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The Role of Gut-Brain Signalling in Functional Responses to Chronic Social StressBharwani, Aadil January 2019 (has links)
Chronic stress has a cumulative physiological impact, causing dysregulation of multiple systems due to allostatic overload. There is growing evidence that one such system, the microbiota, is engaged in persistent bidirectional interplay with the brain—a phenomenon that influences neural function and behaviour. However, the functional role of the microbiota in stress-associated changes and the underlying pathways of communication are unknown. Using a murine model of depression, we demonstrate that chronic stress has top-down effects on the structure of the microbiota community, reducing its richness and diversity, altering its profile, and causing differential abundance of various bacterial genera. These structural changes have functional consequences, including in metabolic pathways responsible for the synthesis of short chain fatty acids, tryptophan, and tyrosine. Using a physiologically active bacteria, Lactobacillus rhamnosus (JB-1), we probed for bottom-up signalling in chronic stress. JB-1 attenuated deficits in anxiety-like and social behaviours, and induced systemic immunoregulatory effects, independent of affecting stress-induced changes in the microbiota. In examining possible mechanisms of gut-brain brain signalling, we observed that in unstressed mice, a single dose of JB-1 causes rapid expression of c-Fos—a marker of neuronal activation—in distributed areas of the brain within 165 minutes, absent behavioural changes. No such effects were observed with heat-killed JB-1, despite that both live and heat-killed preparations facilitated vagal activity. Sub-diaphragmatic vagotomy prevented neuronal activation in most but not all brain regions, suggesting that vagal signalling is critical but indicating the presence of additional independent pathways. Finally, only chronic JB-1 treatment increased ΔFosB expression in the brain, which is indicative of long-term neuronal adaptations, in association with behavioural changes. These studies demonstrate a role for bidirectional gut-brain signalling in chronic stress, and highlight the signalling pathways and brain regions through which gut bacteria exert their influence on host behaviour. / Thesis / Candidate in Philosophy / Stress, which is a leading risk factor for mental illnesses such as depression,
drastically affects the microbiota—the community of intestinal bacteria. However, this
influence is bidirectional as gut bacteria can also influence the brain. Thus, we sought to
understand the role of the microbiota in the negative effects of stress and how these
microorganisms interact with the brain. We observed that behavioural changes in mice
after chronic stress were associated with inflammation and community-wide changes in
the microbiota. Treatment with a bacterial strain, Lactobacillus rhamnosus (JB-1),
attenuated changes in behaviour and inflammation, but had no effect on the microbiota
composition. We observed that the brain rapidly responded to JB-1 via the vagus nerve,
and that chronic treatment caused long-term changes in brain regions. This work will
allow us to discover novel pathways that can be targeted with greater specificity in
clinical settings, providing an innovative approach to treatment of psychiatric conditions.
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Convolutional Neural Networks for Predicting Blood Glucose Levels from Nerve SignalsSay, Daniel, Spang Dyhrberg Nielsen, Frederik January 2024 (has links)
Convolutional Neural Networks (CNNs) have traditionally been used for image analysis and computer vision and are known for their ability to detect complex patterns in data. This report studies an application of CNNs within bioelectronic medicine, namely predicting blood glucose levels using nerve signals. Nerve signals and blood glucose levels were measured on a mouse before and after administration of glucose injections. The nerve signals were measured by placing 16 voltage-measuring electrodes on the vagus nerve of the mouse. The obtained nerve signal data was segmented into time intervals of 5 ms and aligned with the corresponding glucose measurements. Two LeNet-5 based CNN architectures, one 1-dimensional and one 2-dimensional, were implemented and trained on the data. Evaluation of the models’ performance was based on the mean squared error, the mean absolute error, and the R2-score of a simple moving average over the dataset. Both models had promising performance with an R2-score of above 0.92, suggesting a strong correlation between nerve signals and blood glucose levels. The difference in performance between the 1-dimensional and 2-dimensional model was insignificant. These results highlight the potential of using CNNs in bioelectronic medicine for prediction of physiological parameters from nerve signal data.
