Identification of SSRI-evoked antidepressant sensory signals by decoding vagus nerve activity

The vagus nerve relays mood-altering signals originating in the gut lumen to the brain. In mice, an intact vagus is required to mediate the behavioural effects of both intraluminally applied selective serotonin reuptake inhibitors and a strain of Lactobacillus with antidepressant-like activity. Similarly, the prodepressant effect of lipopolysaccharide is vagus nerve dependent. Single vagal fibres are broadly tuned to respond by excitation to both anti- and prodepressant agents, but it remains unclear how neural responses encode behaviour-specific information. Here we demonstrate using ex vivo experiments that for single vagal fibres within the mesenteric neurovascular bundle supplying the mouse small intestine, a unique neural firing pattern code is common to both chemical and bacterial vagus-dependent antidepressant luminal stimuli. This code is qualitatively and statistically discernible from that evoked by lipopolysaccharide, a non-vagus-dependent antidepressant or control non-antidepressant Lactobacillus strain and are not affected by sex status. We found that all vagus dependent antidepressants evoked a decrease in mean spike interval, increase in spike burst duration, decrease in gap duration between bursts and increase in intra-burst spike intervals. Our results offer a novel neuronal electrical perspective as one explanation for mechanisms of action of gut-derived vagal dependent antidepressants. We expect that our ex vivo individual vagal fibre recording model will improve the design and operation of new, extant electroceutical vagal stimulation devices currently used to treat major depression. Furthermore, use of this vagal antidepressant code should provide a valuable screening tool for novel potential oral antidepressant candidates in preclinical animal models.

Spike burst–pause dynamics of Purkinje cells regulate sensorimotor adaptation

Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of targeted medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.Author SummaryCerebellar Purkinje cells regulate accurate eye movement coordination. However, it remains unclear how cerebellar-dependent oculomotor adaptation depends on the interplay between Purkinje cell characteristic response patterns: tonic, high-frequency bursting, and post-complex spike pauses. We explore the role of Purkinje spike burst-pause dynamics in VOR adaptation. A biophysical model of Purkinje cell is at the core of a spiking network model, which captures the cerebellar microcircuit properties and incorporates spike-based synaptic plasticity mechanisms at different cerebellar sites. We show that Purkinje spike burst-pause dynamics are critical for (1) gating the vestibular-motor response association during VOR acquisition; (2) mediating the LTD/LTP balance for VOR consolidation; (3) reshaping synaptic efficacy distributions for VOR phase-reversal adaptation; (4) explaining the reversal VOR gain discontinuities during sleeping.

Ovine small bowel “minute rhythm” intensity related to feeding and phase of migrating myoelectric complex

The presented study was performed to characterize further the ‘minute rhythm’ in the ovine small bowel, notably to assess the role of fasting and feeding as well as of the phase of the MMC upon the number and amplitude of the MR-containing spike bursts. In eight rams the electrodes were attached to the pyloric antrum, duodenal bulb, duodenum and upper jejunum. In the course of chronic experiments, the myoelectrical recordings were conducted in fasted and non-fasted rams, before and after feeding offered during phase 2a or 2b of the MMC. The phases of the MMC and the MR episodes were identified and the MR frequency, the number of the spike bursts in one MR episode and their amplitudes were calculated. 74 per cent of the MR episodes exhibited the propagated character. At the beginning of phase 2a, the MR often arrived exclusively in the duodenal bulb and was disorganized, while at the end of phase 2b of the MMC, the MR-related spike bursts were most prominent and propulsive. In the duodenal bulb, the giant-like spike bursts forming the pattern were observed occasionally. The MR episodes contained usually 1-2 spike bursts. The number of the MR episodes, each containing one spike burst was smaller after feeding mostly in the duodenum and jejunum and it was lower during phase 2b than during phase 2a of the MMC in the duodenal bulb, duodenum and jejunum. The number of the spike bursts in one MR episode increased after feeding and during phase 2b of the migrating myoelectric complex and it was the highest in the jejunum. The spike burst amplitudes of the MR episodes were the highest in the duodenal bulb. Feeding during phase 2b of the MMC decreased the amplitude of the MR-related spike bursts both in the duodenum and the jejunum. It is concluded that the intensity of the MR in the ovine small bowel is related to feeding and to the phase of the MMC and the high variability of the pattern comprises its character and strength that are apparently related to the intraluminal influences affecting the controlling mechanisms.

The specific long spike burst pattern indicates the presence of regional variability in the ovine gallbladder motor function

The myoelectrical activity of ovine gallbladder is incompletely recognized. Accordingly, each of five rams was fitted with six small intestinal and three gallbladder electrodes. The strain gauge force transducer was also mounted near the gallbladder fundic electrode. In two series of chronic experiments the electromyographical and mechanical recordings were conducted during 5–7 h in fasted or non-fasted animals, with or without feeding. The occurrence of the slow waves in the small bowel was common, unlike those in the gallbladder. In the small bowel myoelectrical records both the migrating motility complex and minute rhythm pattern were observed regularly. In the gallbladder, both the migrating motility complex-like activity and the minute rhythm were also denoted in the same time as in the small bowel. In gallbladder infundibulum, and often also in the gallbladder corpus, the specific pattern, called the long spike burst pattern (LSBP) was observed. It comprised usually one or two parts of prolonged duration. The first part resembled the classical (short lasting) spike burst in the small bowel and its amplitude was lower than that of the second part. The spike burst frequency of the second part of the pattern was 2–3 times lower than that of the first part. During phase 1 – and phase 2a-like activity, the frequency of the gallbladder LSBP was reduced in fasted rams. The LSBP amplitude was relatively high and not further enhanced after feeding. In fasted rams, the duration of specific pattern, observed in gallbladder infundibulum, was longer than that in non-fasted animals and its amplitude was low. Similar events were recorded in the gallbladder corpus, but the LSBP was shorter and not regular. In the gallbladder fundus, mostly irregular short spike bursts were recorded. It is concluded that in sheep, specific types of the long-lasting groups of spikes occur in the upper gallbladder areas forming the specific pattern that indicates the presence of the regional variability of the gallbladder motor activity. The character of LSBP depends mostly on feeding conditions.