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Perry, S., Larhammar, M., Vieillard, J., Nagaraja, C., Hilscher, M. M., Tafreshiha, A., . . . Kullander, K. (2019). Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits. Journal of Neuroscience, 39(10), 1771-1782
Open this publication in new window or tab >>Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits
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2019 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 10, p. 1771-1782Article in journal (Refereed) Published
Abstract [en]

Neuronal networks within the spinal cord, collectively known as the central pattern generator (CPG), coordinate rhythmic movements underlying locomotion. The transcription factor doublesex and mab-3-related transcription factor 3 (DMRT3) is involved in the differentiation of the dorsal interneuron 6 class of spinal cord interneurons. In horses, a non-sense mutation in the Dmrt3 gene has major effects on gaiting ability, whereas mice lacking the Dmrt3 gene display impaired locomotor activity. Although the Dmrt3 gene is necessary for normal spinal network formation and function in mice, a direct role for Dmrt3-derived neurons in locomotor-related activities has not been demonstrated. Here we present the characteristics of the Dmrt3-derived spinal cord interneurons. Using transgenic mice of both sexes, we characterized interneurons labeled by their expression of Cre driven by the endogenous Dmrt3 promoter. We used molecular, retrograde tracing and electrophysiological techniques to examine the anatomical, morphological, and electrical properties of the Dmrt3-Cre neurons. We demonstrate that inhibitory Dmrt3-Cre neurons receive extensive synaptic inputs, innervate surrounding CPG neurons, intrinsically regulate CPG neuron's electrical activity, and are rhythmically active during fictive locomotion, bursting at frequencies independent to the ventral root output. The present study provides novel insights on the character of spinal Dmrt3-derived neurons, data demonstrating that these neurons participate in locomotor coordination.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE, 2019
Keywords
central pattern generator, CPG, Dmrt3, interneuron, locomotion
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-379893 (URN)10.1523/JNEUROSCI.0326-18.2018 (DOI)000460403400002 ()30578339 (PubMedID)
Funder
The Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Enjin, A., Perry, S., Hilscher, M. M., Nagaraja, C., Larhammar, M., Gezelius, H., . . . Kullander, K. (2017). Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit. Journal of Neuroscience, 37(23), 5634-5647
Open this publication in new window or tab >>Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 23, p. 5634-5647Article in journal (Refereed) Published
Abstract [en]

When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor α2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre-expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse or change gait, motor coordination, or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance, and had an increased number of proprioceptive glutamatergic and calbindin-labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses, indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons.

Keywords
ChAT, Chrna2, mouse, spinal cord, VIAAT
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-305237 (URN)10.1523/JNEUROSCI.0949-16.2017 (DOI)000402907200007 ()28483975 (PubMedID)
Funder
The Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2016-10-19 Created: 2016-10-13 Last updated: 2017-08-14Bibliographically approved
Nagaraja, C. (2016). Functional Imaging of Spinal Locomotor Networks. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Functional Imaging of Spinal Locomotor Networks
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Movement is necessary for the survival of most animals. The spinal cord contains neuronal networks that are capable of motor coordination and of producing different movements. In particular, a very reduced neuronal network in the spinal cord can produce simple rhythmic outputs even in the absence of descending or sensory inputs. This basic circuit was discovered by Thomas Graham Brown (reported in 1911) and is termed central pattern generator. For over a century a large number of studies have been carried out in order to identify the neuronal components that are part of these networks.

In project 1 we focused on Renshaw cells, which are a population of spinal interneurons expressing the alpha-2 subunit of the nicotinic acetylcholine receptors (Chrna2). Renshaw cells are the only identified central targets for motor neuron inputs, and in turn they mediate inhibition of the motor neurons. We analyzed the activity pattern of Renshaw cells on a cell-population level in neonates when the circuit is still developing. At segment 1 of the lumbar spinal cord, Renshaw cells show significantly greater activity response to functional sensory and motor inputs from rostral compared to the caudal segments. Contrarily, the suppression of the monosynaptic stretch reflex was more pronounced when caudal roots were stimulated. Our data underline the importance of sensory input during motor circuit development and help to understand the functional organization of Renshaw cell connectivity.

Several neurons that play distinct roles in locomotor central pattern generation have been identified with the help of genetics. For instance, the V0 population of spinal interneurons are identified by the expression of transcription factor developing brain homeobox 1 (Dbx1). V0 neurons are necessary for producing an alternating rhythm at all locomotor speeds. In project 2 we have looked at a population of dorsally derived ventrally projecting interneurons that express the transcription factor doublesex and mab-3 related transcription factor 3 (Dmrt3). On a behavioral level Dmrt3 neurons are involved in regulating coordination across different locomotor speeds. On a microcircuit level, we have shown that individual Dmrt3 neurons show distinct frequencies of oscillations for a constant locomotor rhythm. In addition, removal of inhibitory neurotransmission from Dmrt3 neurons results in uncoupling of rhythm in motor neurons.

