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An Integrated view

An Integrated view. Nerve Muscle and Movement. Assessment. SA Q totalling 70 Specimen paper http://biolpc22.york.ac.uk/404 Practical worth 30 marks, deadline 18 Dec Submit 1 practical report. To join together…. Nerve conduction Synaptic physiology Muscle contraction Mechanics of Motion

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An Integrated view

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  1. An Integrated view Nerve Muscle and Movement

  2. Assessment • SA Q totalling 70 • Specimen paper • http://biolpc22.york.ac.uk/404 • Practical worth 30 marks, deadline 18 Dec • Submit 1 practical report

  3. To join together… • Nerve conduction • Synaptic physiology • Muscle contraction • Mechanics of Motion • Axon guidance what could be better than … …fly jumping? • with a little help from our genetics friends

  4. Aim • How a fly is built to get away • Key reference • Allen, MJ et al (2006) Making an escape: Development and function of the Drosophila giant fibre system Sem Cell & Devel Biol. 17: 31-41

  5. Genetic tools • EMS-induced mutations • Sequenced genome • UAS GAL4 system • tissue specific knockouts • tissue specific GFP • tissue may be a few cells

  6. How does a fly jump?

  7. Jump using middle leg Trimarchi & Schneiderman

  8. How far do they go? • Wild type flies go 30 mm 30 max distance jumped (mm) mean ± SE 20 10 0 1 2 3 4 5 6 7 CS female fly #

  9. How much work/force? • Work • KE = ½ m g d = ½ 10-6 x 10 x 0.03 = 150 nJ • Power output = 40 µW or 300 W / kg • at the top end of insect muscle output • Force • measure contraction isometrically • peak force 25 x weight of fly

  10. Which muscles? • zap head and record muscle potentials here given one small and one large stimulus

  11. Summary • thoracic muscles, very energetically demanding Now onto: what neuromuscular systems does the fly use?(What’s in a fly???)

  12. IFM TDT GDN CNS VNC mn foregut tc femur tibia tarsus What’s in a fly? tc - trochanter mn - motor neuron GDN - Giant descending neuron [= GF] IFM – Indirect flight muscles TDT – tergal depressor of the trochanter [= TTM] VNC - ventral nerve cord

  13. What's in the fly CNS ? brain thoracic ganglion

  14. Plan • start with • muscle • motoneuron • giant descending interneuron • sensory input • development

  15. Koenig & Ikeda, 2005 TDT muscle

  16. this end pulls • the wing, • thorax, • stretching the IFMs • TDT has a double whammy • this end pulls • the leg straight

  17. TDT in section

  18. TDT is… • Striated muscle • Tubular muscle • Fast twitch

  19. Innervation • innervated by 3 motoneurons • 1 large – very extensive endings • 2 small

  20. Neuromodulation • by octopamine – containing neuron

  21. TDT motoneuron • thoracic nervous system • lateral cell body • dorsal neuropil

  22. Summary • thoracic muscles, very energetically demanding • muscle and motoneuron designed for speed

  23. PSI • Relay between GDN and ? • drives 5 DLM motoneurons • failure occurs separately • Amplifier ?

  24. GDN (=GF) GDN PSI TDTmn

  25. GDN → TDTmn synapse • electrical ↑ • chemical ▼ • ACh

  26. GDN → TDTmn synapse • shakingB2 • no electrical synapses • an innexin mutant • asymmetry in innexins • shakingB2 and chats2 • neither electrical nor cholinergic synapses

  27. Axonal conduction in GDN • AP with para Na+ channels and K channels • identified shaker potassium channels • differentiate sh from slo • sh – voltage activated K channel • slo - Ca activated K channel

  28. Visual Excitation of GDN zap head flash light +benzaldehyde

  29. Fly eye

  30. Visual input to GDN • Cobalt fill of GDN in Musca lobular cellsprobably electricallycoupled to GDN

  31. Mechanosensory input antennalendings GDN (PDB segment)

  32. Summary • thoracic muscles, very energetically demanding • muscle and motoneuron designed for speed • GDN circuit designed for speed and robustness Now onto: how does the circuit grow?

  33. Development • GDN & TDTmn born during embryogenesis • Connect during pupation

  34. Key steps • GDN neurite outgrowth • Axon pathfinding (larval stages—24 h APF) • Target recognition and initial synapse formation (24–55 h APF) • meet TDTmn • bend • Synapse stabilization and maintenance (55–100 h APF) • So what are the Molecular regulators of growth

  35. Giant axon stops and does not bend Part of ubiqutination system for degrading proteins This degrades signal saying “go” bendless

  36. Semaphorin-1a • Regulates neurite outgrowth • No sema-1a GDN axon goes to retina (50%) • Regulates bend • No sema-1a GDN axon does not bend (50%) • May be the protein bendless degrades

  37. Target of sema-1a • Plexins ? • Which signal via Rac, a GTPase Too much rac rac blocked

  38. Summary • thoracic muscles, very energetically demanding • muscle and motoneuron designed for speed • GDN circuit designed for speed and robustness • Identification of signalling molecules controlling neuronal growth & synapses

  39. Habituation of jump response dunce (phosphodiesterase) & rutabaga (adenyl cyclase)

  40. Jumping as a test for disease • Epilepsy Mutants hyperexcitable followed by paralysis +/+easprior after bang eas

  41. Flies as genetic models • Parkinsonism, Alzheimer, Fragile X… • Behaviour, anatomy, physiology, cell biology well known • Screen for modifiers

  42. Summary • thoracic muscles, very energetically demanding • muscle and motoneuron designed for speed • GDN circuit designed for speed and robustness • Identification of signalling molecules controlling neuronal growth & synapses • System for physiological mutant analysis

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