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Innovative interventions: neuromodulation to enhance motor learning in autismAlaniz, Michele L. 23 August 2024 (has links)
Autism spectrum disorders are best understood as a complex set of symptoms that impact social, communication, and behavioral skills. Autistic brains have abnormalities in the anatomy, neural architecture, cytoarchitecture, and neurotransmitter systems (Bharath et al., 2019; Dicarlo & Wallace, 2022; Fatemi et al., 2012; Friedman et al., 2006; Karvat & Kimchi, 2014; Xu et al., 2020). This unique neurology may partially explain why motor impairments are so widespread in this population. Motor impairments are present in up to 88% of autistic people, emerging in early life and persisting into adulthood (Kangarani-Farahani et al., 2023; Liu et al., 2014). These deficits exert a cascading impact, contributing to impairments in daily living skills (Miller et al., 2024; Ozboke et al., 2021; Travers et al., 2022). Creating motor phenotypes that describe how a person’s physiology relates to their unique neurology may help with developing more effective interventions. This program investigates the correlation between biomarkers and psychomotor measures in autistic children. From there, an adjunct intervention is deployed to improve neuromodulation while engaging in motor learning. The goal is to move the field of occupational therapy towards a more precise and effective delivery model in order to achieve greater gains with less dosing of therapy.
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Body awareness, voluntary physiological regulation, and their modulation by contemplative mental trainingBornemann, Boris 31 July 2017 (has links)
In dieser Dissertation untersuche ich das Zusammenspiel mentaler und körperlicher Prozesse, insbesondere den Einfluss von kontemplativem Mentaltraining (KMT) auf Interozeption (innerliches Spüren des Körpers) und physiologische Regulation. In einer großangelegten Trainingsstudie (n = 332, Trainingsdauer 3-9 Monate), der ReSource-Studie, zeige ich, dass KMT die interozeptive Genauigkeit in den Trainingskohorten erhöht, nicht jedoch in einer Retest-Kontrollgruppe. Die Steigerungen in interozeptiver Genauigkeit gehen mit Veränderungen im emotionalen Gewahrsein einher und sagen diese voraus. Im Einklang mit diesen Befunden berichten die Studienteilnehmenden von positiven Veränderungen in verschiedenen Dimensionen des Körpergewahrseins. Diese betreffen vor allem die Fähigkeit, Aufmerksamkeit auf Körperempfindungen aufrechtzuerhalten sowie deren Gebrauch zur Emotionserkennung und -regulation. Ich beschreibe eine neuentwickelte Biofeedback-Aufgabe, welche die Fähigkeit misst, willentlich die hochfrequente Herzratenvariabilität (HF-HRV) hochzuregulieren, wodurch die willentliche parasympathische Kontrollfähigkeit (WPK) indiziert wird. Ich zeige, dass individuelle Unterschiede in WPK mit dem Oxytocin-Rezeptorgen-Polymorphismus rs53576 zusammenhängen und mit individuellen Unterschieden im altruistisch motivierten Verhalten korrelieren. WPK wird durch KMT verbessert, wobei diese Verbesserungen durch den rs53576 Genotyp moduliert werden. In einer weiteren Untersuchung zeige ich, dass retrospektive, subjektive Berichte über eine emotional erregende Erfahrung teilweise die objektiv gemessene körperliche Erregung widerspiegeln. Das Ausmaß dieser körperlich-mentalen Kohärenz ist abhängig von der interozeptiven Genauigkeit. Zusammengenommen vertiefen diese Studien unser Verständnis des Zusammenspiels von physiologischen und mentalen Prozessen und zeigen wie KMT das innerliche Spüren des Körpers und die willentliche physiologische Regulation verbessert. / In this dissertation, I investigate interactions between mental and bodily processes, specifically by studying the influence of contemplative mental training (CMT) on interoception (inner body sensing) and physiological regulation. In a large-scale mental training study (n = 332, training durations 3–9 months), the ReSource Project, I find that CMT increases interoceptive accuracy in the training cohorts, but not in a retest control cohort. These increases in interoceptive accuracy co-occur with and predict improvements in emotional awareness. In line with these objective data on interoception, participants self-report training-related benefits on multiple dimensions of body awareness. The strongest changes occur in the ability to sustain attention to body sensations and the use of this ability to identify and regulate emotions. I also introduce a novel biofeedback task that measures the ability to voluntarily upregulate high frequency heart rate variability (HF-HRV), indicative of voluntary parasympathetic control. Cross-sectional data of the ReSource Project show that individual differences in voluntary parasympathetic control are related to the oxytocin receptor gene rs53576 polymorphism and correlate to individual differences in altruistically motivated behavior. Furthermore, CMT improves various aspects of voluntary HF-HRV regulation, with modulation of these improvements by rs53576 genotype. An additional investigation in cross-sectional data shows that subjective retrospective reports of an emotionally arousing experience partially mirror the objectively measured bodily arousal during the actual experience. Individual differences in this mind–body coherence are related to individual differences in interoceptive accuracy. Together, these studies highlight the tight interplay between physiological and mental processes and show how CMT improves inner body sensing and voluntary physiological regulation.