In project 3 the activity patterns in populations of flexor related motor neurons are characterized during fictive locomotion in neonatal mice. An interesting and intriguing finding in project 3 is the presence of multiple rhythmicities in motor neurons. Multiple rhythmicities are seen even when the locomotor output shows a constant frequency.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 47
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1190
Keywords
Central pattern generators, two-photon microscopy, locomotor rhythm, multiple rhythmicities, inhibitory neurotransmission
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-280062 (URN)978-91-554-9500-8 (ISBN)
Public defence
2016-04-27, B22, Biomedical Centre, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-04-06 Created: 2016-03-07 Last updated: 2018-01-10
Rogoz, K., Aresh, B., Freitag, F. B., Pettersson, H., Magnúsdóttir, E. I., Larsson Ingwall, L., . . . Lagerström, M. C. (2016). Identification of a Neuronal Receptor Controlling Anaphylaxis. Cell reports, 14(2), 370-379
Open this publication in new window or tab >>Identification of a Neuronal Receptor Controlling Anaphylaxis
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 370-379Article in journal (Refereed) Published
Abstract [en]

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-272637 (URN)10.1016/j.celrep.2015.12.033 (DOI)000368101600019 ()26748715 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationÅke Wiberg FoundationMagnus Bergvall FoundationThe Royal Swedish Academy of Sciences
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2018-01-10Bibliographically approved
Langer, D., van 't Hoff, M., Keller, A. J., Nagaraja, C., Pfaeffli, O. A., Goeldi, M., . . . Helmchen, F. (2013). HelioScan: A software framework for controlling in vivo microscopy setups with high hardware flexibility, functional diversity and extendibility. Journal of Neuroscience Methods, 215(1), 38-52
Open this publication in new window or tab >>HelioScan: A software framework for controlling in vivo microscopy setups with high hardware flexibility, functional diversity and extendibility
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2013 (English)In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 215, no 1, p. 38-52Article in journal (Refereed) Published
Abstract [en]

Intravital microscopy such as in vivo imaging of brain dynamics is often performed with custom-built microscope setups controlled by custom-written software to meet specific requirements. Continuous technological advancement in the field has created a need for new control software that is flexible enough to support the biological researcher with innovative imaging techniques and provide the developer with a solid platform for quickly and easily implementing new extensions. Here, we introduce HelioScan, a software package written in LabVIEW, as a platform serving this dual role. HelioScan is designed as a collection of components that can be flexibly assembled into microscope control software tailored to the particular hardware and functionality requirements. Moreover, HelioScan provides a software framework, within which new functionality can be implemented in a quick and structured manner. A specific HelioScan application assembles at run-time from individual software components, based on user-definable configuration files. Due to its component-based architecture, HelioScan can exploit synergies of multiple developers working in parallel on different components in a community effort. We exemplify the capabilities and versatility of HelioScan by demonstrating several in vivo brain imaging modes, including camera-based intrinsic optical signal imaging for functional mapping of cortical areas, standard two-photon laser-scanning microscopy using galvanometric mirrors, and high-speed in vivo two-photon calcium imaging using either acousto-optic deflectors or a resonant scanner. We recommend HelioScan as a convenient software framework for the in vivo imaging community.

Keywords
Two-photon laser scanning microscopy, Intrinsic optical imaging, Control software, LabVIEW
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-201813 (URN)10.1016/j.jneumeth.2013.02.006 (DOI)000318828100005 ()
Note

Paid Open Access

Available from: 2013-06-17 Created: 2013-06-17 Last updated: 2018-01-11Bibliographically approved
NAGARAJA, C.A microcircuit analysis of motor neuron behaviour during fictive locomotion.
Open this publication in new window or tab >>A microcircuit analysis of motor neuron behaviour during fictive locomotion
(English)Manuscript (preprint) (Other academic)
Keywords
Spinal motor neuron, fictive-locomotion
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-280052 (URN)
Funder
The Swedish Brain Foundation
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2018-01-10
NAGARAJA, C.Dmrt3 derived spinal cord neurons regulate locomotor coordination across different speeds.
Open this publication in new window or tab >>Dmrt3 derived spinal cord neurons regulate locomotor coordination across different speeds
(English)Manuscript (preprint) (Other academic)
Keywords
progenitor domain, left-right coordination, multiple rhythmicities
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-280060 (URN)
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2018-01-10
NAGARAJA, C.Topographical organisation of functional sensory and motor inputs to Renshaw cells.
Open this publication in new window or tab >>Topographical organisation of functional sensory and motor inputs to Renshaw cells
(English)Manuscript (preprint) (Other academic)
Keywords
Spinal interneuron physiology
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-280035 (URN)
Funder
The Swedish Brain Foundation
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2018-01-10
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9768-9462

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