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 109
Number of Neurones in One Human Brain :
~ 8.6 x 1010
Number of Synapses in One Human Brain :
~ 1014
Human Population of Planet Earth:
7.09 x 109
Number of Human Synapses on Planet Earth : ~ 7 x 1023
[Number of protons in one gram of H+: 6.02 x 1023
Number of particles in the Universe : ~ 1080 ]
“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
Action potential
Knee tap
Generator potential
Membrane potential (mV)
40
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
Membrane potential (mV)
40
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
AP
EPSP
+
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
Skin
+
Right Flexor
Contracts
+
+
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
+
+/-
+
-
+
+
+
+/+
Input
+
+
Adaptive
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
Afferents
γ Efferents
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
Afferents
γ Efferents
Ia
II
Dynamic γ
Static γ
Nuclear
Bag fibre
Firing Rate
Nuclear
chain fibre
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