| 1. |
- Broms, Jonas, et al.
(författare)
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Monosynaptic retrograde tracing of neurons expressing the G-protein coupled receptor Gpr151 in the mouse brain
- 2017
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 525:15, s. 3227-3250
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Tidskriftsartikel (refereegranskat)abstract
- GPR151 is a G-protein coupled receptor for which the endogenous ligand remains unknown. In the nervous system of vertebrates, its expression is enriched in specific diencephalic structures, where the highest levels are observed in the habenular area. The habenula has been implicated in a range of different functions including behavioral flexibility, decision making, inhibitory control, and pain processing, which makes it a promising target for treating psychiatric and neurological disease. This study aimed to further characterize neurons expressing the Gpr151 gene, by tracing the afferent connectivity of this diencephalic cell population. Using pseudotyped rabies virus in a transgenic Gpr151-Cre mouse line, monosynaptic afferents of habenular and thalamic Gpr151-expressing neuronal populations could be visualized. The habenular and thalamic Gpr151 systems displayed both shared and distinct connectivity patterns. The habenular neurons primarily received input from basal forebrain structures, the bed nucleus of stria terminalis, the lateral preoptic area, the entopeduncular nucleus, and the lateral hypothalamic area. The Gpr151-expressing neurons in the paraventricular nucleus of the thalamus was primarily contacted by medial hypothalamic areas as well as the zona incerta and projected to specific forebrain areas such as the prelimbic cortex and the accumbens nucleus. Gpr151 mRNA was also detected at low levels in the lateral posterior thalamic nucleus which received input from areas associated with visual processing, including the superior colliculus, zona incerta, and the visual and retrosplenial cortices. Knowledge about the connectivity of Gpr151-expressing neurons will facilitate the interpretation of future functional studies of this receptor.
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| 2. |
- Carlen, Marie, et al.
(författare)
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Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke
- 2009
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 12:3, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.
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| 3. |
- Guillaumin, Adriane
(författare)
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The subthalamic nucleus in motor and affective functions : An optogenetic in vivo-investigation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The basal ganglia form a group of subcortical interconnected nuclei involved in motor, limbic and cognitive functions. According to the classical model of the basal ganglia, two main pathways exert opposing control over movement, one facilitating movement and the other suppressing movement. The subthalamic nucleus (STN) plays a critical role in this function, and has also been implicated in reward processing. Despite ample knowledge of the role of the STN in motor dysfunctions in relation to Parkinson’s disease, less is known about STN’s natural role in healthy subjects.The studies described in this thesis aimed to address the functional role of the STN in its natural neurocircuitry by using a transgenic mouse line which expresses Cre recombinase under the Pitx2 promoter. The Pitx2 gene is restricted to the STN and the use of Pitx2-Cre mice thereby allows selective manipulation of STN neurons by using optogenetics. By expressing Channelrhodopsin (ChR2) or Archaerhodopsin (Arch) in Pitx2-Cre neurons, we could optogenetically excite or inhibit STN Pitx2-Cre neurons and investigate the role of the STN in motor and affective functions. We showed that optogenetic inhibition and excitation of the STN induce opposite effects on motor activity. STN excitation reduced locomotion while STN inhibition enhanced locomotion, thereby providing experimental evidence to classical motor models postulating this role. We also showed that optogenetic excitation of the STN induces potent place avoidance, a behaviour relevant to aversion. Projections from the STN to the ventral pallidum (VP) exist that when excited induced the same behaviour. The VP projects to the lateral habenula (LHb), a structure known for its role in aversion. A glutamatergic multi-synaptic connection between the STN and the LHb was confirmed.Aversive behaviour is also mediated by the hypothalamic-mesencephalic area. The Trpv1 gene is expressed within the posterior hypothalamus. By applying optogenetics in a Trpv1-Cre mouse line, projection patterns to limbic brain areas were identified, and optogenetic excitation of Trpv1-Cre neurons was found to induce place avoidance.The STN and posterior hypothalamus are thereby demonstrated as new players in the aversion neurocircuitry, while the long-assumed role of the STN in motor behaviour is confirmed. To enable future analyses of how STN manipulation might rescue motor and affective deficiency relevant to human disorders, a neuronal degeneration mouse model was generated.To conclude, the results presented in this thesis contribute to enhanced neurobiological understanding of the role played by the STN in motor and affective functions.
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| 4. |
- Guyon, Nicolas, et al.
