Modelling Bursting Pacemaker Neurons in PreBotzinger Complex
Rahul Batra
MT13049
IIIT-Delhi
I. A BSTRACT
In this paper we use the hypothesis that respiratory
rhythm generation in mammals is generated in vitro in
preBotzinger complex by a heterogeneous population
of pacemaker neurons . We use the mathematical mod-
els proposed by Butera et al, to evaluate cellular and
population level component of the pacemaker neurons
and explain the features of respiratory rhythm genera-
tion.
II. I NTRODUCTION
PreBotzinger complex (preBotC) is a specialized re-
gion of ventrolateral medulla . It consists of a heteroge-
neous population of bursting pacemaker neurons which
are necessary and sufficient to generate inspiratory
related motor output in vitro.
Respiratory rhythm generation mechanism incorporates
an excitatory network of synaptically coupled pace-
maker neurons. It does not require any synaptic in-
hibition. A subset of inspiratory interneurons in the
preBotC are bursting pacemaker neurons which are
synchronized by non-N-methyl-D-aspartate (NMDA)
fast excitatory synapses.
III. E XPERIMENTAL M ETHOD
Thin transverse slices capturing the preBotC were
cut from medulla of neonatal rats in artificial cere-
brospinal fluid (ACSF). Rhythmic respiratory activity
was maintained by raising the ACSF K+ concentra-
tion. Inspiratory related motor discharge was recorded
from hypoglossal nerve (XIIn) rootlets (which was also
captured in the slice). Inspiratory neuron population
activity was simultaneously recorded in the preBotC
using macropatch suction electrodes. Both the XIIn
and preBotC recordings were rectified and smoothed
by analog integration. It was found that pre-BotC ac-
tivity preceded XIIn activity, which proved that rhythm
generation originates in the Pre-BotC. Measurement of
cellular and network activity such as inspiratory burst
period, frequency, and burst duration were determined.
To confirm these cells have pacemaker properties (i.e.
they could burst intrinsically in the absence of rhyth-
mic synaptic drive), the excitatory synaptic transmis-
sion was blocked using 6-cyano-7-nitroquinoxaline-
2,3-dione disodium (CNQX) and all sources of chemi-
cal transmission were blocked using low Ca2+ solution.
The changes in the burst period and burst duration of
single cells before and after CNQX application and low
Ca2+ solution were determined.
IV. M ATHEMATICAL M ODELLING
PACEMAKER N EURON M ODEL
It is composed of five ionic currents across the
plasma membrane:
1) a fast sodium current, INa ;
2) a delayed rectifier potassium current, IK ;
3) a fast activating slowly inactivating persistent
sodium current, INaP ;
4) a passive leakage current, IL ;
5) a tonic current, Itonic e (Itonic e is considered to be
inactive in single cell simulations);
INaP primarily constitutes the burst generating mecha-
nism.
This model has three state variables. VM and n are
fast changing, where VM is the membrane potential (in
mV) and n is the gating variable. The third variable h
is a gating variable for slow inactivation of INaP and
influences phase transitions during bursting. The set of
equations used in this model are:
C V̇M = −IN aP − IN a − IK − IL(K) − IL(N a) − Itonic(e)
(1)
ṅ = n∞ (VM ) − n/τn VM (2)
ḣ = h∞ (VM ) − h/τh VM (3)
x∞ (VM ) = {1 + exp[(VM − θx )/σx ]}−1 , x = n, h
(4)
τx (VM ) = τ̄x / cosh[(VM − θx )/2σx ] , x = n, h (5)
IN a = ḡN a m3∞ (VM )(1 − n)(VM − EN a ) (6)
 IK = ḡK n4 (VM − EK ) (7)
IN aP = ḡN aP p∞ (VM )h(VM − EN a ) (8)
IL(K) = gL(K) (VM − EK ) (9)
IL(N a) = gL(N a) (VM − EN a ) (10)
Itonic(e) = gtonic(e) (VM − Esyn(e) ) (11)
B EHAVIOUR OF PACEMAKER N EURON M ODEL -

V. E VALUATION OF PACEMAKER N EURON M ODEL

This model serve as the minimal mathematical model
of voltage dependent bursting pacemaker neurons in the
preBotC . Bursting is influenced by excitability param-
eters that controls the membrane potential VM such as
Ek which acts through K+ dominated leakage current.
At the highest Ek , the neuron exhibits tonic spiking
i.e. a series of continuous action potential without any
inactive period. As VM depolarizes by increasing [K+ ]o
concentration , burst frequency increases monotonically
due to progressive shortening of interburst interval and
burst duration decreases monotonically due to voltage
dependent inactivation of burst generating current INaP .
VI. E FFECT OF REMOVING S YNAPTIC
T RANSMISSION
We examined whether intrinsic Ca2+ currents
contribute towards burst generation by switching
to low Ca2+ solution containing CNQX. We found
that low Ca2+ solution did not prevent bursting nor
diminish burst duration. Ca2+ currents are present in
pacemaker neurons (and other neurons in preBotC) in
neonatal rats but are not essential for bursting in rat.
Thus the burst generating mechanism in pacemaker
neuron model is dominated by INaP .

E FFECT OF C A 2+ CURRENT -

VII. CONCLUSIONS
The tests on pacemaker neuron model affirm that
burst generating mechanism is dominated by persistent
Na+ current , it did not depend on Ca2+ current and per-
sisted after blocking synaptic transmission. Pacemaker
neurons exhibit multistate behaviour with transitions
from quiescence to bursting and tonic spiking states
as cellular excitability was increased via extracellularly
K+ concentration ([K+ ]0 ) and a monotonic increase in
burst frequency and decrease in burst duration with
increasing [K+ ]0 . Thus the model predictions accounts
for various aspects of respiratory rhythm and pattern
generated in vitro in preBotC.
R EFERENCES
[1] Christopher A. Del Negro, Sheree M. Johnson, Robert J.
Butera and Jeffrey C. Smith - Models of Respiratory Rhythm
Generation in the Pre-Btzinger Complex. III. Experimental
Tests of Model Predictions
[2] Robert J. Butera Jr., John Rinzel , Jeffrey C. Smith - Models of
Respiratory Rhythm Generation in the Pre-Btzinger Complex.
I. Bursting Pacemaker Neurons