Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

Abstract

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40–60 s and separated by quiescent episodes lasting 40–200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle.

Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons

“…These occur whether the trains are activated by mucosal field stimulation 33 or direct somal current injection 27 . This self-reinforcing excitatory IPAN network regulates motility 30,40,41 . During slow synaptic transmission to IPANs, a G-protein coupled decrease in constitutive and AP-associated Ca 2 þ currents depolarize the membrane potential, decrease leak conductance, narrow the AP, diminish sAHP and increase intrinsic excitability 30,42,43 .…”

“…Realistic computational models of MMC indicate that sensory stimulation causes a reflexive buildup of excitability in the enteric circuitry over 10-15 min, which is responsible for the eventual slow onset of contractile responses 41 . This is compatible with the observed 10-20 s latency of probiotic or TRAM-34 effects on gut peristalsis 10,44 .…”

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

“…The presence of CMMCs under these conditions not only demonstrates the spontaneity of CMMCs, but further elaborates on the usefulness of this technique to establish changes in colonic motility. Although this approach is applicable to extra-colonic regions of the gastrointestinal tract, the complexity of small intestinal motility requires more detailed analysis strategies than those used for quantifying CMMCs 33 .…”

“…The ex vivo nature of this method enables the role of the enteric nervous system to be assessed in the absence of central nervous system inputs and is therefore an ideal way to investigate gastrointestinal motility in a variety of models, including genetic models of disease (see Figure 2) 6,34 . This method can also be used to compare physiological data to computer simulations of motor activity 23,33,35 . Such simulations can predict motor patterns in the form of spatiotemporal maps for direct comparisons with physiological experiments 33,35 .…”

“…This method can also be used to compare physiological data to computer simulations of motor activity 23,33,35 . Such simulations can predict motor patterns in the form of spatiotemporal maps for direct comparisons with physiological experiments 33,35 . Using Fast Fourier Transform and wavelet analysis 36 , the contribution of smooth muscle pacemakers (generated by interstitial cells of Cajal) to motility can also be extracted.…”