Localization of the Sensory Neurons and Mechanoreceptors Required for Stretch-Evoked Colonic Migrating Motor Complexes in Mouse Colon

The pacemaker and pattern generator that underlies the cyclical generation of spontaneous colonic migrating motor complexes (CMMCs) has recently been identified to lie within the myenteric plexus and/or muscularis externa. Neither the mucosa, nor the release of substances from the mucosa were found to be required for the spontaneous generation of CMMCs. However, it is known that stretch applied to the colonic wall can also evoke CMMCs and since stretch of the gut wall is known to stimulate the mucosa, it is not clear whether release of substances from the mucosa and/or submucosal plexus are required for stretch-evoked CMMCs. Therefore, the aim of this study was to determine whether circumferential stretch-evoked CMMCs require the presence of the mucosa and/or submucosal plexus in isolated mouse colon. Spontaneous CMMCs were recorded from full length sheet preparations of colon in vitro. Graded circumferential stretch (at a rate of 100 μm/s) applied to a 15-mm segment of mid–distal colon reliably evoked a CMMC, which propagated to the oral recording site. Sharp dissection to remove the mucosa and submucosal plexus from the entire colon did not prevent spontaneous CMMCs and circumferential stretch-evoked CMMCs were still reliably evoked by circumferential stretch, even at significantly lower thresholds. In contrast, in intact preparations, direct stimulation of the mucosa (without accompanying stretch) proved highly inconsistent and rarely evoked a CMMC. These observations lead to the inescapable conclusion that the sensory neurons activated by colonic stretch to initiate CMMCs lie in the myenteric plexus, while the mechanoreceptors activated by stretch, lie in the myenteric ganglia and/or muscularis externa. Stretch activation of these mechanoreceptors does not require release of any substance(s) from the mucosa, or neural inputs arising from submucosal ganglia

How should we define a nociceptor in the gut-brain axis?

In the past few years, there has been extraordinary interest in how the gut communicates with the brain. This is because substantial and gathering data has emerged to suggest that sensory nerve pathways between the gut and brain may contribute much more widely in heath and disease, than was originally presumed. In the skin, the different types of sensory nerve endings have been thoroughly characterized, including the morphology of different nerve endings and the sensory modalities they encode. This knowledge is lacking for most types of visceral afferents, particularly spinal afferents that innervate abdominal organs, like the gut. In fact, only recently have the nerve endings of spinal afferents in any visceral organ been identified. What is clear is that spinal afferents play the major role in pain perception from the gut to the brain. Perhaps surprisingly, the majority of spinal afferent nerve endings in the gut express the ion channel TRPV1, which is often considered to be a marker of nociceptive neurons. And, a majority of gut-projecting spinal afferent neurons expressing TRPV1 are activated at low thresholds, in the normal physiological range, well below the normal threshold for detection of painful sensations. This introduces a major conundrum regarding visceral nociception. How should we define a nociceptor in the gut? We discuss the notion that nociception from the gut wall maybe a process encrypted into multiple different morphological types of spinal afferent nerve ending, rather than a single class of sensory ending, like free-endings, suggested to underlie nociception in skin

Identification of a rhythmic firing pattern in the enteric nervous system that generates rhythmic electrical activity in smooth muscle

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs

Identification of the Visceral Pain Pathway Activated by Noxious Colorectal Distension in Mice

In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100–120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2–5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9–15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30–75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1

The district goes global : export vs FDI

Digitised version produced by the EUI Library and made available online in 2020

Modification of neurogenic colonic motor behaviours by chemogenetic ablation of calretinin neurons

How the enteric nervous system determines the pacing and propagation direction of neurogenic contractions along the colon remains largely unknown. We used a chemogenetic strategy to ablate enteric neurons expressing calretinin (CAL). Mice expressing human diphtheria toxin receptor (DTR) in CAL neurons were generated by crossin

Evolution of the melt source during protracted crustal anatexis: An example from the Bhutan Himalaya

