Neuromotor System Updated Lecture Notes PDF

Neuroscience 6th Edition Dale Purves at al. 2018 Principles of Neural Science 6th Edition 2021. Reviews to be posted into Teaching Folders.  Neuromotor System Part 1 Overview of the neuromotor system Direct and indirect inputs into the motor neuron determines its...

Neuroscience 6th Edition Dale Purves at al. 2018 Principles of Neural Science 6th Edition 2021. Reviews to be posted into Teaching Folders.  Neuromotor System Part 1 Overview of the neuromotor system Direct and indirect inputs into the motor neuron determines its out put activity to muscle. Skeletal muscle the effector organ of the neuromotor system. What are the functions of skeletal muscle ? The neuromuscular synapse (neuromuscular junction) It unique features? – Whys it is so important? Excitatory synaptic transmission – generation of muscle action potentials Safety Factor of neuromuscular synapses Diseases of the neuromuscular system, causes and treatments Disease of skeletal muscle causes and treatments How the neuromotor system grades the force of muscle contraction Rate modulation Motor Unit recruitment Active movement but also Shivering heat generation with out contraction (axial muscle groups do this – (Lomo T 2020 Acti Physiologica) The Neuromuscular Synapse has a high Safety Factor to ensure that EPPs do not fail to elicit a muscle action potential Safety Factor Based on many more AChRs than in needed to get the EPP to Threshold (-85 mV to -65 mV EPP varying amplitudes – due to the number of AChRs that are activated by ACh. -65 Threshold -85 -85  Postsynaptic AChR Muscle Below the motor Neve ending Gene Expression Postsynaptic genes (MuSK) Myogenesis Metabolism Growth Factors back to the motor neuron Motor Neuron Disease Loss of neuromuscular connections Death of the alpha Motor neuron  Death of Alpha Motor Neurons – has many causes Muscle * * * * 11.Neuromuscular signaling – muscle * Mejzini – 2019 doi: 10.3389/fnins.2019.01310 Loss of Neuromuscular connections  Treatments for Motor Neuron disease Drugs that lower motor neuron hyper-excitability – counter Glutamate neuro-excitotoxicity. Riluzole – inhibits glutamate release Drugs that lower the energy use within muscle and motor neurons – mitochondria dysfunction/stress EMA – partial fatty acid oxidation inhibitor – decreases fatty acid oxidation and restores efficient glycolysis within Skeletal muscle. Drugs that lower Reactive Oxidative Cellular Stress (ROS) Edaravone – counter acts captures free radicals within cells that cause ROS. Drugs that lower reactive gliosis – lowering neural inflammation PMX205 – Complement C5a receptor 1 inhibitor – lower the activation of the innate immune system (component of complement) in the CNS – in clinical trials. A G protein receptor inhibitor. Drugs that lower cytosolic TDP-43 Lowers the build up of TDP43 with in the cytoplasm of cells - in particular neurons Restore Motor Neuron to Muscle signaling to help maintain muscle strength ARGX 119-2302. Immunotherapy – a MuSK Agonist IgG4 fragment (non-immunogenic) – about to enter clinical trials Results Treatments for auto-immune and congenital Myasthenia Gravis (MG) Acetylcholine Esterase Inhibitors, Pyridostigmine bromide is usually the first-line treatment (Show video) Immuno-therapy injections of antibodies Eculizumab – antibody that targets Complement C5 to lower the pro-inflammatory effect of C5 (C5a and C5b) Immunosuppressive treatment - Corticosteroids Prednisone, - act via the steroid receptor to lower the transcription of pro- inflammatory such as TNF-a and IL-6. (long term issues) so supplemented ewith non- steroidal immuno-suppressive drugs. Immune theapy MuSK IgG 4 treatment for MuSK auto-immune MG Congenital MG Salbutamol, a selective B2-adrenergic agonist https://doi.org/10.1016/j.nmd.2019.12.003 Treatment – K+ channel Blocker. To increase ACh release 3,4-diaminopyridine Diseases of skeletal muscle causes and treatments Muscle Dystrophy – e.g.. Duchenne Muscular Dystrophy (DMD) Loss of Dystrophin Leads to Duchenne Muscular Dystrophy Muscle Basement Membrane Muscle Membrane Muscle Cytoplasm What happens when you lose Dystrophnin ?  Treatment for Duchenne Muscular Dystrophy 1) Drugs that act against inflammation Corticosteroids (Prednisone) bad long term Prostaglandin Inhibitors or Activators 4 Treatment for Duchenne Muscular Dystrophy Deliver into muscle a corrected functional dystrophin gene – AAV delivery doi: 10.3389/fneur.2021.814174 Small cell bodies can also be translated to small axonal diameter  Learning objectives – Lectures 1-2 1) Know the functions of skeletal muscle: primary function and at least 3 other functions. 2) Explain how and excitatory endplate potential (EPP) is generated and how EPPs lead to the generation of a muscle action potential. 3) How are Acetylcholine receptors in muscle clustered into a dense patch under the motor nerve terminal? 4) What is the Neuromuscular synapse Safety Factor? 5) What is Motor neuron disease? What is Myasthenia Gravis? 6) What is type/class of drug is the 1st line drug for treating Myasthenia Gravis ? 7) What is Duchenne Muscle dystrophy – what type/class of drug is the 1st line drug for treating this disease? 8) Describe rate modulation – how does it increase muscle fiber tension? 9) What is a motor unit? 10) Explain how motor unit recruitment leads to an orderly increase in whole muscle tension. This involves understanding Henneman’s size principle. 11) Fiber type grouping and why it can leand to a loss in overall muscle strength. 12) Motor neuron activity determines muscle fibre type