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Relations neurodigestives et stimulation vagale basse-fréquence chez le rat anesthésié : implications du système nerveux central et du système immunitaire / Brain-gut interactions and low-frequency vagus nerve stimulation in an anaesthetized rat model : involvement of the central nervous system and the immune systemPicq, Chloé 29 June 2012 (has links)
IntroductionLa neurostimulation vagale (NSV) à haute fréquence (30 Hz) est utilisée commethérapeutique de certaines formes d’épilepsie et de dépression réfractaires aux traitements chezl’Homme. De plus, la NSV à basse fréquence (5 Hz) a été expérimentée avec succès chez l’animalpour traiter différentes inflammations périphériques, notamment digestives. Des travaux récents ontmis en évidence que cet effet anti-inflammatoire est induit par l’activation des fibres efférentesvagales, libérant en périphérie de l’acétylcholine, inhibant la sécrétion des cytokines proinflammatoires.Cette voie est connue sous le nom de voie anti-inflammatoire cholinergique.Toutefois, le mécanisme d’action de la NSV 5 Hz reste mal connu et d’autres voies pourraient êtremises en jeu impliquant le système nerveux central (SNC) et le système immunitaire périphérique.ButLes travaux réalisés ont eu pour objectif d’étudier l’implication du SNC et du systèmeimmunitaire dans la modulation de l’inflammation induite par la NSV basse fréquence chez unmodèle de rat anesthésié. Tout d’abord, afin d’étudier l’implication du SNC lors de la NSV 5 Hz, uneétude d’imagerie par résonance magnétique fonctionnelle (IRMf) a été réalisée sur le rat «sain»anesthésié. Ensuite, une étude a été effectuée sur l’effet de la NSV sur les cellules immunitairesspléniques ainsi que sur le tube digestif chez un modèle de rat «sain» puis chez un modèle de ratatteint d’une colite expérimentale induite par une injection intra-colique d’acide trinitrobenzènesulfonique (TNBS).RésultatsLes données obtenues lors de l’étude d’IRMf ont mis en évidence un rôle important desfibres afférentes vagales; elles modulent certaines structures du SNC qui pourraient participer à larégulation de l’inflammation digestive induite par la NSV 5 Hz. Les études réalisées sur les souspopulationslymphocytaires spléniques ont révélé que d’autres cellules immunitaires que lesmacrophages étaient impliquées lors de la NSV. Chez le modèle de rat «sain», les résultats decytométrie en flux ont montré que la NSV 3h 5 Hz induisait une diminution de l’activation deslymphocytes T CD4 ainsi que du pourcentage de NKT par rapport aux lymphocytes T. Ces résultatssont en faveur d’un rôle de la NSV 3h inhibant l’activation lymphocytaire et jouant un rôle sur les NKTpossédant des propriétés immunorégulatrices. La NSV 3h n’a pas le même effet chez le modèle de ratprésentant une colite. En effet, le dosage de cytokines sécrétées par les splénocytes en culturemontre que la NSV augmente le potentiel de sécrétion d’IL-10 (cytokine anti-inflammatoire) dessplénocytes et plus particulièrement des lymphocytes T CD4 spléniques. Parallèlement, l’effet antiinflammatoirede la NSV a été mis en évidence au niveau du côlon transverse (au-dessus de la zonelésée) par une diminution des ARNm de SOCS3 et du TNF-α et de la myéloperoxidase. Ces donnéesont démontré un rôle de la NSV sur la fonctionnalité des lymphocytes T CD4 spléniques. La NSV 3h 5Hz orienterait la réponse immunitaire vers une réponse anti-inflammatoire en phase d’initiationd’inflammation digestive. De plus, l’effet anti-inflammatoire de la NSV est retrouvé au niveau du tubedigestif au-dessus de la zone lésée (côlon transverse).ConclusionCes données expérimentales montrent que d’autres voies impliquant différents typescellulaires sont susceptibles d’être mises en oeuvre par la NSV basse fréquence. Elle induitl’implication du SNC par l’activation des afférences vagales et des cellules immunitaires spléniquestelles que les