| 1. |
- Franck, Marina Christina Mikaela, et al.
(författare)
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Urocortin3-expressing neurons in sensory transmission
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Urocortin 3 (UCN3) is a neuropeptide involved in mechanosensation and stress regulation, and Ucn3-Cre neurons have been assigned a role in mechanical itch. Here, we show that Ucn3 marks a population of excitatory neurons in the mouse dorsal horn, divided into two non-overlapping subpopulations expressing protein kinase C g or calretinin/calbindin 2. Chemogenetic activation of spinal Ucn3-Cre neurons evoked a targeted biting/licking behavior towards the corresponding dermatome. Genetic deletion of vesicular glutamate transporter 2 (VGLUT2) in Ucn3-Cre neurons removed the phenotype, showing that the biting/licking behavior is VGLUT2-dependent. Conditional deletion of VGLUT2 did not affect acute thermal or mechanical withdrawal responses, nor thermal withdrawal responses after nerve growth factor-induced hypersensitivity or the prurifensive response to 48/80 or von Frey stimuli applied in nape. Instead, we found that a group of spinal Ucn3 neurons were activated in response to artificial scratching or 48/80-induced itch. Electrophysiological experiments showed that spinal Ucn3 neurons received both glycinergic and GABAergic tonic inhibition, and monosynaptic inputs from both Aβ and C fibers, which could be confirmed by rabies tracing. Spinal Ucn3/Ucn3-Cre neurons thus represent a mechanically sensitive population with several roles in the itch-scratch cycle.
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| 2. |
- Jakobsson, Jon E. T., et al.
(författare)
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scConnect : a method for exploratory analysis of cell–cell communication based on single-cell RNA-sequencing data
- 2021
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Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811 .- 1460-2059. ; 37:20, s. 3501-3508
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Tidskriftsartikel (refereegranskat)abstract
- MotivationCell to cell communication is critical for all multicellular organisms, and single-cell sequencing facilitates the construction of full connectivity graphs between cell types in tissues. Such complex data structures demand novel analysis methods and tools for exploratory analysis.ResultsWe propose a method to predict the putative ligand–receptor interactions between cell types from single-cell RNA-sequencing data. This is achieved by inferring and incorporating interactions in a multi-directional graph, thereby enabling contextual exploratory analysis. We demonstrate that our approach can detect common and specific interactions between cell types in mouse brain and human tumors, and that these interactions fit with expected outcomes. These interactions also include predictions made with molecular ligands integrating information from several types of genes necessary for ligand production and transport. Our implementation is general and can be appended to any transcriptome analysis pipeline to provide unbiased hypothesis generation regarding ligand to receptor interactions between cell populations or for network analysis in silico.Availability and implementationscConnect is open source and available as a Python package at https://github.com/JonETJakobsson/scConnect. scConnect is directly compatible with Scanpy scRNA-sequencing pipelines.
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| 3. |
- Lagerström, Malin C, 1977-
(författare)
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Classification, Evolution, Pharmacology and Structure of G protein-coupled Receptors
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- G protein-coupled receptors (GPCR) are integral membrane proteins with seven α-helices that translate a remarkable diversity of signals into cellular responses. The superfamily of GPCRs is among the largest and most diverse protein families in vertebrates.We have searched the human genome for GPCRs and show that the family includes approximately 800 proteins, which can divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin. This study represents one of the first overall road maps of the GPCR family in a mammalian genome. Moreover, we identified eight novel members of the human Adhesion family which are characterized by long N-termini with various domains. We also investigated the GPCR repertoire of the chicken genome, where we manually verified a total of 557 chicken GPCRs. We detected several specific expansions and deletions that may reflect some of the functional differences between human and chicken.Substantial effort has been made over the years to find compounds that can bind and activate the melanocortin 4 receptor (MC4R). This receptor is involved in food intake and is thus an important target for antiobesity drugs. We used site-directed mutagenesis to insert micromolar affinity binding sites for zinc between transmembrane (TM) regions 2 and 3. We generated a molecular model of the human MC4R which suggests that a rotation of TM3 is important for activation of the MC4R.Furthermore, we present seven new vertebrate prolactin releasing hormone receptors (PRLHRs) and show that they form two separate subtypes, PRLHR1 and PRLHR2. We performed a pharmacological characterization of the human PRLHR which showed that the receptor can bind neuropeptide Y (NPY) related ligands. We propose that an ancestral PRLH peptide has coevolved with a redundant NPY binding receptor, which then became PRLHR. This suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.
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| 4. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 5. |
- Weman, Hannah M., 1993-, et al.
(författare)
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Exon excision of the vesicular glutamate transporter 2 or vesicular inhibitory amino acid transporter from glycine receptor alpha 3-expressing neurons does not alter thermal hypersensitivity induced by interleukin 1 beta
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The glycinergic system serves a protective role in acute itch and pain transmission and further, in inflammatory- and nerve damage-induced hypersensitivity. The glycine receptor alpha 3 (GLRA3) subunit has previously been coupled to inflammatory, but not acute pain. Using the Glra3-Cre mouse line, we investigated the role of Glra3(+) neurons in heat hypersensitivity following administration of the pro-inflammatory and -nociceptive cytokine interleukin 1 beta (IL1β). Spatial transcriptional analysis revealed, in consistency with our previous results, that the Glra3(+) population constitutes of a major excitatory vesicular glutamate transporter 2 (Vglut2) and a minor vesicular inhibitory amino acid transporter (Viaat) expressing subpopulation. Administration of IL1β resulted in hypersensitivity to heat, however, the conditional global attenuation of the fast glutamatergic or inhibitory transmission in Glra3-Cre neurons did not affect the heat withdrawal response, suggesting that the Glra3(+)Vglut2(+) nor Glra3(+)Viaat(+) neurons are involved in interleukin 1 beta-induced heat hypersensitivity. Future experiments for this project will include chemogenetic experiments to overall investigate the hypersensitivity role of the lumbar Glra3-Cre population, as well as investigation of the sensory involvement in nerve growth factor beta (NGFβ)-induced thermal hyperalgesia.
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| 6. |
- Weman, Hannah M., 1993-, et al.
(författare)
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Spinal glycine receptor alpha 3 subunit-expressing cells transmit the sensations of compound 48/80 and chloroquine
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, but the identity and role of the glycine-regulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 (Glra3) subunit-expressing neurons in a Glra3-Cre mouse line. Glra3-Cre neurons express Glra3, are located mainly in laminae III-VI and respond to glycine. Chemogenetic activation of spinal Glra3-Cre neurons induced biting/licking, stamping and guarding behaviors, while inhibition reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for this population. Spinal cells activated by compound 48/80 or chloroquine express Glra3, further supporting the phenotype. Retrograde tracing revealed that spinal Glra3-Cre neurons receive input mainly from NF200(+), IB4(+), TRKA(+), CGRP(+) or SST(+) primary afferents. Dorsal root stimulation validated the monosynaptic input from primary afferents, which was mainly comprised of C-fiber or C-fiber and Aα∕β input. Conclusively, these results show that spinal Glra3 neurons contribute to acute transmission of compound 48/80 and chloroquine-induced itch.
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