Biological Oscill Title

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Biological Oscill Title
Biological Oscillators 2008
LECTURES Monday, March 17 Central Pattern
Generators, Paul Stein Wednesday, March
19 Circadian Systems, Erik Herzog LAB
DEMONSTRATION Wednesday, March 19 Biological
Oscillators, Stein and Herzog Danforth Campus
Demonstration Starts in Monsanto 205 at 130pm
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CPG readings
Biological Oscillators Central Pattern Generators
Paul Stein--Bio 5651--March 17, 2008--Required
Readings Chapter 37 on Locomotion in Kandel,
Schwartz, and Jessell, 4th Edition, pages 737-755
(termed KSJ37).
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motor systems
MOTOR SYSTEMS generate patterns of motor
output. In contrast, SENSORY SYSTEMS filter
patterns of input.
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classification of motor output
Classification of Motor Output
TASK classified according to goal, e.g.,
scratching, swimming, stepping FORM of a task
(also termed MOTOR STRATEGY) the particular
strategy used to achieve the goal, e.g., forward
stepping vs. backward stepping, walk vs. run,
walk vs. trot vs. gallop PARAMETERS of form of
the task particular values of position,
velocity, etc., e.g., walking at 1 mph vs. 2 mph
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levels of experimental analysis
Levels of Experimental Analyses
MOVEMENT LEVEL Neuronal, Muscular, and Skeletal
Systems NEURONAL NETWORK/CIRCUIT LEVEL The
Nervous System CELLULAR/SYNAPTIC/MOLECULAR
LEVEL Specific properties of components of
networks-- the "building blocks" of these
networks (see KSJ37 Table 37-1)
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rhythmic behaviors
Rhythmic Behaviors Generated by Central Pattern
Generators KSJ37 Box 37-1 and Fig 37-1
Cat Stepping, Scratching, Paw Shaking,
Breathing Neonatal Rat and Mouse Stepping,
Breathing Chick Embryo Spontaneous
Movements Turtle Scratching, Swimming,
Stepping Tadpole, Lamprey, Zebrafish, Goldfish
Swimming
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major conclusions
KSJ37 page 740 Major conclusions from early
studies of locomotion

• These conclusions are accepted today as well
• 1. Supraspinal structures are not necessary for
  producing the basic motor pattern for stepping.
• 2. The basic rhythmicity of stepping is produced
  by neuronal circuits termed Central Pattern
  Generators (CPGs) contained entirely within the
  spinal cord.
• 3. Spinal circuits can be activated by tonic
  ("not patterned") descending signals from brain
  and brainstem.
• 4. The spinal pattern-generating networks do not
  require sensory input but nevertheless are
  strongly regulated by inputs from limb
  proprioceptors and other sensory structures.

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changes in understanding static
There have been recent major changes in our
understandings of the pattern-generating networks
(CPGs) controlling motor behavior.

• The CLASSIC STATIC point of view dominated
  research prior to these recent changes. In the
  classic static point of view
• Each neuronal network is associated with one
  behavior.
• 2. All neuronal paths in the network have fixed
  properties.
• 3. Each neuron in the network has fixed
  properties that can not be changed.

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changes in understanding dynamic
There have been recent major changes in our
understandings of the pattern-generating networks
(CPGs) controlling motor behavior.

• Recent work has led to an alternative point of
  view, termed the MODERN DYNAMIC point of view.
  In the modern dynamic point of view,
• 1. Each neuronal network is associated with a
  group of behaviors.
• 2. Specific neuronal pathways, e.g., sensory
  reflex pathways, within the network can be
  dynamically modulated by the pattern generator so
  that a given pathway may be gain adjusted, e.g.,
  enabled or disabled, on a half-cycle by
  half-cycle basis.
• 3. Each neuron in the network may be modulated by
  specific neuromolecules.

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changes in understanding dynamic
There have been recent major changes in our
understandings of the pattern-generating networks
(CPGs) controlling motor behavior.

• In the modern dynamic point of view,
• 3. Each neuron in the network may be modulated,
  i.e., its properties (channels, receptors, 2nd
  messengers) may be modified by specific
  neuromolecules (transmitters, modulators,
  hormones, etc.).
• When the properties of individual neurons are
  altered, there is a corresponding change in the
  properties of the network in which the neurons
  reside.
• From this point of view, the network is
  "reconfigured" to have a specific set of
  properties according to the instructions of the
  neuromolecules.