(författare)
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Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics
- 2021
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Ingår i: Journal of Neuroscience. - Stockholm : Karolinska Institutet, Dept of Neuroscience. - 0270-6474. ; 41:14, s. 3120-3141
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of c oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.
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| 5. |
- Lebrigand, Kevin, et al.
(författare)
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The spatial landscape of gene expression isoforms in tissue sections
- 2023
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- In situ capturing technologies add tissue context to gene expression data, with the potential of providing a greater understanding of complex biological systems. However, splicing variants and full-length sequence heterogeneity cannot be characterized at spatial resolution with current transcriptome profiling methods. To that end, we introduce spatial isoform transcriptomics (SiT), an explorative method for characterizing spatial isoform variation and sequence heterogeneity using long-read sequencing. We show in mouse brain how SiT can be used to profile isoform expression and sequence heterogeneity in different areas of the tissue. SiT reveals regional isoform switching of Plp1 gene between different layers of the olfactory bulb, and the use of external single-cell data allows the nomination of cell types expressing each isoform. Furthermore, SiT identifies differential isoform usage for several major genes implicated in brain function (Snap25, Bin1, Gnas) that are independently validated by in situ sequencing. SiT also provides for the first time an in-depth A-to-I RNA editing map of the adult mouse brain. Data exploration can be performed through an online resource, where isoform expression and RNA editing can be visualized in a spatial context.
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| 6. |
- Masarapu, Yuvarani, et al.
(författare)
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Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).
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| 7. |
- Meletis, Konstantinos, et al.
(författare)
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p53 suppresses the self-renewal of adult neural stem cells
- 2006
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 133:2, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing evidence that tumors are heterogeneous and that a subset of cells act as cancer stem cells. Several proto-oncogenes and tumor suppressors control key aspects of stem cell function, suggesting that similar mechanisms control normal and cancer stem cell properties. We show here that the prototypical tumor suppressor p53, which plays an important role in brain tumor initiation and growth, is expressed in the neural stem cell lineage in the adult brain. p53 negatively regulates proliferation and survival, and thereby self-renewal, of neural stem cells. Analysis of the neural stem cell transcriptome identified the dysregulation of several cell cycle regulators in the absence of p53, most notably a pronounced downregulation of p21 expression. These data implicate p53 as a suppressor of tissue and cancer stem cell self-renewal.
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| 8. |
- Meletis, Konstantinos
(författare)
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Studies on adult stem cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- While our bodies are aging, in quite a few tissues, new cells are born every day, till the day we die. As you are reading this sentence, there is perhaps a new neuron born in your brain (and some are dying). Where does it come from, why does it come now and will it do any good? The field of adult stem cell biology deals with the basic functions of stem cells as found in most species and with their therapeutic potential. It is the stem cells found in each tissue that possess that almost magical regenerative ability. Having endogenous cell replacement is not without risks. Most of us will at some point develop tumors; is there a connection between aging, stem cells and cancer? It is likely, but we don't know. Accumulating evidence these days, including research presented in this thesis, points to the common molecular pathways that govern behavior of stem cells and cancer development. There are several ways one can study stem cells of the adult mammalian brain; our efforts have focused on employing unbiased searches for stem cell signatures, testing candidate genes for their importance in regulating adult stem cell characteristics and creating transgenic mice for the study of the stem cell progeny during health and injury. The first two studies presented in this thesis aim at developing methods for the analysis of gene expression profiles of stem and progenitor cells. Based on a collaborative effort, we constructed cDNA libraries representing transcripts present in adult neural stem cells in vivo and in vitro as well as genes expressed by cells in the neurogenic microenvironment of the lateral ventricle. The cDNA libraries have further been used for the assembly of cDNA arrays for the quantitative analysis of gene expression in stem cells. The collected sequencing data and gene expression profiles have been used in a bioinformatic search for genes that are preferentially expressed in neural stem cells. We have found several interesting targets that could serve as new stem and progenitor cell markers. Studies III and IV are based on the same investigative principle: we chose two candidate pathways for the analysis of their influence on adult neural stem cell biology. A clinically important issue is the cellular origin of tumors. There is an emerging view in tumor biology that only a subset of the cells in a tumor supports the expansive cancer growth. Consequently, study Ill describes the functions of a tumor suppressor, p53, in adult neural stem/progenitor cells as a way of finding common mechanisms between stem cells and tumor formation. p53 is established as an important inhibitor of tumorigenesis and p53 mutations are found in most human cancers. We have found that p53 is an important negative regulator of self-renewal and proliferation of neural stem cells. Study IV continues with a signaling pathway involved in stem cell identity and selfmaintenance. We focused on elucidating the importance of RBP-J/Notch signaling in adult neural stem cells. Using viral approaches in vivo by ventricular injections of adenoviruses and lentiviruses expressing Cre recombinase in a conditional floxed RBP-J mouse line we have been able to pinpoint the effects of deleting RBP-J in a specific cell population, ependymal cells. The deletion of RBP-J in ependymal cells has uncovered their differentiation potential along the neurogenic pathway and the importance of Notch signaling in maintenance of ependymal cell quiescence. Studies V and VI are based on transgenic mice for genetic tracing of candidate stem cell populations. We have constructed two mouse lines: a Nestin-CreER line and a FoxJ1-CreER line. Nestin-CreER expresses CreER T2 in stem and progenitor cells of the central nervous system providing a lineage tool by temporal induction of recombination and thereby visualization of neurogenesis as well as temporal gene deletion. FoxJ1-CreER expresses CreER T2 in ependymal cells of the brain and spinal cord and is used in study six for delineating the functions of ependyma-derived progeny in response to spinal cord injury. In conclusion, by defining the molecular events that are instrumental in neural stem cell biology and following cell fates of candidate stem cell populations, 1 have contributed to our understanding of stem cell behavior.