lymphocytes T CD4 et les NKT. Un effet anti-inflammatoire de la NSV est retrouvé auniveau du côlon transverse, mais pas au niveau des lésions dans le côlon distal. Ces résultatsprésentent des implications thérapeutiques : la NSV basse fréquence est actuellement en essaiclinique pour être utilisée comme traitement dans la maladie de Crohn. / Introduction High frequency(30 Hz)vagus nerve stimulation(VNS)has been approved as a treatment for some types of epilepsy and depression in humans. Low-frequency (5 Hz)VNS has also been successful for the treatment of different animal inflammation models, notably digestive inflammation. Recent studies have shown that the anti-inflammatory effect is induced by the activation of the efferent vagal fibers, which secrete acetylcholine in periphery. It links itself to α-7-nicotinic receptors on the macrophages surface, inhibiting the release of pro-inflammatory cytokines. This pathway is known by the name of the cholinergic anti-inflammatory pathway. However, the mechanism of action of low-frequency VNS remains unclear and other pathways could be involved implicating the central nervous system (CNS) and the immune system. Aim The aim of this study was to evaluate the implication of the CNS and the immune system in the modulation of inflammation induced by low-frequency VNS in an anaesthetized rat model. Firstly, to study the implication of the CNS and the contribution of the afferent vagal fibers during 5Hz VNS, a study using functional magnetic resonance imaging (fMRI) on a «healthy» anaesthetized rat model was carried out. Secondly, an experiment on the effect of VNS on splenic immune cells as well as on the digestive tract was fulfilled on a «healthy» rat model followed by a study on a rat model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). Results fMRI data brought to light an important role of the afferent vagal fibers. They modulate some structures of the CNS which could contribute to the modulation of digestive inflammation by 5Hz VNS. The studies carried out by FACS on the sub-populations of splenic lymphocytes revealed that other immune cells than macrophages could be implicated by VNS. In the «healthy» rat model, with no digestive inflammation, FACS data show that 3h VNS decreases T CD4 lymphocytes activation and the percentage of NKT in relation to T lymphocytes. These data are in favor of an inhibiting role of VNS on lymphocytes activation and also has an impact on NKT cells which have immunoregulatory properties. 3h VNS does not have the same effect on the rat model of colitis. In fact, the quantification of secreted cytokines by cultured splenocytes show that VNS increases the potential of IL-10(anti-iflammatory)cytokine by splenocytes and particularly splenic T CD4 lymphocytes. In the same way, the anti-inflammatory effect of VNS is seen in the transverse colon (above the lesions): decrease of TNF-α and SOCS3 mRNA and of myeloperoxidase. These results show a role of VNS on the functionality of splenic T CD4 lymphocytes inducing an important secretion of IL-10. 3h low-frequency VNS turns the immune response towards an anti-inflammatory response during the early phase of digestive inflammation. Moreover, VNS anti-inflammatory effect is seen in the transverse colon, above the lesions. Conclusion These results reveal that other pathways implicating different cell types are potentially involved besides the classic cholinergic anti-inflammatory pathway by low-frequency VNS. It implicates CNS by the activation of vagal afferents and splenic immune cells such as T CD4 lymphocytes and NKT cells. An anti-inflammatory effect of VNS is found in the transverse colon (above the lesions) even during the initiation phase of digestive inflammation, but not in the distal colon (in the lesions). These date have therapeutic implications: low-frequency VNS is being clinically tested at the moment as a treatment for Crohn's disease.
