Modelling Bursting

Pacemaker Neuronal
Network
Based on: Models of Respiratory Rhythm Generation in the
Pre-Botzinger Complex. III. Experimental Tests of Model Predictions
Christopher A. Del Negro, Sheree M. Johnson, Robert J. Butera, Jeffery
C. Smith

BY-
RAHUL BATRA
MT13049
Introduction
Pre-Bötzinger Complex(Pre-BotC)-
A cluster of interneurons in ventrolateral medulla
Hypothesized site for respiratory rhythm generation in
mammals
Pacemaker Neurons-
Pre-BotC houses a heterogeneous population of bursting
pacemaker neurons
Respiratory rhythm generation mechanism incorporates an
excitatory network of synaptically coupled pacemaker
neurons
Background of Research Paper
In the first two paper of this series , Butera et al. created
mathematical models of inspiratory pacemaker neurons,
which were assembled to form a network model of rhythm
generating kernel
In this paper we evaluate basis for the models and the
predictions that emerged from modelling studies at cellular
and network levels
The objective of this paper is to show that pacemaker
neuron and network models successfully predicted features
of inspiratory rhythm generation in vitro in the Pre-BotC
Experimental Method
Thin slices were cut from the medulla of neonatal rats in
ACSF that captured the Pre-BotC and XIIn rootlets
Rhythmic respiratory activity was maintained by raising the
ACSF K+ concentration ([K+]o )
 Inspiratory related motor discharge was recorded from the
XIIn rootlets and inspiratory neuron population was
simultaneously recorded from the Pre-BotC using macro
patch suction electrodes
Measurement of cellular and network activity such as
inspiratory burst period, frequency, and burst duration were
determined
To identify pacemaker neurons CNQX and low Ca2+
solution was used
A schematic showing the 350-μm-thick neonatal rat medullary
slice preparation and typical recording configuration

Pre-BotC activity preceded XIIn activity by 100-400 ms, which proves that
rhythm generation originates in the Pre-BotC
Mathematical Model
Pacemaker Neuron Model

It is composed of five ionic currents across the plasma membrane:

a fast sodium current, INa
a delayed rectifier potassium current, IK
a fast activating slowly inactivating persistent sodium current, INaP
a passive leakage current, IL
a tonic current, Itonic_e ( Itonic_e is considered to be inactive in single cell
simulations)
Model Formulation
Simulations
 Simulations

 At the highest Ek = -72 mV neuron exhibits tonic spiking

 At hyperpolarized Vm , Ek = -80 mV model is quiescent
 Ek is used to depolarize Vm , resulting in bursting oscillations
Results
A monotonic increase in burst frequency and decrease in
burst duration with increasing [K+]o concentration reflecting
the inactivation kinetics of INaP
Multistate behaviour with transitions from quiescence to
bursting and tonic spiking states as cells depolarizes i.e.
cellular excitability was increased via extracellular [K+]o
concentration
This model incorporates the minimum set of conductances
to generate bursting similar to pacemaker cells in the Pre-
BotC
Effect of Ca2+ current
Results
Intrinsic bursting behaviour did not depend on Ca2+ currents
and persisted after blocking synaptic transmission
Switching to low Ca2+ + CNQX solution did not
significantly affect burst duration nor the spike frequency –
time relationship
INaP dominates the burst generating mechanism of
pacemaker neuron model
Burst generation mechanism in inspiratory pacemaker
neurons is a Ca2+ independent persistent Na+ current
Conclusion
Pacemaker neuron model explains the features of
respiratory rhythm generation in Pre-BotC
 ?

? Questions ?