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reconfiguration
There have been recent major changes in our
understandings of the pattern-generating networks
(CPGs) controlling motor behavior.
The best evidence for reconfiguration of a
pattern-generating network has come from
invertebrates, in particular, from studies of
crab and lobster stomatogastric ganglion that
contains Central Pattern Generators for chewing
movements of the stomach. Recent evidence by
Edgerton and co-workers demonstrate spinal
learning of locomotion in the cat spinal cord. A
current hypothesis is that this spinal learning
occurs due to a reconfiguration of spinal
pattern-generating circuits. See paper by De
Leon et al. (1999) for April 9, 2008 discussion.
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edgerton 2004
Plasticity of spinal neural circuitry after injury
Fig 1, Edgerton et al, Ann Rev Neurosci 2004
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descendingcontrol
Descending signals from the brain stem and motor
cortex initiate locomotion and adjust stepping
movements to the immediate needs of the animal
KSJ37 Fig 10
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types of preps
Types of Preparations with Reduced Portions of
the Nervous System Levels of Transection
Decerebrate Preparation Transection of the brain
stem at the level a-a' isolates the spinal cord
and the lower brain stem from the cerebral
hemispheres. Constant frequency stimulation of
the Mesencephalic Locomotor Region (MLR)
activates stepping in decerebrate cats. Spinal
Preparation Transection of the spinal cord at
the level b-b' isolates the spinal cord from
supraspinal structures. Tactile stimulation
below the level of transection activates
scratching in spinal frogs, turtles, cats, and
dogs. Just following transection, stepping in
spinal cats and in spinal neonatal rodents can be
activated by various neuromodulators, e.g., NMDA
and serotonin (5-HT). After a few weeks of
exercise on a treadmill, spinal cats can step
with little or no additional neuromodulation.
KSJ37 Fig 1A
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overall view
An Overall View--KSJ37 page 754 See also Marder
(2001) Moving rhythms. Nature 410 755.
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching. 2. Tonic descending
signals from supraspinal structures are needed to
activate locomotor CPGs. 3. Movement-related
sensory inputs modulate CPG outputs these inputs
adjust the outputs to current conditions. 4. The
spinal CPG modulates sensory pathways so that the
gain of reflex pathways is appropriate to the
specific phase of the motor cycle. 5. Phasic
descending signals from supraspinal structures
fine-tune locomotor output for specific demands,
such as stepping over uneven terrain.
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1A.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
(1) MOTOR PATTERN The pattern of motor neuron
discharge during a motor behavior. (2) ENG The
electroneurogram is the electrical recording of
extracellular motor neuron action potentials in a
peripheral nerve, usually a peripheral nerve
innervating a specific muscle. For preparations
in vitro, ventral root recordings are
obtained. (3) MOTOR POOL The set of motor
neurons that innervate a specific muscle. (4)
EMG The electromyogram is the electrical
recording of extracellular muscle action
potentials from a specific muscle. (5) There is a
11 correspondence of action potentials in the
ENG recorded from a nerve innervating a specific
muscle and in the EMG recorded from that
muscle. (6) The (real) motor pattern for a
specific form of a task can be recorded with
either EMGs or ENGs (usually EMGs) during actual
movements with movement-related sensory
feedback. (7) The fictive motor pattern for a
specific form of a task can be recorded with ENGs
in the absence of movement-related sensory
feedback, e.g., following blockade with a
neuromuscular blocking agent such as a nAChR
antagonist.
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1Aa.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
(6) The (real) motor pattern for a specific form
of a task can be recorded with either EMGs or
ENGs (usually EMGs) during actual movements with
movement-related sensory feedback. (6A) The
neurons in the nervous system responsible for
generating the (real) motor pattern during the
movements of an actual behavior with sensory
feedback are termed the "pattern generator" for
that behavior. (7) The fictive motor pattern for
a specific form of a task can be recorded with
ENGs in the absence of movement-related sensory