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Participação do sistema nervoso parassimpático no metabolismo energético e na proliferação celular em ilhotas pancreáticas de ratos obesos-MSGLubaczeuski, Camila 01 August 2013 (has links)
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Previous issue date: 2013-08-01 / The growing number of overweight and obesity has led to an increase in the number of patients with insulin resistance and diabetes mellitus type 2. MSG obese rats were glucose intolerant, insulin resistant and theirs pancreatic islets secrete more insulin in response to glucose. Subdiafragmatic vagotomy changes the response of islets to glucose and improves glucose homeostasis, supporting the hypothesis that an unbalance of autonomic nervous system with increased parasympathetic nervous system (PNS) action but a decreased sympathetic nervous system function. Studies showed that the PNS is also involved in β-cell proliferation. Therefore, we investigated of PNS participation, using a subdiafragmatic vagal denervation, upon pancreatic β-cell function and mass regulation, and the body glucose control disruption in MSG-obese rats. For this, Male Wistar rats received during the first five days of life monosodium glutamate (MSG) or saline. Subdiaphragmatic vagotomy was performed at 30 days of life. At 90 days of age, we verified static insulin secretion, pancreas morphometric, ERK expression in islets, glucose homeostasis and lipidis. The MSG treatment caused obesity at 90 days of life. MSG rats presented lower body weight and nasoanal length, increased Lee index and fat depots, normoglycemia, hyperinsulinemia, dyslipidemia, glucose intolerance and insulin resistance when compared to CTL. Vagotomy performed at 30-days of age prevented obesity, fat deposition in the liver and ameliorated glucose tolerance and insulin sensitivity in adult MVAG rats in relation to MSG rats. Islets from MSG rats secreted more insulin at stimulatory glucose concentrations than CTL islets. Histological analysis showed that pancreatic islets from MSG rats were lower with a reduction in β-cell area without modification in α-cell content when compared with CTL. Also, MSG group presented an increased number of pancreatic islets per mm2, with higher number of islets, which may contributes to the higher islet and β-cell relative mass in the MSG pancreas. These effects were associated with enhanced proliferation in MSG group. The number of MVAG pancreatic islet were less than MSG. Vagotomoy performed at 30-days of age, reduced islet and β-cell area in the pancreas from 90-days old CVAG rats. Finally, the relative islet and β-cell mass in MVAG and CVAG rats was similar to CTL. Here we verified if ERK was involved in β-cell replication in MSG rats, but presented no alteration. We demonstrate for the first time that adult MSG rats showed enhanced pancreatic β-cell proliferation which contributes to the higher islet insulin secretion in response to glucose. The vagus nerve is the main factor involved in such a process, since vagotomy performed at 30 days of age prevented islet morphological alterations in adult MVAG rats. Possibly this increase PNS activity in MSG endocrine pancreas is responsible to hyperinsulinemia that enhanced fat storage, damaged glucose homeostasis and insulin action in MSG obesity. / O crescente número de pessoas com sobrepeso e obesidade tem levado ao aumento no número de pacientes com resistência à insulina (RI) e portadores do Diabetes mellitus tipo 2. Ratos obesos MSG são intolerantes