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In JoVE (1)
Other Publications (5)
Articles by Jill M. Hoffman in JoVE
JoVE General
Gastrointestinal Motility Monitor (GIMM)
Department of Anatomy and Neurobiology, The University of Vermont
Evaluation of colonic motility in the guinea pig distal colon with the Gastrointestinal Motility Monitor (GIMM) is a straightforward and simple to learn approach to quantitatively evaluate propulsive motility in the gastrointestinal tract.
Other articles by Jill M. Hoffman on PubMed
Inhibition of Serotonergic Neurons in the Nucleus Paragigantocellularis Lateralis Fragments Sleep and Decreases Rapid Eye Movement Sleep in the Piglet: Implications for Sudden Infant Death Syndrome
Serotonergic receptor binding is altered in the medullary serotonergic nuclei, including the paragigantocellularis lateralis (PGCL), in many infants who die of sudden infant death syndrome (SIDS). The PGCL receives inputs from many sites in the caudal brainstem and projects to the spinal cord and to more rostral areas important for arousal and vigilance. We have shown previously that local unilateral nonspecific neuronal inhibition in this region with GABA(A) agonists disrupts sleep architecture. We hypothesized that specifically inhibiting serotonergic activity in the PGCL would result in less sleep and heightened vigilance. We analyzed sleep before and after unilaterally dialyzing the 5-HT1A agonist (+/-)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) into the juxtafacial PGCL in conscious newborn piglets. 8-OH-DPAT dialysis resulted in fragmented sleep with an increase in the number and a decrease in the duration of bouts of nonrapid eye movement (NREM) sleep and a marked decrease in amount of rapid eye movement (REM) sleep. After 8-OH-DPAT dialysis, there were decreases in body movements, including shivering, during NREM sleep; body temperature and heart rate also decreased. The effects of 8-OH-DPAT were blocked by local pretreatment with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane-carboxamide, a selective 5-HT1A antagonist. Destruction of serotonergic neurons with 5,7-DHT resulted in fragmented sleep and eliminated the effects of subsequent 8-OH-DPAT dialysis on REM but not the effects on body temperature or heart rate. We conclude that neurons expressing 5-HT1A autoreceptors in the juxtafacial PGCL are involved in regulating or modulating sleep. Abnormalities in the function of these neurons may alter sleep homeostasis and contribute to the etiology of SIDS.
Functional Interrelations Between Nucleus Raphé Dorsalis and Nucleus Raphé Medianus: a Dual Probe Microdialysis Study of Glutamate-stimulated Serotonin Release
Dual-probe in vivo microdialysis was used to explore the relationships between the two midbrain raphé nuclei, raphé dorsalis (DRN) and raphé medianus (MRN). Infusion of the excitatory neurotransmitter glutamate (10 mM) into the dorsal raphé nucleus produced a large increase in the extracellular 5-HT (5-HT(ext)) in the dorsal raphé (1400% of control values) that was limited to the time of infusion. This was followed by a significant decrease in extracellular 5-HT below baseline levels that continued for the duration of the experiment (3 h). Extracellular 5-HT (5-HT(ext)) was also increased to 500% of control values in the median raphé nucleus following infusion of 10 mM glutamate (GLU) into the dorsal raphé nucleus. Infusion of the competitive NMDA receptor antagonist AP5 prior to and during infusion of GLU into the DRN resulted in a decrease in the response to GLU in the DRN and an antagonism of the increase of 5-HT(ext) in the MRN. Infusion of 10mM GLU into the lateral midbrain tegmentum, an area of the brain just lateral to the DRN, also increased 5-HT(ext) in the probe in the lateral midbrain tegmentum (900% of control) but did not alter 5-HT(ext) in the MRN. When glutamate was infused into the MRN, 5-HT(ext) was also increased to 1400% of control in a time course similar to that seen with infusion of GLU into the DRN. Infusion of glutamate into the MRN, however, did not alter the 5-HT(ext) in the DRN. These data suggest a serotonergic innervation of the median raphé nucleus by the dorsal raphé nucleus. A reciprocal innervation from the median raphé to the dorsal raphé is not mediated by glutamate, does not appear to be serotonergic, and does not regulate extracellular serotonin in the dorsal raphé.
Purinergic Neuromuscular Transmission is Selectively Attenuated in Ulcerated Regions of Inflamed Guinea Pig Distal Colon
This study was undertaken to investigate neuromuscular transmission in regions of the inflamed colon in which motility is disrupted. Propulsive motility was evaluated in segments of control guinea pigs and those treated 6 days previously with trinitrobenzene sulfonic acid. Intracellular recordings were then obtained from circular muscle cells to examine excitatory and inhibitory junction potentials (EJPs and IJPs). In inflamed preparations, propulsion of fecal pellets was temporarily halted or obstructed at sites of mucosal damage, whereas the propulsive motility was linear in control colons. The amplitudes of evoked and spontaneous IJPs were significantly reduced in ulcerated regions of inflamed preparations, but EJPs were comparable to controls. Pharmacological dissection of the IJP revealed that the purinergic component was reduced, while the nitrergic IJP was slightly increased. Furthermore, the reduction in the purinergic IJP in inflamed preparations persisted in the presence of hexamethonium, suggesting that the deficit involved the inhibitory motor neuron and/or smooth muscle. Nerve fibre density was not altered in the circular muscle, and pre-contracted rings of inflamed colon relaxed normally to ATP, suggesting that the deficit involves altered ATP release and/or degradation. The P2Y(1) receptor antagonist MRS2179 slowed propulsive motility indicating that decreased purinergic neuromuscular transmission could contribute to the inflammation-induced motor deficit. We conclude that purinergic inhibitory neuronal input to the circular muscle is selectively reduced in regions of the colon in experimental colitis where the mucosa is damaged, and this is likely to contribute to altered motility in colitis by diminishing downstream relaxation during the peristaltic reflex.
Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome
Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS.
Activation of Colonic Mucosal 5-HT(4) Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity
BACKGROUND & AIMS: 5-hydroxytryptamine (5-HT(4))-receptor agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4) agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS: Mucosal expression of the 5-HT(4) receptor was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl(-) secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT(4) compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS: Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5-HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of the 5-HT(4) receptor evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)-receptor agonists accelerated propulsive motility; a 5-HT(4) antagonist blocked this effect. Bath application of 5-HT(4) agonists did not affect motility. Oral or intracolonic administration of 5-HT(4) agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4) antagonist. CONCLUSIONS: Mucosal 5-HT(4)-receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4) agonists. Colon-targeted, intraluminal delivery of 5-HT(4) agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.
