Recurrent networks of submucous neurons controlling intestinal secretion: a modeling study

Abstract

Secretomotor neurons, immunoreactive for vasoactive intestinal peptide (VIP), are important in controlling chloride secretion in the small intestine. These neurons form functional synapses with other submucosal VIP neurons and transmit via slow excitatory postsynaptic potentials (EPSPs). Thus they form a recurrent network with positive feedback. Intrinsic sensory neurons within the submucosa are also likely to form recurrent networks with positive feedback, provide substantial output to VIP neurons, and receive input from VIP neurons. If positive feedback within recurrent networks is sufficiently large, then neurons in the network respond to even small stimuli by firing at their maximum possible rate, even after the stimulus is removed. However, it is not clear whether such a mechanism operates within the recurrent networks of submucous neurons. We investigated this question by performing computer simulations of realistic models of VIP and intrinsic sensory neuron networks. In the expected range of electrophysiological properties, we found that activity in the VIP neuron network decayed slowly after cessation of a stimulus, indicating that positive feedback is not strong enough to support the uncontrolled firing state. The addition of intrinsic sensory neurons produced a low stable firing rate consistent with the common finding that basal secretory activity is, in part, neurogenic. Changing electrophysiological properties enables these recurrent networks to support the uncontrolled firing state, which may have implications with hypersecretion in the presence of enterotoxins such as cholera-toxin.

Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo

“…The finding that nicotinic receptors are not required for the induction of CT-evoked secretion is also compatible with our modelling study (9). In our model, hyperactivity in the recurrent networks is enhanced by fast synaptic transmission of the type mediated by nicotinic receptors but is not dependent on it.…”

“…We (9) have recently reported that an anatomically realistic model of the submucous plexus can account for such a divergence in mechanism. This model predicts that the induction of hypersecretion depends on positive feedback within recurrent excitatory networks of VIP neurons and the intrinsic sensory neurons of the submucosa.…”

“…In a recent study (9), we proposed that hypersecretion may be due to hyperactivity in recurrent networks of submucous secretomotor neurons. We showed that this was feasible using computer simulations of the activity of anatomically realistic networks of such neurons, as long as the networks in turn interact with sensory neural networks in a physiologically realistic fashion.…”

Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo

“…One possibility is that a combination of NK 1 receptor and nicotinic input is required for the circuit to activate rapidly and that blockade of either component will prolong the time taken to activate the circuit and reduce final firing rate. A pattern of this type was described in previous modeling work on the submucous plexus (9). Serosal lidocaine might, in that case, affect both components.…”

“…Nurgali et al (43) have shown that in mouse distal colon, neurons with Dogiel type II morphology often do not exhibit a pronounced after-hyperpolarizing potential (AHP). Interestingly, in recent modeling studies (9, 59), we have shown that suppression of the AHP and/or increased synaptic efficacy in submucous sensory networks will lead to enhanced responses of VIP secretomotor neurons to sensory stimulation (9). Thus a potential explanation for the increased response in mice could be due to a reduced AHP in AH neurons, rendering them more sensitive to, for instance, mechanical stimuli.…”