à glicose (Gli), RI e suas ilhotas pancreáticas secretam mais insulina em resposta à concentrações de Gli. A vagotomia subdiafragamática altera a responsividade das ilhotas à Gli e melhora a homeostase glicêmica nestes animais, sugerindo um desbalanço do sistema nervoso autonômico, com aumento do tônus parassimpático e redução do simpático. Estudos demonstram que o sistema nervoso parassimpático (SNP) possui efeito na proliferação das células β-pancreáticas. Desta forma, investigamos a participação do SNP, através da vagotomia subdiafragmática, no metabolismo energético e na proliferação das ilhotas e de células β-pancreáticas de ratos obesos-MSG. Para isto, ratos Wistar machos receberem durante os cinco primeiros dias de vida glutamato monossódico (grupo MSG) ou salina (grupo CTL). A vagotomia subdiafragmática foi realizada aos 30 dias de vida formando os grupos MVAG e CVAG. Aos 90 dias, verificamos a secreção estática de insulina, homeostase glicêmica e lipídica, morfometria do pâncreas e conteúdo proteico da ERK nas ilhotas. Ratos MSG apresentaram redução do peso corporal e comprimento nasoanal, aumento do índice de Lee e acúmulo de gordura, normoglicêmia, hiperinsulinemia, dislipidemia, intolerância à Gli e RI comparados aos CTL. A vagotomia realizada aos 30 dias de vida preveniu obesidade, acúmulo de gordura no fígado e melhorou a tolerância à Gli e a sensibilidade à insulina em ratos MVAG adultos em relação aos ratos MSG. As ilhotas dos animais MSG secretaram mais insulina quando estimulada pela Gli, em relação aos animais CTL. As análises histológicas mostram que as ilhotas pancreáticas dos animais MSG são menores com redução da área das células β sem alteração nas células α em relação aos CTL. O grupo MSG apresenta um aumento do número das ilhotas por mm2, que pode estar contribuindo com o aumento da massa relativa das ilhotas e das células β. Esse efeito está associado ao aumento da proliferação no grupo MSG. O número de ilhotas foi menor nos MVAG em relação aos MSG. A vagotomia realizada aos 30 dias de vida reduziu a área das ilhotas e das células β aos 90 dias de vida nos animais CVAG. Finalmente, a massa relativa das ilhotas e da células β no MVAG e CVAG foram similares ao CTL. Verificamos se a ERK estava envolvida na proliferação das células β nos ratos MSG, porém não apresentaram alterações desta proteína. Pela primeira vez demonstramos que ratos MSG apresentam aumento da proliferação das células β que contribui com o aumento da secreção de insulina em resposta à Gli. O nervo vago é o principal fator envolvido neste processo, visto que a vagotomia realizada aos 30 dias de vida preveniu as alterações morfológicas das ilhotas nos ratos MVAG adultos.
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Vagus Nerve Stimulation Mitigates Intrinsic Cardiac Neuronal Remodeling and Cardiac Hypertrophy Induced by Chronic Pressure Overload in Guinea PigBeaumont, Eric, Wright, Gary L., Southerland, Elizabeth M., Li, Ying, Chui, Ray, KenKnight, Bruce H., Andrew Armour, J., Ardell, Jeffrey L. 01 May 2016 (has links)
Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling.
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Vagus Nerve Stimulation Mitigates Intrinsic Cardiac Neuronal and Adverse Myocyte Remodeling Postmyocardial InfarctionBeaumont, Eric, Southerland, Elizabeth M., Hardwick, Jean C., Wright, Gary L., Ryan, Shannon, Li, Ying, KenKnight, Bruce H., Andrew Armour, J., Ardell, Jeffrey L. 01 January 2015 (has links)
This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions.