The chemical compositions of magmatic zircon growth zones provide powerful insight into evolving magma compositions due to their ability to record both time and the local chemical environment. In situ U-Pb and Hf isotope analyses of zircon rims from Oligocene–Miocene leucogranites of the Bhutan Himalaya reveal, for the first time, an evolution in melt composition between 32 and 12 Ma. The data indicate a uniform melt source from 32 Ma to 17 Ma, and the progressive addition of an older source component to the melt from at least ca. 17 Ma. Age-corrected εHf ratios decrease from between –10 and –15 down to values as low as –23 by 12 Ma. Complementary whole-rock Nd isotope data corroborate the Hf data, with a progressive decrease in εNd(t) from ca. 18 to 12 Ma. Published zircon and whole-rock Nd data from different lithotectonic units in the Himalaya suggest a chemical distinction between the younger Greater Himalayan Series (GHS) and the older Lesser Himalayan Series (LHS). The time-dependent isotopic evolution shown in the leucogranites demonstrates a progressive increase in melt contribution from older lithologies, suggestive of increasing LHS involvement in Himalayan melting over time. The time-resolved data are consistent with LHS material being progressively accreted to the base of the GHS from ca. 17 Ma, facilitated by deformation along the Main Central thrust. From 17 Ma, decompression, which had triggered anatexis in the GHS since the Paleogene, enabled melting in older sources from the accreted LHS, now forming the lowermost hanging wall of the thrust

On the enigmatic mid-Proterozoic : Single-lid versus plate tectonics

The mid-Proterozoic (ca. 1850-850 Ma) is a peculiar period of Earth history in many respects: ophiolites and passive margins of this age are rare, whereas anorthosite and A-type granite suites are abundant; metamorphic rocks typically record high thermobaric (temperature/pressure) ratios, whereas ultrahigh pressure (UHP) rocks are rare; and the abundance of economic mineral deposits features rare porphyry Cu-Au and abundant Ni-Cu and Fe-oxide Cu-Ag (IOCG) deposit types. These collective observations have been used to propose that a stagnant-lid, or single-lid, tectonic regime operated at this time, between periods of plate tectonics in the Paleoproterozoic and Neoproterozoic. In our reappraisal of the mid -Proterozoic geological record, we not only assess the viability of the single-lid hypothesis for each line of evidence, but also that of the plate tectonic alternative. We find that evidence for the single-lid hypothesis is equivocal in all cases, whereas for plate tectonics the evidence is equivocal or supporting. We therefore find no reason to abandon a plate tectonic model for the mid-Proterozoic time period. Instead, we propose that the peculiarities of this enigmatic interval can be reconciled through the combination of two processes working in tandem: secular mantle cooling and the exceptionally long tenure and incomplete breakup of Earth's first supercontinent, where both of these phenomena had a dramatic effect on lithospheric behaviour and its resulting imprint in the geological record. (c) 2022 British Geological Survey (c) UKRI 2022. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Enhanced U-Pb detrital zircon, Lu-Hf zircon, δ18O zircon, and Sm-Nd whole rock global databases

High-quality global isotopic databases provide Earth scientists with robust means for developing and testing a variety of geological hypotheses. Database design establishes the range of questions that can be addressed, and validation techniques can enhance data quality. Here, six validated global isotopic databases provide extensive records of analyses from U-Pb in detrital zircon, Lu-Hf in zircon, Sm-Nd from whole rocks, and δ18O in zircon. The U-Pb detrital zircon records are segregated into three independently sampled databases. Independent samples are critical for testing the replicability of results, a key requisite for gaining confidence in the validity of a hypothesis. An advantage of our updated databases is that a hypothesis developed from one of the global detrital zircon databases can be immediately tested with the other two independent detrital zircon databases to assess the replicability of results. The independent εHf(t) and εNd(t) values provide similar means of testing for replicable results. This contribution discusses database design, data limitations, and validation techniques used to ensure the data are optimal for subsequent geological investigations