Transcript Document

Rhythms in central pattern generators –
implications of escape and release
Jonathan Rubin
Department of Mathematics
University of Pittsburgh
Linking neural dynamics and coding
BIRS – October 5, 2010
funding: U.S. National Science Foundation
goal: to understand the mechanisms of
rhythm generation, and modulation, in the
mammalian brainstem respiratory network
and other central pattern generators (CPGs)
Talk Outline
•Brief introduction to CPGs
•Transition mechanisms in pairs with reciprocal inhibition
-- escape/release
-- changes in drives to single component
• Applications of ideas to larger networks
examples of central
pattern generators
crustacean STG – Rabbeh and Nadim,
J. Neurophysiol., 2007
leech heart IN network – Cymbalyuk
et al., J. Neurosci., 2002
overall, central pattern generators (CPGs)
• exhibit rhythms featuring ordered, alternating phases of
synchronized activity
• rhythms are intrinsically produced by the network
• rhythms can be modulated by external signals (CPG
output encodes environmental conditions)
group 1
+
group 2
=
CPG rhythm
Nat. Rev. Neurosci., 2005
starting point for modeling CPG rhythms: eliminate spikes!
Pace et al., Eur. J. Neurosci., 2007:
preBötzinger Complex (mammalian respiratory brainstem)
half-center oscillator (Brown, 1911): components not
intrinsically rhythmic; generates rhythmic activity without
rhythmic drive
−
−
reciprocal inhibition
time courses for half-center oscillations from 3 mechanisms:
persistent sodium, post-inhibitory rebound (T-current), adaptation
(Ca/K-Ca)
simulation results:
unequal constant drives
fixed
persistent sodium
−
varied
−
intermediate
relative silent phase duration
for cell with varied drive
relative silent phase duration
for cell with fixed drive
post-inhibitory rebound
Daun et al., J. Comp. Neurosci., 2009
adaptation
slow
Why? transition mechanisms: escape vs. release
inhibition off
inhibition off
inhibition on
inhibition on
fast
fast
Wang & Rinzel, Neural Comp., 1992; Skinner et al., Biol. Cyb., 1994
slow
example: persistent sodium current w/escape
fast
V
Daun, Rubin, and Rybak, JCNS, 2009
persistent sodium w/ unequal drives
−
baseline
slow
inhibition on
baseline orbit
extra drive
baseline drive
inhibition off
V
fast
short silent phase for cell w/extra drive
Daun, Rubin, and Rybak, JCNS, 2009
−
extra drive
Summary
• escape: independent phase modulation (e.g., persistent sodium
current)
• release: poor phase modulation (e.g., post-inhibitory rebound)
• adaptation = mix of release and escape: phase modulation by NOT
independent (e.g., Ca/K-Ca currents)
Daun et al., JCNS, 2009
applications to respiratory model (1)
3
4
2
1
1
4
3
2
inhibition
excitation
Smith et al., J. Neurophysiol., 2007
I-to-E
E-to-I
baseline 3-phase
rhythm: slow projection
(expiratory adaptation)
E
E-to-I transition by
escape: cells 1 & 2
escape to start I phase
I
1
4
(inspiratory adaptation)
3
2
I-to-E transition forced to be by
release: cell 2 releases cells 3 & 4
main predictions (T = duration):
• increase D1, D2
decrease TE , little ΔTI
• increase D3
little ΔTI, ΔTE
Rubin et al., J.
Neurophysiol.,
2009
predictions:
increase D1, D2
decrease TE, little ΔTI
increase D3
little ΔTI, ΔTE
Rubin et al., J. Neurophysiol., 2009
applications to respiratory model (2): include RTN/pFRG,
possible source of active expiration
Rubin et al., J. Comp.
Neurosci., 2010
basic rhythm lacks late-E
(RTN/pFRG) activity
hypercapnia
(high CO2 ):
• model as
increase in drive
to late-E neuron
• late-E
oscillations
emerge
quantally
• I period does
not change
Why is the period invariant? Phase plane for early-I (cell 2):
trajectories
live here!
read off
m2 values
synapses on
synapses ½-max
repeat for different input levels
excited
inhibited
synapses on
synapses ½-max
Why is the period invariant?
even with late-E activation, early-I activates by
escape - starts inhibiting expiratory cells while they
are fully active (full inhibition to early-I and
late-E)
inhibition
excitation
thus, late-E activation has no impact on period!
(similar result if pre-I escapes and recruits early-I)
applications (3) – limbed locomotion model
CPG
(RGs, INs)
motoneurons
muscles +
pendulum
Markin et al.,
Ann. NY Acad.
Sci., 2009
Spardy et al.,
SFN, 2010
locomotion with feedback – asymmetric phase modulation
under variation of drive
drive
does this asymmetry imply asymmetry of CPG?
no! – model has symmetric CPG yet still gives
asymmetry if feedback is present
locomotion with
feedback –
asymmetric phase
modulation under
variation of drive
drive
locomotion without
feedback – loss of
asymmetry
drive
Markin et al.,
SFN, 2009
rhythm with/without feedback: what is the difference?
with
feedback
IN escape
controls
phase
transitions
Lucy Spardy
rhythm with/without feedback: what is the difference?
without
feedback
RG escape
controls
phase
transitions
Lucy Spardy
idea: drive
strength affects
timing of INF
escape (end of
stance), RGE, RGF
escape but not
timing of INE
escape
OP : how does
feedback shelter
INE from drive?
drive
drive
Conclusions
• escape and release are different transition
mechanisms that can yield similar rhythms in
synaptically coupled networks
• in respiration, different mechanisms are predicted
to be involved in different transitions
• transition mechanisms within one network may
change with changes in state
• transition mechanisms determine responses to
changes in drives to particular neurons – could be
key for feedback control
THANK YOU!