Vagus nerve stimulation (VNS) is a promising neuromodulatory therapy under investigation for a range of disorders, including heart failure, gastric dysmotility, and migraine. Two primary forms of VNS are currently investigated: cervical VNS (cVNS), involving surgically implantation to activate vagal afferents in the cervical branch in the neck and transcutaneous auricular VNS (taVNS) which subcutaneously stimulates the auricular branch in the outer ear. The nucleus of the solitary tract (NTS) serves as a relay-station receiving 90% of vagal afferents, enabling connections with higher-order brain regions and other brainstem nuclei like the spinal trigeminal nucleus (Sp5) and locus coeruleus (LC), facilitating neuromodulation through VNS. Research has established the efficacy of VNS at 20–30 Hz for disorders like depression, but the impact of alternative stimulation parameters on medullary nuclei neuromodulation remains unclear. These studies used anesthetized rats to extracellularly record neuronal activity across varying VNS parameters within NTS, Sp5, and LC. Neuronal responses were classified as positive (increased activity), negative (decreased activity), or non-responders (no response). In LC, cVNS at standard paradigms (≥ 10 Hz) and bursting paradigms with shorter interburst intervals or increased pulses induced more positive responders, while standard 5 Hz generated more negative responders. Additionally, a build-up effect was observed in LC, with increased responders over consecutive VNS cycles. In NTS and Sp5, taVNS evoked comparable activation, with more positive responders at 20 Hz and 100 Hz and stronger responses at higher intensities. However, Sp5 responses were twice as strong compared to NTS. Furthermore, comparative analysis between taVNS and cVNS revealed similar overall activation in NTS, but distinct activation profiles in individual neurons indicate different pathways. Finally, the therapeutic efficacy of VNS therapy was evaluated in heart failure using a pressure-overload rat model. A 60-day cVNS treatment restored adverse cardiac remodeling and dysfunction, mitigated cardiac molecular changes, and prevented neuroinflammatory responses within brainstem nuclei. The findings presented herein demonstrated differential parameter-specific and nuclei-specific responses to taVNS and cVNS, investigated the mechanisms responsible for taVNS modulation, and confirmed that VNS therapy, when initiated early, can mitigate heart failure development and restore multiorgan homeostasis in a PO model.

Morphine withdrawal increases the HPA axis activity, which is dependent on a hyperactivity of noradrenergic pathways (NTS-A2) innervating the PVN. In this Thesis we found that morphine withdrawal resulted in an increase in ACTH and corticosterone secretion and a neuronal activation in the PVN. Additionally, we found robust increases in CRF and AVP hnRNAs in the PVN, concomitantly with an increase in c-Fos expression. Morphine withdrawal activated ERK1/2 in PVN and NTS, which could be involved in the c-Fos expression. Morphine withdrawal induced an increase in TH mRNA levels in the NTS-A2, total TH protein in the NTS and TH phosphorylation at Ser31 in PVN and NTS-A2, which resulted in an augmentation of TH activity in the PVN. The enhancement in TH phosphorylated at Ser31 was blocked by SL327 in both nuclei. Finally, we have found that adrenalectomy eliminated the hyperactivity of noradrenergic pathways innervating the PVN during morphine withdrawal. / La abstinencia a morfina aumenta la actividad del eje HHA, que depende de la hiperactivación de las vías noradrenérgicas (NTS-A2) que inervan al PVN. En esta Tesis encontramos que la abstinencia a morfina induce la liberación de ACTH y corticosterona y la activación neuronal del PVN. Además, observamos un aumento en los niveles de hnRNA para CRF y AVP en el PVN, concomitantemente con un incremento en la expresión de c-Fos. El síndrome de abstinencia a morfina activó a ERK1/2 en PVN y NTS. También indujo un incremento en el mRNA para TH en el NTS-A2, proteína TH total y fosforilación de TH en su Ser31 en PVN y NTS-A2, que se tradujo en un aumento en su actividad enzimática. El aumento de TH fosforilada en Ser31 fue bloqueado por SL327. Finalmente, la adrenalectomía eliminó la hiperactividad de las vías noradrenérgicas que inervan al PVN durante la abstinencia a morfina.

