computational neural model of the alterations in...
TRANSCRIPT
REFERENCES
METHODS
RESULTS
ACKNOWLEDGMENTS
INTRODUCTION
CONCLUSIONS
1: Department of Physiology, 2: Division of Neurobiology and Evelyn F. McKnight Brain Institute, 3: Department of Psychology and Applied Mathematics, University of Arizona, Tucson, AZ.
, , Gregory L Powell Jason Q Pilarski Ralph F Fregosi, and Jean-Marc Fellous 1 1,21 3
Contact information: [email protected]
Prenatal nicotine exposure (PNE) alters nicotinic transmission in the PreBotzinger Complex (PBC), particularly rhythm frequency (Fregosi and Pilarski 2008)
Creation of a computational model will allow for prediction of the mechanisms of action in currents mediated by nicotinic acetylcholine receptors (nAChRs)
A hybrid pacemaker-follower network model of rhythm generation with a strong persistent sodium current (I ) in 10% of the neurons was NaP
used in the NEURON Simulation Environment
Simulated the effect of the up- or down-regulation of nicotinic receptors on membrane and synaptic currents and how respiratory frequency and network synchrony were affected
Current models of PBC neurons do not include the effects of nicotinic receptors
Nicotinic receptors are known to modulate inspiratory rhythm frequency, but their location and density are unknown
Both persistent sodium currents and calcium currents have been speculated to control rhythm generation in the PBC network (Butera et al 1999; Rybak et al 1997)
Channel properties were obtained from previously published work
50 neurons = 5 bursters + 45 followers
Synaptic conductances varied with neuron type.
No neurons synapsed ontothemselves.
Oscillations within the network are initiated by a controlled current pulse to the bursters only.Synchrony was calculated in MATLAB using a 10ms bin size.Data is presented as mean +/- SD.Fits are 2nd order polynomial.Significance was determined using Student’s t-test. All significances are computed relative to the baseline network. P<0.05.N=10 simulations for all trials unless otherwise noted.
Increases in persistent sodium conductance cause increases in burst frequency but little significant change in intraburst
frequency or network synchrony
Computational neural model of the alterations in respiratory rhythm generationcaused by developmental, environmental, and genetic abnormalities
BurstersInterconnected
Interconnections not shown
Individual Connections between Neurons
Increases in calcium conductance cause no significant change in intraburst or burst frequency, but a slight increase in network synchrony
Increases in potassium-IAHP conductance cause decreases in intraburst frequency, but no significant change in burst frequency or
network synchrony
Increases in synaptic conductance cause an increase in intraburst frequency, a decrease in burst frequency, and an increase in
network synchrony
Ectopic bursts are synchronous throughout the network but do not elicit a
full burst
Model cell
Leak current
Potassium, delayed-rectifier current
Voltage-senstive sodium currrent Potassium-
IAHP current
Persistent sodium current
Calcium current
Calcium shell
AMPA receptor
NMDA receptor
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-15% of baseline persistent sodium current.
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+25% of baseline persistent sodium current.+15% baseline synaptic conductance.
-25% baseline synaptic conductance.
+25% baseline calcium conductance.
-25% of baseline calcium conductance.
+25% baseline calcium-dependent K+ current.
-25% baseline calcium-dependent K+ current.
An ectopic burst (*) seen experimentally
(Del Negro et al 2002)
A comparison of a bursting PBC neuron obtained experimentally and seen in the model.
Burst Frequency
gkbar_iahp(% difference from control)
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Frequency (Hz)
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Intraburst Frequency
gbar_ca(% difference from control)
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Frequency (Hz)
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486.16
50 neuron network with 10% increases in I , I , and I and synaptic NaP Ca ahp
conductance, mimics changes seen after acute exposure to nicotine in vitro
The authors would like to thank the Science Foundation of Arizona and the American Heart Association (AHA 0855713G) for funding this work.
Del Negro et al.(2002). Respiratory Rhythm: An Emergent Network Property? Neuron, Vol. 34: 821-830.
Shao and Feldman (2001). Mechanisms Underlying Regulation of Respiratory Pattern by Nicotine in PreBotzinger Complex. J Neurophysiol,. 85: 2461-246, 2001.
Fregosi and Pilarski (2008). Prenatal nicotine exposure and development of nicotinic and fast amino acid-mediated neurotransmission in the control of breathing. Resp. Phsy. & Neurobio. Vol 184: 80-86.
Butera et al (1999). Models of Respiratory Rhythm Generation in the Pre-Bo¨tzingerComplex. I. Bursting Pacemaker Neurons. J Neurophysiol 82:382-397, 1999.
Rybak et al (1997). Modeling Neural Mechanisms for Genesis of Respiratory Rhythm and Pattern. I. Models of Respiratory Neurons. J Neurophysiol 77:1994-2006, 1997.
5 sec
10 mV
5 sec
10 mV
5 sec
10 mV
Bursting cell recorded experimentally (unpublished, Pilarski, JQ)
Shao and Feldman (2001)
Model with simulated exposure to nicotine.
The model is able to reproduce bursts similar to that seen experimentally
Ectopic bursts comparable to those seen in vitro are present within the model and are synchronous throughout the network, but do not elicit a full burst
Increases in persistent sodium conductance cause a significant increase in network burst frequency, whereas changes to calcium and calcium-dependent potassium conductances have no significant effect on burst frequency
The model is able to accurately reproduce the effects of nicotine on PBC network behavior
Calcium pump
5 sec
10 mV
5 sec
10 mV
5 sec
10 mV
Burst Frequency
g_NaP (% difference from control)
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Frequency (Hz)
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Synchrony
g_NaP (% difference from control)
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Synchrony Index
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1.0
Intraburst Frequency
gkbar_iahp(% difference from control)
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Frequency (Hz)
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140
Synchrony
gkbar_iahp(% difference from control)
-60 -40 -20 0 20 40 60
Synchrony Index
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Burst Frequency
gbar_ca(% difference from control)
-60 -40 -20 0 20 40 60
Frequency (Hz)
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Synchrony
gbar_ca(% difference from control)
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Synchrony Index
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Synchrony
Synaptic Conductance (% difference from control)-60 -40 -20 0 20 40 60
Synchrony Index
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Experimental dataExperimental data
Intraburst Frequency
g_NaP (% difference from control)
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Frequency (Hz)
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N= 20 for g_NaP(-15)
Intraburst Frequency
Fre
quency
(Hz)
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Baseline
Nicotine
Synchrony
Syn
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Index
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Baseline
Nicotine
Burst Frequency
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quency
(Hz)
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BaselineNicotine
Burst Frequency
Synaptic conductance (%difference from control)
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Frequency (Hz)
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Intraburst Frequency
Synaptic conductance (% difference from control)
-60 -40 -20 0 20 40 60Frequency (Hz)
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Time (s)
For nicotine simulations, n=7