feedback, e.g., following blockade with a
neuromuscular blocking agent such as a nAChR
antagonist. (7A) If the fictive motor pattern
that is produced in the absence of
movement-related sensory feedback is an excellent
replica of the real motor pattern during actual
behavior with movement-related sensory feedback,
then the fictive motor pattern is termed a
"central motor pattern" since it is produced
entirely within the central nervous system.
(7B) The pattern generator for a central motor
pattern is termed a "central pattern generator"
or CPG. Goals of CPG research are to reveal the
molecular, cellular, and network properties of
CPGs responsible for their generation of motor
patterns.
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1B.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
Stein Lab Demo Turtle Spinal Preparation In Vivo
for Fictive Rostral Scratch Complete
transection of the spinal cord just posterior to
the forelimb enlargement. Neuromuscular synapses
blocked by nAChR antagonist. Electroneurographic
recordings (ENGs) from individual nerves
innervating specific muscles. Activate fictive
rostral scratch reflex by mechanical stimulation
of site on the mid-body shell bridge in the
rostral scratch receptive field.
Stein, J Comp Physiol A 2005
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1C.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
NORMAL MOTOR PATTERN OF FICTIVE ROSTRAL SCRATCH
IN TURTLE Hip-flexor motor neurons alternate
activity with hip-extensor motor
neurons. Hip-flexor activity alternates with
hip-flexor quiescence. Knee extensor is active
during latter portion of hip-flexor burst.
Stein Daniels-McQueen, J Neurosci 2002
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1D.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
KSJ37 Fig 4A,B Spinal, immobilized cat treated
with L-DOPA and nialamide generates
flexor-extensor rhythmic alternation in response
to stimulation of high-threshold sensory
afferents. These data are consistent with the
Half-Center Hypothesis initially proposed by
Brown 1911. Adapted from Jankowska et al 1967.
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1E.spinalcordCPGs
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching.
Cat Stepping Unit-Burst-Generator Hypothesis
Grillner, Handbook of Physiology 1981
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2.tonicdescending
2. Tonic descending signals from supraspinal
structures are needed to activate locomotor CPGs.
KSJ37 Fig 11 Locomotor responses to
constant-frequency electrical stimulation of the
MLR (Mesencephalic Locomotor Region) in a
decerebrate cat with limbs that locomote on a
treadmill. Low-amplitude stimulation evokes a
slow walk. Increases in amplitude evoke a fast
walk, then a trot, and, with highest amplitude, a
gallop. Adapted from Shik Severin Orlovsky,
Biophysics 1966
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3A.movementrelatedsensory
3. Movement-related sensory inputs modulate CPG
outputs these inputs adjust the outputs to
current conditions.
KSJ37 Fig 8A Oscillating movements around the
hip joint in an immobilized decerebrate cat
entrains the fictive locomotor pattern in
extensor and flexor motor neurons. Adapted from
Kriellaars et al. 1994
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3B.movementrelatedsensory
3. Movement-related sensory inputs modulate CPG
outputs these inputs adjust the outputs to
current conditions.
Kriellaars et al. 1994, Fig 2 Mesencephalic
Locomotor Region (MLR) activation of fictive
locomotion in a decerebrate, immobilized cat.
Entrainment of locomotor rhythm by imposed
movements of the hip. Top 4 traces rectified,
integrated ENG (electroneurographic) recordings
from nerves to 4 hindlimb muscles. Bottom trace
hip angle
Kriellaars Brownstone Noga Jordan, J Neurophysiol
1994
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4A.CPGmodGain
4. The spinal CPG modulates sensory pathways so
that the gain of reflex pathways is appropriate
to the specific phase of the motor cycle.
KSJ Chapter 36 Fig 2B1 Dr. Thach's lectures will
describe the properties of Ia afferents,
mechanosensory neurons whose peripheral processes
are located in muscle spindles. Ia afferents
from agonist muscles excite agonist Ia inhibitory
interneurons in the spinal cord. Agonist Ia
inhibitory interneurons inhibit antagonist motor
neurons. This disynaptic reflex pathway is
dynamically modulated by the spinal cord CPG
during the production of rhythmic motor patterns.
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4B.CPGmodGain
4. The spinal CPG modulates sensory pathways so
