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Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw cells suggest that Renshaw cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 660
Keyword [en]
motor neuron, proprioception, recurrent inhibition, molecular marker, Ia afferent, development, transgenic mice, Renshaw cell
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-147361ISBN: 978-91-554-8043-1OAI: oai:DiVA.org:uu-147361DiVA: diva2:406876
Public defence
2011-05-14, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-04-20 Created: 2011-02-25 Last updated: 2011-05-05Bibliographically approved
List of papers
1. Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
Open this publication in new window or tab >>Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
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2010 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 518, no 12, 2284-2304 p.Article in journal (Refereed) Published
Abstract [en]

Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons and nine genes expressed in unknown subtypes of somatic motor neurons. Further, we present evidence that Chondrolectin (Chodl) is a novel genetic marker for putative fast motor neurons and that estrogen-related receptor b (ERRb) is a candidate genetic marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells.

Keyword
mouse genetics, neuronal network, interneuron, motor neuron, spinal cord, genetic screen
National Category
Medical and Health Sciences
Research subject
Developmental Neurosciences; Genetics
Identifiers
urn:nbn:se:uu:diva-109916 (URN)10.1002/cne.22332 (DOI)000277580600007 ()20437528 (PubMedID)
Available from: 2009-10-30 Created: 2009-10-29 Last updated: 2012-02-29Bibliographically approved
2. Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice
Open this publication in new window or tab >>Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice
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2010 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 37, no 1, 58-66 p.Article in journal (Refereed) Published
Abstract [en]

Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS. we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased. neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERR beta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS. (C) 2009 Elsevier Inc. All rights reserved

Keyword
ALS, Amyotrophic lateral sclerosis, Glutamate, Vglut2, Vesicular glutamate transporters, Excitotoxicity, Motor neuron, Neurodegeneration, Motor neuron subpopulations, Calca, Chondrolectin, Chodl, ERRb
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-127378 (URN)10.1016/j.nbd.2009.09.006 (DOI)000272533000008 ()
Available from: 2010-07-13 Created: 2010-07-13 Last updated: 2016-05-11Bibliographically approved
3. Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons
Open this publication in new window or tab >>Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons
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2012 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 49, no 3, 322-332 p.Article in journal (Refereed) Published
Abstract [en]

Gamma motor neurons (MNs), the efferent component of the fusimotor system, regulate muscle spindle sensitivity. Muscle spindle sensory feedback is required for proprioception that includes sensing the relative position of neighboring body parts and appropriately adjust the employed strength in a movement. The lack of a single and specific genetic marker has long hampered functional and developmental studies of gamma MNs. Here we show that the serotonin receptor 1d (5-ht1d) is specifically expressed by gamma MNs and proprioceptive sensory neurons. Using mice expressing GFP driven by the 5-ht1d promotor, we performed whole-cell patch-clamp recordings of 5-ht1d::GFP(+) and 5-ht1d::GFP(-) motor neurons from young mice. Hierarchal clustering analysis revealed that gamma MNs have distinct electrophysiological properties intermediate to fast-like and slow-like alpha MNs. Moreover, mice lacking 5-ht1d displayed lower monosynaptic reflex amplitudes suggesting a reduced response to sensory stimulation in motor neurons. Interestingly, adult 5-ht1d knockout mice also displayed improved coordination skills on a beam-walking task, implying that reduced activation of MNs by Ia afferents during provoked movement tasks could reduce undesired exaggerated muscle output. In summary, we show that 5-ht1d is a novel marker for gamma MNs and that the 5-ht1d receptor is important for the ability of proprioceptive circuits to receive and relay accurate sensory information in developing and mature spinal cord motor circuits.

Keyword
5-ht1d, Serotonin, Gamma motor neurons, Muscle spindle, Fusimotor system, Spinal cord, Proprioception, Motor behavior
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-150257 (URN)10.1016/j.mcn.2012.01.003 (DOI)000302202100008 ()
Available from: 2011-03-28 Created: 2011-03-28 Last updated: 2012-04-24Bibliographically approved
4. Development of spinal motor circuits in the absence of VIAAT-mediated Renshaw cell signaling
Open this publication in new window or tab >>Development of spinal motor circuits in the absence of VIAAT-mediated Renshaw cell signaling
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-150256 (URN)
Available from: 2011-03-28 Created: 2011-03-28 Last updated: 2012-02-24

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