| 21. |
- Hallén, Kristofer, et al.
(författare)
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mGluR-Mediated calcium oscillations in the lamprey: a computational model
- 2004
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Ingår i: Neurocomputing. - AMSTERDAM : Elsevier BV. - 0925-2312 .- 1872-8286. ; 58-60, s. 431-435, s. 431-435
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Tidskriftsartikel (refereegranskat)abstract
- Slow Ca2+ oscillations caused by release from intracellular stores have been observed in neurons in the lamprey spinal cord. These oscillations are triggered by activation of metabotropic glutamate receptors on the cell surface. The pathway leading from receptor activation to the inositol triphosphate-mediated release of Ca2+ from the endoplasmatic reticulum has been modelled in order to facilitate further understanding of the nature of these oscillations. The model generates Ca2+ oscillations with a frequency range of 0.01–0.09 Hz. A prediction of the model is that the frequency will increase with a stronger extracellular glutamate signal.
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| 22. |
- Hong, Shengjun, et al.
(författare)
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Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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| 23. |
- Issa, Fadi A, et al.
(författare)
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Neural circuit activity in freely behaving zebrafish (Danio rerio).
- 2011
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Ingår i: The Journal of experimental biology. - : The Company of Biologists. - 1477-9145 .- 0022-0949. ; 214:Pt 6, s. 1028-38
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Tidskriftsartikel (refereegranskat)abstract
- Examining neuronal network activity in freely behaving animals is advantageous for probing the function of the vertebrate central nervous system. Here, we describe a simple, robust technique for monitoring the activity of neural circuits in unfettered, freely behaving zebrafish (Danio rerio). Zebrafish respond to unexpected tactile stimuli with short- or long-latency escape behaviors, which are mediated by distinct neural circuits. Using dipole electrodes immersed in the aquarium, we measured electric field potentials generated in muscle during short- and long-latency escapes. We found that activation of the underlying neural circuits produced unique field potential signatures that are easily recognized and can be repeatedly monitored. In conjunction with behavioral analysis, we used this technique to track changes in the pattern of circuit activation during the first week of development in animals whose trigeminal sensory neurons were unilaterally ablated. One day post-ablation, the frequency of short- and long-latency responses was significantly lower on the ablated side than on the intact side. Three days post-ablation, a significant fraction of escapes evoked by stimuli on the ablated side was improperly executed, with the animal turning towards rather than away from the stimulus. However, the overall response rate remained low. Seven days post-ablation, the frequency of escapes increased dramatically and the percentage of improperly executed escapes declined. Our results demonstrate that trigeminal ablation results in rapid reconfiguration of the escape circuitry, with reinnervation by new sensory neurons and adaptive changes in behavior. This technique is valuable for probing the activity, development, plasticity and regeneration of neural circuits under natural conditions.
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| 24. |
- Jeppsson, Anna, et al.
(författare)
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Shared CSF Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus and Subcortical Small Vessel Disease.
- 2022
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers.We analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ isoforms -38, -40, and -42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP -1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale.All amyloid fragments were reduced in iNPH and SSVD (p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP (p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD.The results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.
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| 25. |
- Karlsson, Sara, 1980, et al.
(författare)
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Effects of sex and gonadectomy on social investigation and social recognition in mice
- 2015
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Ingår i: Bmc Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: An individual's ability to recognise and pay attention to others is crucial in order to behave appropriately in various social situations. Studies in humans have shown a sex bias in sociability as well as social memory, indicating that females have better face memory and gaze more at the eyes of others, but information about the factors that underpin these differences is sparse. Our aim was therefore to investigate if sociability and social recognition differ between female and male mice, and if so, to what extent gonadal hormones may be involved. Intact and gona-dectomised male and female mice were assessed for sociability and social recognition using the three-chambered sociability paradigm, as well as the social discrimination test. Furthermore, we conducted a novel object recognition test, a locomotor activity test and an odour habituation/dishabituation test. Results: The present study showed that the ability to recognise other individuals is intact in males with and without gonads, as well as in intact females, whereas it is hampered in gonadectomised females. Additionally, intact male mice displayed more persistent investigatory behaviour compared to the other groups, although the intact females showed elevated basal locomotor activity. In addition, all groups had intact object memory and habituated to odours. Conclusions: Our results suggest that intact male mice investigate conspecifics more than females do, and these differences seem to depend upon circulating hormones released from the testis. As these results seem to contrast what is known from human studies, they should be taken into consideration when using the three-chambered apparatus, and similar paradigms as animal models of social deficits in e.g. autism. Other behavioural tests, and animal models, may be more suitable for translational studies between patients and experimental animals.
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| 26. |
- Karlsson, Sara, 1980, et al.