that the gain of reflex pathways is appropriate
to the specific phase of the motor cycle.
From Orlovsky Deliagina Grillner, Neuronal
Control of Locomotion 1999, Fig 11.10B,C and
adapted from Feldman and Orlovsky 1975. IaINQ
is a Ia inhibitory interneuron excited by
Quadriceps (Q) Ia afferents. B. Stimulation of
Q Ia afferents during resting conditions
activates the IaINQ. C. Stimulation of Q Ia
afferents during fictive locomotion activates
IaINQ during the extension phase and does not
activate the IaINQ during the flexion
phase. Thus, this reflex pathway is dynamically
modulated by the spinal cord CPG during each
half-cycle of fictive locomotion.
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5.phasic descending
5. Phasic descending signals from supraspinal
structures fine-tune locomotor output for
specific demands, such as stepping over uneven
terrain.
KSJ37 Fig 12 Activity of neurons in the motor
cortex is modulated by visual system inputs to
adapt stepping movements. Top trace single unit
recording from motor cortex. Bottom 4 traces
EMG recordings from forelimb muscles. Adapted
from Drew 1988.
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human walking
Human walking may involve spinal CPGs KSJ37 page
753-754
1. Current rehabilitation strategies with
spinal-injured patients with some spinal pathways
intact include body-weight supported (BWS)
treadmill locomotion while therapists move the
limbs of the patient on the treadmill much of
the weight of the patient is supported by a
harness similar to a parachute support. 2. As the
patient improves, the patient can support greater
percentages of body weight and less intervention
by therapists is needed to move the limbs of the
patient. 3. FES (Functional Electrical
Stimulation) of muscles and/or nerves can also
supplement the BWS treadmill therapies. 4. Some
spinal-injured patients treated with these
strategies of therapy have regained the ability
to walk.
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overall view
An Overall View--KSJ37 page 754 See also Marder
(2001) Moving rhythms. Nature 410 755.
1. Spinal cord CPGs contain necessary and
sufficient circuitry to produce the basic motor
patterns underlying rhythmic motor behaviors such
as stepping and scratching. 2. Tonic descending
signals from supraspinal structures are needed to
activate locomotor CPGs. 3. Movement-related
sensory inputs modulate CPG outputs these inputs
adjust the outputs to current conditions. 4. The
spinal CPG modulates sensory pathways so that the
gain of reflex pathways is appropriate to the
specific phase of the motor cycle. 5. Phasic
descending signals from supraspinal structures
fine-tune locomotor output for specific demands,
such as stepping over uneven terrain.
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2002 stein fig 1
Single-Unit Recording of Spinal Interneurons with
a Descending Axon during Fictive Rostral Scratch
Two complete transections of the spinal cord 1)
just posterior to the forelimb enlargement and
2) just posterior to the third segment of the
five-segment hindlimb enlargement. Neuromuscular
synapses blocked by nAChR antagonist. Record
ENGs from individual nerves. Activate fictive
rostral scratch reflex by mechanical stimulation
of mid-body shell bridge. Place micro-suction
electrode in white matter of posterior cut face
of spinal cord and record single-unit action
potentials of a spinal interneuron with a
descending axon during fictive scratch.
Stein Daniels-McQueen, J Neurosci 2002
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2003 SteinDMcQ
Single-unit interneuronal recordings during
fictive rostral scratch in the spinal turtle.
The unit illustrated here is termed an
OFF-unit. OFF-units are spinal interneurons
whose end-phases are near the onsets of
knee-extensor motor neuron bursts during rostral
scratch. The end-phases of OFF-units are
positively correlated with the start-phases of
knee-extensor motor neuron bursts during rostral
scratch. OFF-units are candidate members of the
knee-flexor module.
Stein Daniels-McQueen, J Neurophysiol 2003
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turt UBG hypoth
Turtle Rostral Scratch Unit-Burst-Generator
Hypothesis
During normal pattern of rostral scratch, neurons
in all four modules are active. Hip-flexor
module rhythmically alternates with hip-extensor
module. Knee-flexor module rhythmically
alternates with knee-extensor module. Knee-extens
or module is active during the latter portion of
hip-flexor module activity this is a
mixed-synergy motor pattern.
Stein, J Comp Physiol A 2005