Neuroscience with Pharmacology 2 Functions and Mechanisms of Reflexes Prof Richard Ribchester René Descartes Cogito, ergo sum
The 21st century still holds many challenges to Neuroscience and Pharmacology Motor Neurone Disease Alzheimer s Disease Spinal cord injury
Neuroscience is studied at many different levels: from brain, to system, network, neurone, synapse, and molecule... Top Up Down Bottom
How are these movements controlled? What is the mechanism?
What are the functions of this molecule? Brain-derived Neurotrophic Factor (BDNF)
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
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
Santiago Ramon y Cajal (ca 1900) : the Neurone Doctrine
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. 1897 συν together απτειν to clasp
Synaptic potentials underlie reflex excitation and inhibition EPSP John Eccles IPSP
The brain is mostly synapses (1000 times more synapses than neurones) 1 µm
Neurones and their connections are self-organising
Jeff Lichtman (2007) makes a transgenic Brainbow mouse Livet et al. (2007) Nature. 450:56-62
The Brain is not like a computer Cerebral cortex (rat) Integrated Circuit
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 10 10 Number of Synapses in One Human Brain : ~ 10 14 Human Population of Planet Earth: 7.09 x 10 9 Number of Human Synapses on Planet Earth : ~ 7 x 10 23 [Number of protons in one gram of H + : 6.02 x 10 23 Number of particles in the Universe : ~ 10 80 ]
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
Prof Ribchester
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
We can start at the network level and ask in one direction about function and in the other about mechanism. Top Middle Bottom
The monosynaptic knee-jerk (myotatic) reflex: How does it work (mechanism)? What is it for (function)?
Let s examine the components Dorsal (Posterior) Afferent Efferent Ventral (Anterior)
The Monosynaptic Stretch ( myotatic ) Reflex Dorsal Root Ganglion Sensory Neurone Muscle Spindle Motor Neurone Neuromuscular Junction
Dorsal Root Ganglion Muscle Spindle Axon Motor Neurone and Synapses Neuromuscular junction
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 http://www.csus.edu/indiv/m/mckeoughd/aanatomyrev/mm_recept/mmreceptors.htm
The simplest neural circuit. + + A monosynaptic reflex Initiation Conduction Transmission End effect
Knee tap Action potential 40 Generator potential Membrane potential (mv) 20 0-20 -40-60 -80 Time (ms) 0 1 2 3 Time (ms) 7111152 Copyright motifolio.com
Frequency of action potentials is increased by depolarization Injected current 40 Membrane potential (mv) 20 0-20 -40-60 -80 7111154 Copyright motifolio.com
Excitatory synapse glutamate Na + Na+ EPSP 5 Time (ms)
Glutamate and ACh are neurotransmitters in the monosynaptic stretch reflex EPSP AP glutamate + + AP AP Acetylcholine EPP
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
Charles Sherrington From : Sherrington,C.S.(1906/47). The integrative action of the nervous system. Cambridge University Press
Disynaptic Reciprocal Inhibition + Extensor Stretch + Contracts - Relaxes Flexor
Flexion withdrawal reflex Crossed Extension reflex
Flexion and Crossed Extension Excitation Right Flexor Contracts Skin + + + Left Extensor Contracts +
But don t expect to see this.!!
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
Synaptic potentials underlie reflex excitation and inhibition EPSP John Eccles IPSP
Spatial Summation Glutamate: EPSP GABA: IPSP
Temporal Summation Firing Threshold S1 S2
.increasing the complexity: + +/- +/- + - - + + + + - - + + Input Integration Output
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.
Synaptic depression - reduces EPSP s http://snnap.uth.tmc.edu/images/examples/psm_deprsn.gif
.increasing the complexity:.adding plasticity + + +/- - + - + - + +/- + - + + Adaptive Input Integration Output
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
Voluntary control
Muscle spindles monitor and signal muscle stretch/length http://upload.wikimedia.org/wikipedia/commons/6/67/spindle.gif http://content.answers.com/main/content/img/oxford/oxford_food_fitness/0198631472.muscle.1.jpg
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, 849-853 (2006) R.W Carr, J.E Gregory & U Proske Brain ResearchVolume 800, 1998, Pages 97 104
Muscle spindle γ Efferents Afferents Ia II Dynamic γ Static γ Nuclear Bag fibre Nuclear chain fibre
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
Most movements are the result of a complex interplay between voluntary and reflex components:
Spindle afferents signal muscle length and velocity of shortening continuously during sinusoidal movements
Spinal reflex circuits can be trained by treadmill therapy after spinal injury
and some promising results have been reported for some spinal injured patients
..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):364-8. Li, Field & Raisman (2005) Science 26 September 1997:Vol. 277. no. 5334, pp. 2000-2002
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