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Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition

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Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Enjin A, Rabe N, Nakanishi ST, Vallstedt A, Gezelius H, Mem- ic F, Lind M, Hjalt T, Tourtellotte WG, Bruder C, Eichele G, Whelan PJ, Kullander K (2010) Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as mark- ers for fast motor neurons and partition cells. J Comp Neurol 518:2284-2304. II Wootz H, Enjin A, Wallen-Mackenzie Å, Lindholm D, Kul- lander K (2010) Reduced VGLUT2 expression increases motor neuron viability in Sod1G93A mice. Neurobiol Dis 37:58-66 III Enjin A, Leao KE, Mikulovic S, Le Merre P, Tourtellotte WG, Kullander K. 5-ht1d marks gamma motor neurons and regulates development of sensorimotor connections Manuscript IV Enjin A, Leao KE, Eriksson A, Larhammar M, Gezelius H, Lamotte d’Incamps B, Nagaraja C, Kullander K. Development of spinal motor circuits in the absence of VIAAT-mediated Renshaw cell signaling Manuscript Reprints were made with permission from the respective publishers. Cover illustration Carousel by Sasha Svensson Contents Introduction.....................................................................................................9 Background...................................................................................................11 Neural control of movement.....................................................................11 The motor neuron.....................................................................................12 Organization of motor neurons............................................................14 Motor neuron subtypes ........................................................................14 Development of motor neurons ...........................................................16 Degeneration of motor neurons in ALS...............................................17 Proprioception ..........................................................................................18 Anatomy and physiology of the muscle spindle..................................18 Proprioceptive circuits.........................................................................20 Development of the monosynaptic stretch reflex ................................21 Recurrent inhibition..................................................................................22 Development of recurrent inhibition ...................................................23 Aims..............................................................................................................24 Methodological considerations .....................................................................25 Mice..........................................................................................................25 Transgenic mice...................................................................................25 Mouse lines..........................................................................................26 Histological staining procedures ..............................................................26 In situ hybridization.............................................................................26 Immunofluorescence............................................................................27 Quantification of stainings...................................................................28 Ventral root electrophysiology.................................................................28 Stretch reflex measurements................................................................29 Fictive locomotion...............................................................................30 Behavioral testing.....................................................................................30 Rotarod ................................................................................................31 Beam Walking .....................................................................................31 Hanging wire .......................................................................................31 Grip strength........................................................................................32 Digigait ................................................................................................32 Result summary ............................................................................................33 Paper I ......................................................................................................33 Paper II .....................................................................................................34 Paper III....................................................................................................34 Paper IV ...................................................................................................35 Discussion.....................................................................................................37 Novel markers for subtypes of motor neurons and premotor interneurons ..................................................................................................................37 Fast and slow motor neurons ...............................................................38 Gamma motor neurons ........................................................................39 Renshaw cells ......................................................................................40 Partition cells .......................................................................................40 Excitotoxicity and motor neuron subtypes in ALS.....................................40 The influence of 5-ht1d and VIAAT-mediated Renshaw cell signaling on the development of spinal motor circuits .................................................42 Development of the stretch reflex in 5-ht1d-/- knockout mice .............42 Development of spinal motor circuits in the absence of VIAAT- mediated Renshaw cell signaling.........................................................44 Motor behavior in 5-ht1d-/- and Chrna2::Cre;Viaatlx/lx mice ...................46 The stretch reflex amplitude in locomotion.........................................46 Recurrent inhibition in locomotion......................................................47 Acknowledgements.......................................................................................49 References.....................................................................................................51 Abbreviations 5-HT Serotonin 5-ht1d Serotonin receptor 1d AHP After hyperpolarization ALS Amyotrophic lateral sclerosis Calca Calcitonin/Calcitonin-related polypeptide alpha ChAT Choline acetyltransferase Chodl Chondrolectin Chrna2 Cholinergic receptor alpha 2 CNS Central nervous system CPG Central pattern generator DRG Dorsal root ganglia Egr3 Early growth response 3 En1 Engrailed 1 EPSP/EPSC Excitatory postsynaptic potential/current ERR Estrogen-related receptor beta FF Fast fatigable motor unit FR Fatigue-resistant motor unit GPCR G protein-coupled receptor GTO Golgi tendon organ IPSP/IPSC Inhibitory postsynaptic potential/current LMC Lateral motor column MMC Medial motor column NMJ Neuromuscular junction Pitx2 Paired-like homeodomain transcription factor 2 S Slow motor unit SMA Spinal muscular atrophy TrkC Neurotrophic tyrosine receptor kinase C . VAChT Vesicular acetylcholine transporter Introduction Movement is central for the life of animals. From the relatively simple but vital breathing movements to the subtler act of communicating an emotion through facial expression, in essence what is happening is a movement - a muscle contraction. Most of us perform these behaviors every day without any apparent effort, and they may seem plain, but in fact, correct movement is a delicate interplay between the brain, muscles and the environment. Consider for example the routine act picking up a coffee cup. What you do is to stretch out your arm in a straight trajectory, grab the ear of the coffee cup and lift it to your mouth to have a sip. Consider that movement again: moving your arm in a straight trajectory requires precise activation of just the right ones of the approximately 50 muscles in your upper arm in the cor- rect sequence. Depending on the starting position of your arm and the loca- tion of the cup, different sets muscles are activated, still performing the same straight trajectory. Grabbing and lifting the coffee cup to your mouth in- volves activating even more muscles of the arm and digits, again in the right sequence with just the right force. When the cup reaches your mouth, you need to form a tight seal with your lips around the cup and then activate muscles in your mouth and throat to swallow the coffee. In view of the com- plexity of this simple act, it is not surprising that most parts of the brain and much of the brains computational power in fact are involved in creating and tuning movements The structures in the central nervous system (CNS) directly involved in movements are the motor cortex, basal ganglia, cerebellum, parts of the brain stem and spinal cord. Lesions to any of these structures in humans or experimental animals leads to deficiencies in movement, from paralysis after a complete transection of the spinal cord to the tremor and difficulties of initiating movements in a patient with Parkinson’s disease caused by a lesion of the substantia nigra of the basal ganglia. Correct and automatic move- ments also require the integration of information from sensory systems
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