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Reversible Nerve Conduction Block Using Low Frequency Alternating CurrentsMuzquiz, Maria I. 08 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / This thesis describes a novel method to reversibly and safely block nerve conduction using a low frequency alternating current (LFAC) waveform at 1 Hz applied through a bipolar extrafascicular electrode. This work follows up on observations made on excised mammalian peripheral nerves and earthworm nerve cords. An in-situ electrophysiology setup was used to assess the LFAC waveform on propagating action potentials (APs) within the cervical vagus nerve in anaesthetized Sprague-Dawley rats (n = 12). Two sets of bipolar cuff or hook electrodes were applied unilaterally to the cervical vagus nerve, which was crushed rostral to the electrodes to exclude reflex effects on the animal. Pulse stimulation was applied to the rostral electrode, while the LFAC conditioning waveform was applied to the caudal electrode. The efferent volley, if unblocked, elicits acute
bradycardia and hypotension. The degree of block of the vagal stimulation induced bradycardia was used as a biomarker. Block was assessed by the ability to reduce the bradycardic drive by monitoring the heart rate (HR) and blood pressure (BP) during LFAC alone, LFAC with vagal stimulation, and vagal stimulation alone. LFAC applied via a hook electrode (n = 7) achieved 86.6 +/- 11% block at current levels 95 +/- 38 uAp (current to peak). When applied via a cuff electrode (n = 5) 85.3 +/- 4.60% block was achieved using current levels of 110+/-65 uAp. Furthermore, LFAC was explored on larger vagal afferent fibers in larger human sized nerve bundles projecting to effects mediated by a reflex. The effectiveness of LFAC was assessed in an in-situ electrophysiological setup on the left cervical vagus in anaesthetized domestic swine (n = 5). Two bipolar cuff electrodes were applied unilaterally to the cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar extrafascicular cuff electrode was placed most rostral on the nerve for recording of propagating APs induced by electrical stimulation and blocked via the LFAC waveform. Standard pulse stimulation was applied to the left cervical vagus to induce the Hering-Breuer reflex. If unblocked, the activation of the Hering-Breuer reflex would cause breathing to slow down and potentially cease. Block was quantified by the ability to reduce the effect of the Hering-Breuer reflex by monitoring the breathing rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. LFAC achieved 87.2 +/- 8.8% (n = 5) block at current levels of 0.8 +/- 0.3 mAp. Compound nerve action potentials (CNAP) were monitored directly. They show changes
in nerve activity during LFAC, which manifests itself as the slowing and amplitude reduction of components of the CNAPs. Since the waveform is balanced, all forward reactions are reversed, leading to a blocking method that is similar in nature to DC block without the potential issues of toxic byproduct production. These results suggest that LFAC can achieve a high degree of nerve block in both small and large nerve bundles, resulting in the change in behavior of a biomarker, in-vivo in the mammalian nervous system at low amplitudes of electrical stimulation that are within the water window of the electrode.
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Autonomic Nerve Activity and Cardiovascular Function in the Chicken Embryo (Gallus gallus)Onyemaechi, Clinton 12 1900 (has links)
The goal of this study was to build on the historic use of the avian model of development and also to further the knowledge of autonomic nervous system (ANS) regulation of cardiovascular function in vertebrates. Vasoactive drugs sodium nitroprusside, a vasodilator and phenylephrine, a vasoconstrictor were used to study the correlation of cardiovascular function relationship with nerve activity, both sympathetic and parasympathetic (vagal). Additionally, ANG II was used to assess its effects on vagal inhibition. The present study shows that pharmacologically-induced hypertension is associated with a fall in mSNA, indicating that the capacity for sympathetic autonomic cardiovascular regulation is established by late incubation however, late-stage embryonic chickens did not show a significant increase in mSNA during hypotension. The hypotensive response of the embryo was not accompanied by the expected inhibition of vagal discharge; however a slight but insignificant reduction in vagal discharge was noted. When vagal efferent output was isolated, a significant drop in vagal efferent activity was noted in response to hypotension. The present study showed late-stage embryonic chickens lack a vagal response to hypertension in both efferent and sensory limbs. In this study, vagal discharge was reduced from baseline levels in response to Ang II. Collectively, the present study indicates that the lack of a decreased heart rate, in response to increases in Pm caused by Ang II, is due to a central inhibitory action of Ang II on the vagus. Data from the present study suggests that although autonomic interaction with the cardiovascular system in present in late-stage chicken embryos, it is still underdeveloped and possesses a limited capacity.
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