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| 9. |
- Ortiz, Cantin, et al.
(författare)
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Molecular atlas of the adult mouse brain
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain organization based on unbiased extraction of spatially-defining features. Applying whole-brain spatial transcriptomics, we captured the gene expression signatures to define the spatial organization of molecularly discrete subregions. We found that the molecular code contained sufficiently detailed information to directly deduce the complex spatial organization of the brain. This unsupervised molecular classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and a new division of striatum. The whole-brain molecular atlas further supports the identification of the spatial origin of single neurons using their gene expression profile, and forms the foundation to define a minimal gene set - a brain palette – that is sufficient to spatially annotate the adult brain. In summary, we have established a new molecular atlas to formally define the identity of brain regions, and a molecular code for mapping and targeting of discrete neuroanatomical domains.
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| 10. |
- Ortiz, Cantin, et al.
(författare)
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Molecular atlas of the adult mouse brain
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:26
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Tidskriftsartikel (refereegranskat)abstract
- Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain based purely on the unbiased identification of spatially defining features by employing whole-brain spatial transcriptomics. We found that the molecular information was sufficient to deduce the complex and detailed neuroanatomical organization of the brain. The unsupervised (non-expert, data-driven) classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and new subdivisions of striatum. The molecular atlas further supports the characterization of the spatial identity of neurons from their single-cell RNA profile, and provides a resource for annotating the brain using a minimal gene set-a brain palette. In summary, we have established a molecular atlas to formally define the spatial organization of brain regions, including the molecular code for mapping and targeting of discrete neuroanatomical domains.
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| 11. |
- Seidel, Sascha, et al.
(författare)
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A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha
- 2010
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 133, s. 983-995
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Tidskriftsartikel (refereegranskat)abstract
- Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2 alpha and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.
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| 12. |
- Sievertzon, Maria, et al.
(författare)
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Transcriptome analysis in primary neural stem cells using a tag cDNA amplification method
- 2005
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 6:28, s. 13-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neural stem cells ( NSCs) can be isolated from the adult mammalian brain and expanded in culture, in the form of cellular aggregates called neurospheres. Neurospheres provide an in vitro model for studying NSC behaviour and give information on the factors and mechanisms that govern their proliferation and differentiation. They are also a promising source for cell replacement therapies of the central nervous system. Neurospheres are complex structures consisting of several cell types of varying degrees of differentiation. One way of characterising neurospheres is to analyse their gene expression profiles. The value of such studies is however uncertain since they are heterogeneous structures and different populations of neurospheres may vary significantly in their gene expression. Results: To address this issue, we have used cDNA microarrays and a recently reported tag cDNA amplification method to analyse the gene expression profiles of neurospheres originating from separate isolations of the lateral ventricle wall of adult mice and passaged to varying degrees. Separate isolations as well as consecutive passages yield a high variability in gene expression while parallel cultures yield the lowest variability. Conclusions: We demonstrate a low technical amplification variability using the employed amplification strategy and conclude that neurospheres from the same isolation and passage are sufficiently similar to be used for comparative gene expression analysis.
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| 13. |
- Terpos, Evangelos, et al.
(författare)
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Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: Reduction post-bortezomib monotherapy
- 2011
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 131:6, s. 1466-1471
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Tidskriftsartikel (refereegranskat)abstract
- Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.
