In the atropine test (50 mg/kg, IP), both the impaired and the nonimpaired rats showed a severe disruption of their search behavior compared to young subjects. This effect was due to blockade of central receptors since peripheral cholinergic blockade using atropine methylbromide did not produce any impairments. Experiment 2 investigated effects of atropine on rats with septal lesions (SL), nucleus basalis lesions (NBL), and rats with both lesions combined (SL + NBL). Before drug treatment, the groups with septal lesions (SL and SL + NBL groups) displayed a moderate impairment in locating the platform site. However, similar to the aged rats, the septal-lesioned rats exhibited severe impairments in the water maze during atropine treatment. This effect was not seen in the normal controls or in the NBL rats. Aged rats, either impaired or nonimpaired in a spatial memory task, showed a pronounced sensitivity to pharmacological blockade of central cholinergic neurotransmission which resulted in severe deficits in spatial navigation in the water maze. Since the same behavioral deficit was produced by cholinergic blockade in young rats with septal lesions, we concluded that the impaired water maze performance seen in the aged rats during cholinergic blockade resulted from impaired function in the septohippocampal system.
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| 23. |
- Nilsson, O G, et al.
(författare)
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Spatial learning and memory following fimbria-fornix transection and grafting of fetal septal neurons to the hippocampus
- 1987
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Ingår i: Experimental Brain Research. - 0014-4819. ; 67:1, s. 195-215
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Tidskriftsartikel (refereegranskat)abstract
- The ability of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in developing cholinergic neurons, to ameliorate cognitive impairments induced by bilateral fimbria-fornix transections in rats was examined in three experiments using the Morris water-maze to test different aspects of spatial memory. Experiment 1. Rats with fimbriafornix lesions received either septal cell suspension grafts or solid septal grafts; normal rats and rats with lesions alone were used as controls. Sixteen weeks after surgery, the rats' spatial learning and memory were tested in the water-maze using a place test, designed to investigate place navigation performance, in which rats learned to escape from the water by swimming to a platform hidden beneath the water's surface. After 5 days of training, the rats were given a spatial probe test in which the platform was removed from the tank to test spatial reference memory. Experiment 2. The same rats used in Exp. 1 were tested in a delayed-match-to-sample, working memory version of the water-maze task. The platform was located in one of two possible locations during each trial, which was composed of 2 swims. If the rat remembered the location of the platform on the 2nd swim of a trial, it should find the platform more quickly on that swim, and thereby demonstrate working memory. Experiment 3. Prior to receiving fimbria-fornix lesions, normal rats were trained in a modification of the water-maze task using alternating cue navigation and place navigation trials (i.e., with visible or non-visible escape platforms). The retention and reacquisition of the place task and the spatial probe test were examined in repeated tests up to 6 months after the lesion and intrahippocampal grafting of septal cell suspensions. The effects of central muscarinic cholinergic receptor blockade with atropine were also tested. Normal rats performed well in both the place and spatial probe tests. In contrast, rats with fimbria-fornix lesions only were unable to acquire or retain spatial information in any test. Instead, these rats adopted a random, non-spatial search strategy, whereby their latencies to find the platform decreased in the place navigation tasks. Sixty to 80% of the rats with septal suspension or solid grafts had recovered place navigation, i.e., the ability to locate the platform site in the tank, in Exp. 1 and 3, and they showed a significantly improved performance in the working memory test in Exp. 2. Atropine abolished the recovered place navigation in the grafted rats, whereas normal rats were impaired to a lesser extent.(ABSTRACT TRUNCATED AT 400 WORDS)
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| 24. |
- Shahsavani, M, et al.
(författare)
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An in vitro model of lissencephaly : expanding the role of DCX during neurogenesis
- 2018
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 23:7, s. 1674-1684
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Tidskriftsartikel (refereegranskat)abstract
- Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.175.
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| 25. |
- Wieloch, T., et al.
(författare)
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Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path
- 1985
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Ingår i: Neurological Research. - : Informa UK Limited. - 0161-6412 .- 1743-1328. ; 7:1, s. 24-26
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Tidskriftsartikel (refereegranskat)abstract
- The effect of lesions of two excitatory afferent pathways on the cellular damage in the hippocampus following complete cerebral ischaemia was investigated in the rat Lesions transecting the perforant path led to a significant decrease in cellular damage in the hippocampal CA1 region ipsilateral to the lesion as compared to the contatterai side and to control. Lesions of the fimbria-fornix, on the other hand, had no significant effects. We propose that the protective effect of the perforant path lesions is due to removal of glutamatergic/aspartergic pathways and that release of these excitatory amino acids might be a critical factor for neuronal necrosis following cerebral ischaemia.
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