Neuroscience with Pharmacology 2 Functions and Mechanisms of Reflexes. Prof Richard Ribchester

Transcription

1 Neuroscience with Pharmacology 2 Functions and Mechanisms of Reflexes Prof Richard Ribchester René Descartes Cogito, ergo sum

2 The 21st century still holds many challenges to Neuroscience and Pharmacology Motor Neurone Disease Alzheimer s Disease Spinal cord injury

3 Neuroscience is studied at many different levels: from brain, to system, network, neurone, synapse, and molecule... Top Up Down Bottom

4 How are these movements controlled? What is the mechanism?

5 What are the functions of this molecule? Brain-derived Neurotrophic Factor (BDNF)

6 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

7 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

8 Santiago Ramon y Cajal (ca 1900) : the Neurone Doctrine

9 ca. 1900: Sherrington proposes the concept of the synapse So far as our present knowledge goes we are led to think that the tip of the [axon s] arborescence is not continuous with but merely in contact with the substance of the dendrite or cell body on which it impinges. Such a special connection of one nerve cell with another might be called a synapse. C.S. Sherrington; in Foster,M. A Textbook of Physiology. 7th edn συν together απτειν to clasp

10 Synaptic potentials underlie reflex excitation and inhibition EPSP John Eccles IPSP

11 The brain is mostly synapses (1000 times more synapses than neurones) 1 µm

12 Neurones and their connections are self-organising

13 Jeff Lichtman (2007) makes a transgenic Brainbow mouse Livet et al. (2007) Nature. 450:56-62

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15 The Brain is not like a computer Cerebral cortex (rat) Integrated Circuit

16 Number of Transistors in an Intel 10-core Xeon Westmere-EX microprocessor : 2.5 x 10 9 Number of Neurones in One Human Brain : ~ 8.6 x Number of Synapses in One Human Brain : ~ Human Population of Planet Earth: 7.09 x 10 9 Number of Human Synapses on Planet Earth : ~ 7 x [Number of protons in one gram of H + : 6.02 x Number of particles in the Universe : ~ ]

17 Neurones and their synaptic connections behave more like organisms in a biological system than elements in an electrical circuit. Purves & Lichtman(1985) Principles of Neural Development

18 Prof Ribchester

19 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

20 We can start at the network level and ask in one direction about function and in the other about mechanism. Top Middle Bottom

21 The monosynaptic knee-jerk (myotatic) reflex: How does it work (mechanism)? What is it for (function)?

22 Let s examine the components Dorsal (Posterior) Afferent Efferent Ventral (Anterior)

23 The Monosynaptic Stretch ( myotatic ) Reflex Dorsal Root Ganglion Sensory Neurone Muscle Spindle Motor Neurone Neuromuscular Junction

24 Dorsal Root Ganglion Muscle Spindle Axon Motor Neurone and Synapses Neuromuscular junction

25 Sensory receptors in skeletal muscle. Skeletal (Extrafusal) muscle Extrafusal (skeletal) muscle fiber Muscle spindle Intrafusal muscle fibers Nuclear bag fiber Nuclear chain fiber Equatorial region Polar regions Muscle spindle primary afferent (Ia) Ia facilitatory reflex connections Muscle spindle secondary afferent (II) Golgi tendon organ (GTO) GTO primary afferent (Ib) Ib inhibitory reflex connections Inhibitory interneuron Dorsal (Posterior) spinocerebellar tract Ventral (Anterior) spinocerebellar tract Alpha lower motor neuron Dynamic gamma lower motor neuron Static gamma lower motor neuron

26 The simplest neural circuit. + + A monosynaptic reflex Initiation Conduction Transmission End effect

27 Knee tap Action potential 40 Generator potential Membrane potential (mv) Time (ms) Time (ms) Copyright motifolio.com

28 Frequency of action potentials is increased by depolarization Injected current 40 Membrane potential (mv) Copyright motifolio.com

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30 Excitatory synapse glutamate Na + Na+ EPSP 5 Time (ms)

