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- Aresh, Bejan, 1984-, et al.
(författare)
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Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling
- 2017
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 158:5, s. 945-961
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Tidskriftsartikel (refereegranskat)abstract
- Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.
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| 2. |
- Franck, Marina C M
(författare)
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Genetic control of sensory neuron diversification
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The somatosensory system of vertebrates transmits information from external and internal environments to the brain. This information relates to various modalities such as touch, temperature, itch and pain. The different modalities require a variety of subtypes of sensory neurons, tuned to detect and transmit specific stimuli. Each of these subtypes expresses a specific set of proteins to serve this highly specialized function and to control the cell type specific gene expression. This thesis explores the development and diversity of sensory neuronal subtypes in the dorsal root ganglion (DRG) of the mouse. In the five studies included in this thesis, we have investigated the roles of several genes in the development and function of sensory neurons. In Paper I, the focus is on a transcription factor, Cux2. We described that its expression is limited to large, early born neurons, which are mainly mechanosensitive, including a lineage of poorly characterized large TrkA+ neurons. We found no evidence that Cux2 would affect neuronal subtype specification, but instead we showed that it contributes to regulation of mechanosensation. Transcription factors themselves are closely regulated in order to be expressed at the right time and place in development. In Paper II we identified that FGF signaling from earlier-born neurons triggers the upregulation of the transcription factor Runx1 early in the development of the thermo-nociceptive lineage. Signaling by soluble factors is also involved in the late stages of maturation of neuronal identity, as we demonstrated in Paper IV for the Ret receptor. We reported that the loss of Ret expression caused a hypersensitivity to several sensory modalities and showed that Ret is necessary for the expression of a large number of ion channels and receptors. One of the Ret-regulated genes was the cold receptor TrpM8. In Paper III we showed that TrpM8 expression was confined to a small population of neurons lacking coexpression with most subtype markers. We also characterized the developmental expression of all members of the TrpM family in the DRG and showed that most of them were expressed with individual temporal patterns. Finally, in Paper V, we characterized the expression pattern of the enzyme Tyrosine hydroxylase (TH), the function of which is unknown in the DRG. TH is central in the catecholamine synthesis pathway, but whether or not that pathway is active in the DRG is uncertain. We showed that neurons expressing TH belong to the Ret+ population and that the expression of TH depends on Runx1 but not Ret. In summary, we have described a number of novel sensory neuron populations as well as genetic mechanisms governing development and diversification of specific populations. These results lead to a better understanding of the somatosensory system and hopefully in extension to better treatments for patients with somatosensory disturbances such as chronic pain conditions.
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| 3. |
- Vieillard, Jennifer, et al.
(författare)
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Adult spinal Dmrt3 neurons receive direct somatosensory inputs from ipsi- and contralateral primary afferents and from brainstem motor nuclei
- 2023
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Ingår i: Journal of Comparative Neurology. - : John Wiley & Sons. - 0021-9967 .- 1096-9861. ; 531:1, s. 5-24
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Tidskriftsartikel (refereegranskat)abstract
- In the spinal cord, sensory-motor circuits controlling motor activity are situated in the dorso-ventral interface. The neurons identified by the expression of the transcription factor Doublesex and mab-3 related transcription factor 3 (Dmrt3) have previously been associated with the coordination of locomotion in horses (Equus caballus, Linnaeus, 1758), mice (Mus musculus, Linnaeus, 1758), and zebrafish (Danio rerio, F. Hamilton, 1822). Based on earlier studies, we hypothesized that, in mice, these neurons may be positioned to receive sensory and central inputs to relay processed commands to motor neurons. Thus, we investigated the presynaptic inputs to spinal Dmrt3 neurons using monosynaptic retrograde replication-deficient rabies tracing. The analysis showed that lumbar Dmrt3 neurons receive inputs from intrasegmental neurons, and intersegmental neurons from the cervical, thoracic, and sacral segments. Some of these neurons belong to the excitatory V2a interneurons and to plausible Renshaw cells, defined by the expression of Chx10 and calbindin, respectively. We also found that proprioceptive primary sensory neurons of type Ia2, Ia3, and Ib, defined by the expression of calbindin, calretinin, and Brn3c, respectively, provide presynaptic inputs to spinal Dmrt3 neurons. In addition, we demonstrated that Dmrt3 neurons receive inputs from brain areas involved in motor regulation, including the red nucleus, primary sensory-motor cortex, and pontine nuclei. In conclusion, adult spinal Dmrt3 neurons receive inputs from motor-related brain areas as well as proprioceptive primary sensory neurons and have been shown to connect directly to motor neurons. Dmrt3 neurons are thus positioned to provide sensory-motor control and their connectivity is suggestive of the classical reflex pathways present in the spinal cord.
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