Vection-induced gastric dysrhythmias and motion sickness

Gastric electrical and mechanical activity during vection-induced motion sickness was investigated. The contractile events of the antrum and gastric myoelectric activity in healthy subjects exposed to vection were measured simultaneously. Symptomatic and myoelectric responses of subjects with vagotomy and gastric resections during vection stimuli were determined. And laboratory based computer systems for analysis of the myoelectric signal were developed. Gastric myoelectric activity was recorded from cutaneous electrodes, i.e., electrogastrograms (EGGs), and antral contractions were measured with intraluminal pressure transducers. Vection was induced by a rotating drum. gastric electromechanical activity was recorded during three periods: 15 min baseline, 15 min drum rotation (vection), and 15 to 30 min recovery. Preliminary results showed that catecholamine responses in nauseated versus symptom-free subjects were divergent and pretreatment with metoclopramide HC1 (Reglan) prevented vection-induced nausea and reduced tachygastrias in two previously symptomatic subjects

Distinct Neuromuscular Patterns from a Single Motor Network

My thesis aimed to elucidate several aspects of motor circuit regulation and its impact on movement. It is well established that a single motor network can produce different output patterns in response to different inputs. However, in most model systems it remains challenging to identify the neurons comprising these networks and determine their role(s) in network operation, including whether each network neuron retains its role(s) when the network generates different output patterns. Also, most work on these circuits has occurred in the isolated nervous system, so little is known about how muscles respond to distinct neural outputs. I therefore aimed to address the cellular and synaptic mechanisms underlying these unresolved issues using the decapod crustacean stomatogastric nervous system. My work focused on a rhythmically active, network-driven motor circuit (central pattern generator [CPG] circuit) called the gastric mill (chewing) CPG in the crab stomatogastric ganglion. This circuit generates the gastric mill rhythm when activated by modulatory projection neurons (e.g. MCN1, CPN2) located in the commissural ganglia, and it is regulated by identified sensory feedback. I addressed and confirmed the hypothesis that, in the isolated nervous system, different extrinsic inputs can drive different gastric mill motor patterns. This enabled me to determine, for the first time in a network-driven motor circuit, that different motor patterns generated by the same motor circuit are paced by the same set of rhythm generator neurons. I further hypothesized and confirmed that these distinct motor patterns are retained at the level of at least some target muscles, and hence likely underlie different behavioral patterns. Lastly, I obtained data supporting the hypothesis that different extrinsic inputs distinctly modify the influence of a sensory feedback pathway on the relevant projection neurons (MCN1, CPN2), enabling the same sensory system to have different effects on different gastric mill rhythms. These results provide among the most detailed comparisons of how motor patterns generated by a single sensorimotor system are selected and regulated. The results thereby provide evidence for several novel cellular and synaptic mechanisms that expand our appreciation of the number of degrees of freedom available to even small sensorimotor systems

Differential gene expression in the murine gastric fundus lacking interstitial cells of Cajal.

BACKGROUND: The muscle layers of murine gastric fundus have no interstitial cells of Cajal at the level of the myenteric plexus and only possess intramuscular interstitial cells and this tissue does not generate electric slow waves. The absence of intramuscular interstitial cells in W/WV mutants provides a unique opportunity to study the molecular changes that are associated with the loss of these intercalating cells. METHOD: The gene expression profile of the gastric fundus of wild type and W/WV mice was assayed by murine microarray analysis displaying a total of 8734 elements. Queried genes from the microarray analysis were confirmed by semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: Twenty-one genes were differentially expressed in wild type and W/WV mice. Eleven transcripts had 2.0-2.5 fold higher mRNA expression in W/WV gastric fundus when compared to wild type tissues. Ten transcripts had 2.1-3.9 fold lower expression in W/WV mutants in comparison with wild type animals. None of these genes have ever been implicated in any bowel motility function. CONCLUSIONS: These data provides evidence that several important genes have significantly changed in the murine fundus of W/WV mutants that lack intramuscular interstitial cells of Cajal and have reduced enteric motor neurotransmission

The Potential of Electrical Stimulation and Smart Textiles for Patients with Diabetes Mellitus

Diabetes mellitus is one of the most frequent diseases in the general population. Electrical stimulation is a treatment modality based on the transmission of electrical pulses into the body that has been widely used for improving wound healing and for managing acute and chronic pain. Here, we discuss recent advancements in electroceuticals and haptic/smart devices for quality of life and present in which patients and how electrical stimulation may prove to be useful for the treatment of diabetes-related complications

Distinct Circuit States Enable State-dependent Flexibility in a Rhythm Generating Network