31 Glutamate and ACh are neurotransmitters in the monosynaptic stretch reflex EPSP AP glutamate + + AP AP Acetylcholine EPP

32 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

33 Charles Sherrington From : Sherrington,C.S.(1906/47). The integrative action of the nervous system. Cambridge University Press

34 Disynaptic Reciprocal Inhibition + Extensor Stretch + Contracts - Relaxes Flexor

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38 Flexion withdrawal reflex Crossed Extension reflex

39 Flexion and Crossed Extension Excitation Right Flexor Contracts Skin Left Extensor Contracts +

40 But don t expect to see this.!!

41 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

42 Synaptic potentials underlie reflex excitation and inhibition EPSP John Eccles IPSP

43 Spatial Summation Glutamate: EPSP GABA: IPSP

44 Temporal Summation Firing Threshold S1 S2

45 .increasing the complexity: + +/- +/ Input Integration Output

46 Synaptic Plasticity Systematic changes in the strength of synaptic connections in response to their activity. Hebbian synapses Types of synaptic connection where enduring growth processes or metabolic changes occur when presynaptic neurones consistently activate the postsynaptic neurone.

47 Synaptic depression - reduces EPSP s

48 .increasing the complexity:.adding plasticity + + +/ / Adaptive Input Integration Output

49 1. Neurones and synapses 2. The monosynaptic stretch reflex 3. Polysynaptic reflexes 4. Synaptic integration (EPSP s/ipsp s) 5. The challenge of reconnecting damaged circuitry: spinal injury

50 Voluntary control

51 Muscle spindles monitor and signal muscle stretch/length

52 Muscle stretch is encoded in the frequency of firing and has dynamic (velocity) and static (position) components Impulses/sec Yabushita et al (2006) J DENTAL RES, Vol. 85, No. 9, (2006) R.W Carr, J.E Gregory & U Proske Brain ResearchVolume 800, 1998, Pages

53 Muscle spindle γ Efferents Afferents Ia II Dynamic γ Static γ Nuclear Bag fibre Nuclear chain fibre

54 Selective stimulation of dynamic and static gamma motor axons enhances dynamic and static responses to stretch respectively γ Efferents Afferents Dynamic γ Static γ Ia II Nuclear Bag fibre Nuclear chain fibre Firing Rate No γ stim Dynamic γ stim Static γ stim

55 Most movements are the result of a complex interplay between voluntary and reflex components:

56 Spindle afferents signal muscle length and velocity of shortening continuously during sinusoidal movements

57 Spinal reflex circuits can be trained by treadmill therapy after spinal injury

58 and some promising results have been reported for some spinal injured patients

59 ..but there is still a long way to go to achieve full repair. Stem-cell based treatments offer one approach. Raisman G. Olfactory ensheathing cells and repair of brain and spinal cord injuries. Cloning Stem Cells. 2004;6(4): Li, Field & Raisman (2005) Science 26 September 1997:Vol no. 5334, pp

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61 Summary 1. Neuroscience is studied at many levels: from clinical to basic; from systems to cells to molecules 2. Complex neural functions arise from the ways neurones are connected at synapses, in specific neural circuits. 3. Reflexes are stereotyped responses to defined stimuli. The monosynaptic stretch reflex (knee-jerk reflex) is an example of the simplest neural circuit; it involves only two neurones: a primary afferent sensory neurone and an efferent motor neurone 4. Information is encoded in the pattern and frequency of action potentials and in the size and shape of synaptic potentials. 5. EPSPs and IPSPs mediate excitatory and inhibitory synaptic transmission respectively, using distinct neurotransmitters (e.g. glutamate, excitatory; GABA, inhibitory) and specific receptors. 6. Multi-synaptic excitatory and inhibitory spinal reflexes are integrated to generate complex motor patterns, refined by learning ( plasticity ) 7. Engineering recovery from spinal injury requires reconnection of injured descending motor pathways to intact spinal reflex circuits