(författare)
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Neural Androgen Receptors Modulate Gene Expression and Social Recognition But Not Social Investigation
- 2016
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media SA. - 1662-5153. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The role of sex and androgen receptors (ARs) for social preference and social memory is rather unknown. In this study of mice we compared males, females and males lacking ARs specifically in the nervous system, ARNesDel, with respect to social preference, assessed with the three-chambered apparatus test, and social recognition, assessed with the social discrimination procedure. In the social discrimination test we also evaluated the tentative importance of the sex of the stimulus animal. Novel object recognition and olfaction were investigated to complement the results from the social tests. Gene expression analysis was performed to reveal molecules involved in the effects of sex and androgens on social behaviors. All three test groups showed social preference in the three-chambered apparatus test. In both social tests an AR independent sexual dimorphism was seen in the persistence of social investigation of female conspecifics, whereas the social interest toward male stimuli mice was similar in all groups. Male and female controls recognized conspecifics independent of their sex, whereas ARNesDel males recognized female but not male stimuli mice. Moreover, the non-social behaviors were not affected by AR deficiency. The gene expression analyses of hypothalamus and amygdala indicated that Oxtr, Cd38, Esrl, Cyp19a1, Ucn3, Crh. and Gtf2i were differentially expressed between the three groups. In conclusion, our results suggest that ARs are required for recognition of male but not female conspecifics, while being dispensable for social investigation toward both sexes. In addition, the AR seems to regulate genes related to oxytocin, estrogen and William's syndrome.
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| 27. |
- Kettunen, Petronella, et al.
(författare)
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Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease.
- 2022
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers.We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-β (Aβ)x-38, Aβx-40, Aβx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-β.sAPP-β was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-β moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses.SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-β could be additional tools to diagnose SSVD.Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-β and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.
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| 28. |
- Kettunen, Petronella, et al.
(författare)
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Calcium imaging in the zebrafish.
- 2012
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Ingår i: Calcium Signaling. Advances in Experimental Medicine and Biology, Vol. 740, Ed. Shahidul Islam. - Dordrecht : Springer. - 0065-2598. - 9789400728875 ; 740, s. 1039-71
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Bokkapitel (refereegranskat)abstract
- The zebrafish (Danio rerio) has emerged as a new model system during the last three decades. The fact that the zebrafish larva is transparent enables sophisticated in vivo imaging. While being the vertebrate, the reduced complexity of its nervous system and small size make it possible to follow large-scale activity in the whole brain. Its genome is sequenced and many genetic and molecular tools have been developed that simplify the study of gene function. Since the mid 1990s, the embryonic development and neuronal function of the larval, and later, adult zebrafish have been studied using calcium imaging methods. The choice of calcium indicator depends on the desired number of cells to study and cell accessibility. Dextran indicators have been used to label cells in the developing embryo from dye injection into the one-cell stage. Dextrans have also been useful for retrograde labeling of spinal cord neurons and cells in the olfactory system. Acetoxymethyl (AM) esters permit labeling of larger areas of tissue such as the tectum, a region responsible for visual processing. Genetically encoded calcium indicators have been expressed in various tissues by the use of cell-specific promoters. These studies have contributed greatly to our understanding of basic biological principles during development and adulthood, and of the function of disease-related genes in a vertebrate system.
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| 29. |
- Kettunen, Petronella, et al.
(författare)
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Calcium Imaging in the Zebrafish.
- 2020
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Ingår i: Calcium Signaling. Advances in experimental medicine and biology. Islam M. (red.). - Cham : Springer. - 0065-2598. - 9783030124564 ; , s. 901-942
-
Bokkapitel (refereegranskat)abstract
- The zebrafish (Danio rerio) has emerged as a widely used model system during the last four decades. The fact that the zebrafish larva is transparent enables sophisticated in vivo imaging, including calcium imaging of intracellular transients in many different tissues. While being a vertebrate, the reduced complexity of its nervous system and small size make it possible to follow large-scale activity in the whole brain. Its genome is sequenced and many genetic and molecular tools have been developed that simplify the study of gene function in health and disease. Since the mid 90's, the development and neuronal function of the embryonic, larval, and later, adult zebrafish have been studied using calcium imaging methods. This updated chapter is reviewing the advances in methods and research findings of zebrafish calcium imaging during the last decade. The choice of calcium indicator depends on the desired number of cells to study and cell accessibility. Synthetic calcium indicators, conjugated to dextrans and acetoxymethyl (AM) esters, are still used to label specific neuronal cell types in the hindbrain and the olfactory system. However, genetically encoded calcium indicators, such as aequorin and the GCaMP family of indicators, expressed in various tissues by the use of cell-specific promoters, are now the choice for most applications, including brain-wide imaging. Calcium imaging in the zebrafish has contributed greatly to our understanding of basic biological principles during development and adulthood, and the function of disease-related genes in a vertebrate system.
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| 30. |
- Kettunen, Petronella, et al.
(författare)
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Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function
- 2015
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Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 44:4, s. 1313-1322
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood.Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau(181)), and amyloid-beta (A beta(42)).Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (p(c) = 0.04). Next, rs1154597 showed association with reducedA beta(42) levels (pc = 0.007). Lastly, rs3107669was associated with lower MMSE scores (p(c) = 0.03). In addition, one more SNP was nominally significantly associated with reduced A beta(42) levels and another was associated with reduced MMSE.Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and A beta(42). To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (A beta(42)). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis.
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