My thesis aimed to elucidate general organizing principles underlying the modulation of neural circuits. These circuits are flexible constructs that, when modulated, can occupy many distinct states and produce different output patterns. Distinct circuit states can also produce the same output pattern in some cases. However, understanding the mechanisms and consequences of this latter phenomenon is impossible to achieve without the capability to observe and manipulate the cellular and synaptic properties of all circuit neurons. This work takes advantage of our detailed, cellular-level access to the central pattern generator (CPG) circuits found in the decapod crustacean stomatogastric nervous system, a specialized extension of the CNS dedicated to internal feeding-related behaviors. As CPGs are rhythmically active networks, much of this work focuses on the ability of such circuits to produce rhythmic output patterns (i.e. rhythm generation). Using this system, I found that distinct circuit states (configured by MCN1 projection neuron stimulation and CabPK peptide application) can enable comparable rhythm generation by recruiting distinct ionic conductances with overlapping functional roles (i.e. IMI and ITrans-LTS), each being regulated by synaptic inhibition to produce phasic excitatory drive to a pivotal circuit neuron (LG). In one case (MCN1 stimulation), the conductance is activated by a modulatory peptide transmitter whose release is regulated by presynaptic feedback inhibition. In the other case (CabPK application), the conductance has a slow inactivation property that is removed by hyperpolarization caused by synaptic inhibition. I also describe the consequences of having different circuit states that produce identical outputs by assaying their responses to the same, well-defined modulatory inputs - peptide (CCAP) hormone modulation and sensory feedback (GPR neuron). I found that hormonal modulation produced opposite effects on these two circuits states even though the cellular-level hormonal action is likely the same in both states. In contrast, I found these circuits were similarly sensitive to sensory feedback, despite this feedback acting via different synapses under each condition. My work thereby provides the first mechanistic understanding of input-pathway specific rhythm generators that produce convergent output patterns and the flexibility enabled by these circuit states when responding to additional modulatory inputs

Gut microbiota-motility interregulation:Insights from in vivo, ex vivo and in silico studies

The human gastrointestinal tract is home to trillions of microbes. Gut microbial communities have a significant regulatory role in the intestinal physiology, such as gut motility. Microbial effect on gut motility is often evoked by bioactive molecules from various sources, including microbial break down of carbohydrates, fibers or proteins. In turn, gut motility regulates the colonization within the microbial ecosystem. However, the underlying mechanisms of such regulation remain obscure. Deciphering the inter-regulatory mechanisms of the microbiota and bowel function is crucial for the prevention and treatment of gut dysmotility, a comorbidity associated with many diseases. In this review, we present an overview of the current knowledge on the impact of gut microbiota and its products on bowel motility. We discuss the currently available techniques employed to assess the changes in the intestinal motility. Further, we highlight the open challenges, and incorporate biophysical elements of microbes-motility interplay, in an attempt to lay the foundation for describing long-term impacts of microbial metabolite-induced changes in gut motility

Mechanisms of ionic current changes underlying rhythmic activity recovery after decentralization

Neuronal networks capableof generating rhythmic output in the absence of patterned sensory or central inputs are widely represented in the nervous system where they support a variety of functions, from learning and memory to rhythmic motor activity such as breathing. To perfectly function in a living organism, rhythm-generating networks have to combine the capability of producing a stable output with the plasticity needed to adapt to the changing demands of the organism and environment. This dissertation used the pyloric network of the crab Cancer borealis to identify potential mechanisms that ensure stability and adaptation of rhythm generation by neuronal networks under changing environmental conditions, in particular after the removal of neuromodulatory input to this network (decentralization). For this purpose, changes in ionic currents during the process of network activity recovery after decentralization were studied. The previously unreported phenomenon of coordinated expression of ionic currents within and between network neurons under normal physiological conditions was described. Detailed time course of alterations in current levels and in the coordination of ionic currents during the process of activity recovery after decentralization was determined for pacemaker and follower neurons. During the investigation of the molecular mechanisms underlying the post-decentralization changes, a novel role of central neuromodulators and of the cell-to-cell communication within the network in maintaining ionic current levels and their coordinations was demonstrated. Finally, the involvement of the two mechanisms of network plasticity, namely extrinsic (activity-dependent) and intrinsic (neuromodulator-dependent) regulation, in the recovery process after decentralization was shown. A thorough understanding of the mechanisms that are responsible for the stability and plasticity of neuronal circuits is an important step in learning how to manipulate such networks to cure diseases, enhance performance, build advanced robotic systems, create a functioning computer model of a living organism, etc. The discovery of a novel mechanism of ionic current regulation, i.e. the inter-dependent coordination of different ionic currents, will potentially contribute to this process

Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Serotonin (5-hydroxytryptamine: 5-HT) affects numerous functions in the gut, such as secretion, muscle contraction, and enteric nervous activity, and therefore to clarify details of 5-HT's actions leads to good therapeutic strategies for gut functional disorders. The role of interstitial cells of Cajal (ICC), as pacemaker cells, has been recognised relatively recently. We thus investigated 5-HT actions on ICC pacemaker activity. Muscle preparations with myenteric plexus were isolated from the murine ileum. Spatio-temporal measurements of intracellular Ca2+ and electric activities in ICC were performed by employing fluorescent Ca2+ imaging and microelectrode array (MEA) systems, respectively. Dihydropyridine (DHP) Ca2+ antagonists and tetrodotoxin (TTX) were applied to suppress smooth muscle and nerve activities, respectively. 5-HT significantly enhanced spontaneous Ca2+ oscillations that are considered to underlie electric pacemaker activity in ICC. LY-278584, a 5-HT3 receptor antagonist suppressed spontaneous Ca2+ activity in ICC, while 2-methylserotonin (2-Me-5-HT), a 5-HT3 receptor agonist, restored it. GR113808, a selective antagonist for 5-HT4, and O-methyl-5-HT (O-Me-5-HT), a non-selective 5-HT receptor agonist lacking affinity for 5-HT3 receptors, had little effect on ICC Ca2+ activity. In MEA measurements of ICC electric activity, 5-HT and 2-Me-5-HT caused excitatory effects. RT-PCR and immunostaining confirmed expression of 5-HT3 receptors in ICC. The results indicate that 5-HT augments ICC pacemaker activity via 5-HT3 receptors. ICC appear to be a promising target for treatment of functional motility disorders of the gut, for example, irritable bowel syndrome

Similarities and differences in circuit responses to applied Gly \u3csup\u3e1\u3c/sup\u3e -SIFamide and peptidergic (Gly \u3csup\u3e1\u3c/sup\u3e -SIFamide) neuron stimulation

Similarities and differences in circuit responses to applied Gly 1 -SIFamide and peptidergic (Gly 1 -SIFamide) neuron stimulation. J Neurophysiol 121: 950 –972, 2019. First published January 16, 2019; doi:10.1152/jn.00567.2018.—Microcircuit modulation by peptides is well established, but the cellular/synaptic mechanisms whereby identified neurons with identified peptide transmitters modulate microcircuits remain unknown for most systems. Here, we describe the distribution of GYRKPPFNGSIFamide (Gly 1 -SIFamide) immunoreactivity (Gly 1 -SIFamide-IR) in the stomatogastric nervous system (STNS) of the crab Cancer borealis and the Gly 1 -SIFamide actions on the two feeding-related circuits in the stomatogastric ganglion (STG). Gly 1 -SIFamide-IR localized to somata in the paired commissural ganglia (CoGs), two axons in the nerves connecting each CoG with the STG, and the CoG and STG neuropil. We identified one Gly 1 -SIFamide-IR projection neuron innervating the STG as the previously identified modulatory commissural neuron 5 (MCN5). Brief (~10 s) MCN5 stimulation excites some pyloric circuit neurons. We now find that bath applying Gly 1 -SIFamide to the isolated STG also enhanced pyloric rhythm activity and activated an imperfectly coordinated gastric mill rhythm that included unusually prolonged bursts in two circuit neurons [inferior cardiac (IC), lateral posterior gastric (LPG)]. Furthermore, longer duration (±30 s) MCN5 stimulation activated a Gly 1 -SIFamide-like gastric mill rhythm, including prolonged IC and LPG bursting. The prolonged LPG bursting decreased the coincidence of its activity with neurons to which it is electrically coupled. We also identified local circuit feedback onto the MCN5 axon terminals, which may contribute to some distinctions between the responses to MCN5 stimulation and Gly 1 -SIFamide application. Thus, MCN5 adds to the few identified projection neurons that modulate a well-defined circuit at least partly via an identified neuropeptide transmitter and provides an opportunity to study peptide regulation of electrical coupled neurons in a functional context. NEW & NOTEWORTHY Limited insight exists regarding how identified peptidergic neurons modulate microcircuits. We show that the modulatory projection neuron modulatory commissural neuron 5 (MCN5) is peptidergic, containing Gly 1 -SIFamide. MCN5 and Gly 1 -SIFamide elicit similar output from two well-defined motor circuits. Their distinct actions may result partly from circuit feedback onto the MCN5 axon terminals. Their similar actions include eliciting divergent activity patterns in normally coactive, electrically coupled neurons, providing an opportunity to examine peptide modulation of electrically coupled neurons in a functional context