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| 14. |
- Weglage, Moritz, et al.
(författare)
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Complete representation of action space and value in all dorsal striatal pathways
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 36:4
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Tidskriftsartikel (refereegranskat)abstract
- The dorsal striatum plays a central role in the selection, execution, and evaluation of actions. An emerging model attributes action selection to the matrix and evaluation to the striosome compartment. Here, we use large-scale cell-type-specific calcium imaging to determine the activity of striatal projection neurons (SPNs) during motor and decision behaviors in the three major outputs of the dorsomedial striatum: Oprm1+ striosome versus D1+ direct and A2A+ indirect pathway SPNs. We find that Oprm1+ SPNs show complex tunings to simple movements and value-guided actions, which are conserved across many sessions in a single task but remap between contexts. During decision making, the SPN tuning profiles form a complete representation in which sequential SPN activity jointly encodes task progress and value. We propose that the three major output pathways in the dorsomedial striatum share a similarly complete representation of the entire action space, including task- and phase-specific signals of action value and choice.
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| 15. |
- Williams, Cecilia, et al.
(författare)
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Catalog of gene expression in adult neural stem cells and their in vivo microenvironment
- 2006
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Ingår i: Experimental Cell Research. - San Diego : Elsevier BV. - 0014-4827 .- 1090-2422. ; 312:10, s. 1798-1812
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells generally reside in a stem cell micro environment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique sternness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.
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| 16. |
- Wärnberg, Emil
(författare)
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On learning in mice and machines : continuous population codes in natural and artificial neural networks
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neural networks, whether artificial in a computer or natural in the brain, could represent information either using discrete symbols or continuous vector spaces. In this thesis, I explore how neural networks can represent continuous vector spaces, using both simulated neural networks and analysis of real neural population data recorded from mice. A special focus is on the networks of the basal ganglia circuit and on reinforcement learning, i.e., learning from rewards and punishments.The thesis includes four scientific papers: two theoretical/computational (Papers I and IV) and two with analysis of real data (Papers II and III).In Paper I, we explore methods for implementing continuous vector spaces in networks of spiking neurons using multidimensional attractors, and propose an explanation for why it is hard to escape the neural manifolds created by such attractors.In Paper II, we analyze experimental data from dorsomedial striatum collected using 1-photon calcium imaging of transgenic mice with celltype-specific markers for the striatal direct, indirect and patch pathways, as the mice were gathering rewards in a 2-choice task. In line with extensive previous results, our data analysis revealed a number of neural signatures of reinforcement learning, but no apparent difference between the pathways.In Paper III, we present a new software tool for tracking neurons across weeks of 1-photon calcium imaging, and employ it to follow patch-specific striatal projection neurons from the dorsomedial striatum across two weeks of daily recordings.In Paper IV, we propose a model for how the nigrostriatal dopaminergic projection could, in a biologically plausible way, convey a vector-valued error gradient to the dorsal striatum, as required for backpropagation.Based on the results of the papers and a review of existing literature, I argue that while the basal ganglia indeed make up a circuit for reinforcement learning as previously thought, this circuit represents reinforcement learning states, actions and policies using a continuous population code and not using discrete symbols.
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| 17. |
- Wärnberg, Emil, et al.
(författare)
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Tracking activity of neurons across weeks from 1-photon calcium imaging
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- One-photon calcium imaging using head-mounted miniaturized endoscopes ("miniscopes") is a powerful method for imaging neuron activity of genetically-labeled neurons with single-cellresolution from awake and freely moving animals. A major challenge in analysis of imagingdata is the recording of single neurons over multiple days. To improve speed and accuracy,we created a software package for calcium extraction with a highly optimized GPU-basedimplementation of the Constrained Non-negative Matrix Factorization (CNMF) algorithmwith OASIS deconvolution of the traces. Additionally, we introduce negentropy as a robust statistical measure to rapidly initialize spatial footprints as well as to automatically find the best regularization and time constant of the OASIS deconvolution. We found that our implementation is 50x-100x faster compared to a state-of-the-art calcium processing tool. The significant speed advantage enables processing of a large number of calcium videos from separate recording days as a single concatenated video, making it feasible to follow individual cells across multiple days in a consistent manner. We demonstrate how our approach can capture the neural dynamics across more than two weeks of daily recordings with 1-photon miniscope of Oprm1-Cre+ striatal projection neurons as mice develop a task strategy in a maze.
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