Intensive Forschung hat in den vergangenen Jahrzehnten zu einer sehr detaillierten Charakterisierung des Geschmackssystems der Säugetiere geführt. Dennoch sind mit den bislang eingesetzten Methoden wichtige Fragestellungen unbeantwortet geblieben. Eine dieser Fragen gilt der Unterscheidung von Bitterstoffen. Die Zahl der Substanzen, die für den Menschen bitter schmecken und in Tieren angeborenes Aversionsverhalten auslösen, geht in die Tausende. Diese Substanzen sind sowohl von der chemischen Struktur als auch von ihrer Wirkung auf den Organismus sehr verschieden. Während viele Bitterstoffe potente Gifte darstellen, sind andere in den Mengen, die mit der Nahrung aufgenommen werden, harmlos oder haben sogar positive Effekte auf den Körper. Zwischen diesen Gruppen unterscheiden zu können, wäre für ein Tier von Vorteil. Ein solcher Mechanismus ist jedoch bei Säugetieren nicht bekannt. Das Ziel dieser Arbeit war die Untersuchung der Verarbeitung von Geschmacksinformation in der ersten Station der Geschmacksbahn im Mausgehirn, dem Nucleus tractus solitarii (NTS), mit besonderem Augenmerk auf der Frage nach der Diskriminierung verschiedener Bitterstoffe. Zu diesem Zweck wurde eine neue Untersuchungsmethode für das Geschmackssystem etabliert, die die Nachteile bereits verfügbarer Methoden umgeht und ihre Vorteile kombiniert. Die Arc-catFISH-Methode (cellular compartment analysis of temporal activity by fluorescent in situ hybridization), die die Charakterisierung der Antwort großer Neuronengruppen auf zwei Stimuli erlaubt, wurde zur Untersuchung geschmacksverarbeitender Zellen im NTS angewandt. Im Zuge dieses Projekts wurde erstmals eine stimulusinduzierte Arc-Expression im NTS gezeigt. Die ersten Ergebnisse offenbarten, dass die Arc-Expression im NTS spezifisch nach Stimulation mit Bitterstoffen auftritt und sich die Arc exprimierenden Neurone vornehmlich im gustatorischen Teil des NTS befinden. Dies weist darauf hin, dass Arc-Expression ein Marker für bitterverarbeitende gustatorische Neurone im NTS ist. Nach zweimaliger Stimulation mit Bittersubstanzen konnten überlappende, aber verschiedene Populationen von Neuronen beobachtet werden, die unterschiedlich auf die drei verwendeten Bittersubstanzen Cycloheximid, Chininhydrochlorid und Cucurbitacin I reagierten. Diese Neurone sind vermutlich an der Steuerung von Abwehrreflexen beteiligt und könnten so die Grundlage für divergentes Verhalten gegenüber verschiedenen Bitterstoffen bilden. / Intense research in the past decades has led to a detailed understanding of the mammalian taste system. Some important issues, however, have remained unanswered with the established methods that have been applied so far. One of these questions is whether different bitter substances can be distinguished. There are thousands of compounds which taste bitter to humans and elicit innate aversive behavior in animals. Moreover, these bitter substances are very heterogeneous regarding their structure as well as their effect on the organism. While many bitter tastants are potent poisons, others are harmless or even have beneficial effects in the amounts that are typically ingested. The ability to discriminate between those groups of bitter tastants could be an evolutionary advantage. Such a mechanism, however, is not known for mammals. The aim of this thesis was to study the processing of taste information in the first station of gustatory processing in the mouse brain, the nucleus of the solitary tract (NTS). Of particular interest was the question concerning discrimination of bitter tastants. To this end a new method was established for the taste system combining the advantages of methods used before while circumventing their disadvantages. The Arc catFISH method (cellular compartment analysis of temporal activity by fluorescent in situ hybridization), which allows the characterization of responses of large neuron populations to two stimuli, was used to analyze taste-processing cells in the NTS. In the course of this project a stimulus-induced Arc expression in the NTS was shown for the first time. The results demonstrated that Arc expression in the NTS appears specifically after stimulation with bitter tastants and that the Arc expressing neurons are located primarily in the gustatory part of the NTS. This indicates that Arc expression is a marker for bitter-processing gustatory neurons in the NTS. Upon stimulating twice with bitter compounds, distinct, yet overlapping neuron populations were identified, that reacted differently to the three bitter substances cycloheximide, quinine hydrochloride, and cucurbitacin I. Presumably these neurons are involved in the regulation of aversive reflexes and could form a basis for divergent behavior towards different bitter substances.

Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-03-30T19:56:57Z No. of bitstreams: 1 TeseMTF.pdf: 2239287 bytes, checksum: 3b29490f6ed81c7556b00699c35d839c (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-04-18T12:48:13Z (GMT) No. of bitstreams: 1 TeseMTF.pdf: 2239287 bytes, checksum: 3b29490f6ed81c7556b00699c35d839c (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-04-18T12:48:24Z (GMT) No. of bitstreams: 1 TeseMTF.pdf: 2239287 bytes, checksum: 3b29490f6ed81c7556b00699c35d839c (MD5) / Made available in DSpace on 2017-04-18T12:57:37Z (GMT). No. of bitstreams: 1 TeseMTF.pdf: 2239287 bytes, checksum: 3b29490f6ed81c7556b00699c35d839c (MD5) Previous issue date: 2016-09-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Arthropods and vertebrates have a great ability to concentrate urine by the kidney and behaviors directed the conservation and acquisition of water and salt due to activities controlled by mechanisms involving hormones and neural circuits. The loss of water or body volume can occur in the intracellular compartment (intracellular dehydration), the extracellular compartment (extracellular dehydration) or both (absolute or duble dehydration). Studies from our laboratory had shown that in unanesthetized animals extracellular dehydration produced by furosemide injection followed by keeping animals with a sodium deficient diet does not alter the basal cardiovascular parameters, but change the basal ventilation.Therefore, the objectives of our study in unanesthetized rats submitted to intracellular dehydration or duble dehydration were: 1) to characterize the baseline cardiorespiratory responses; 2) evaluate the arterial blood gas parameters; 3) to evaluate plasma concentrations of sodium, potassium and plasma osmolality; 4) evaluate the cardiorespiratory responses to the activation of glutamate NMDA receptors in the NTS before and after pretreatment with glutamate NMDA receptor antagonist (AP5) of rats submitted to mixed dehydration. Holtzman rats were implanted with cannula in the NTS and catheter inserted in the abdominal aorta via the femoral artery and femoral vein. The ventilation (VE) measurement were obtained by whole body plethysmography method. The protocols was performed in rats euhydrated (before dehydration), dehydrated (following the methodology to induce dehydration) and/or rehydrated rats (2 h after free access to water and 0.3 M NaCl). The intracellular dehydration induced by intragastric overload 2 M NaCl (2 mL) produced an increase 22 in mean arterial pressure (MAP), without change the heart rate (HR), tidal volume (VT), respiratory rate (fR) and VE. The duble dehydration (intracellular and extracellular combined) induced by 24 h of water deprivation, produced an increase in MAP and VT without modifying the HR, fR and VE. In rehydrated rats PAM and VT returned to baseline. Unilateral injections of L-glutamate and NMDA glutamatergic receptor agonist into NTS of euhydrated rats produced pressor responses and bradycardia. After 24 hours of water deprivation these pressor and bradycardic responses produced by NMDA injection in the NTS were reduced, without changing the bradycardia produced by L-glutamate injection in the NTS. After rehydration, the pressor responses to L-glutamate and NMDA receptors in the NTS remained low and bradycardia produced by NMDA injection in the NTS. Furthermore, the objectives of our study in anesthetized animals subjected to extracellular dehydration were: 1) to characterize the baseline cardiorespiratory responses and renal sympathetic nerve activity (RSNA); 2) to evaluate the effect of peripheral blockade of AT1 receptors angiotensinergic on basal cardiorespiratory responses and on RSNA; 3) to evaluate the arterial blood gas parameters; 4) to evaluate plasma concentrations of sodium and potassium. Extracellular dehydration induced by subcutaneous injection of the diuretic furosemide did not affect the basal MAP and HR, phrenic nerve activity (PNA) and RSNA. Extracellular dehydration did not affect the pressor response produced by intravenous (iv) injection of ANG II, decreased ASNR and did not change the HR and PNA. The iv injection of losartan (AT1 receptor antagonist, 1 mg/kg body weight) induced a decrease in MAP without changing HR, and RSNA and PNA. The hypotensive response after iv injection of losartan was greater in dehydrated animals. Extracellular dehydration did not affect the response of RSNA and PNA after losartan administration. The results suggest that changes in the volume and composition of body fluids affect the cardiovascular control in animals with intracellular 23 dehydration. Furthermore, it affects the cardiorespiratory control in animals with mixed dehydration and glutamatergic neurotransmission in the NTS. Moreover, in anesthetized animals with extracellular dehydration showed no changes in baseline cardiorespiratory responses and RSNA. / Os mamíferos apresentam uma grande capacidade de concentração de urina pelo rim e comportamentos dirigidos à conservação e aquisição de água e sal, devido a atividades controladas por mecanismos envolvendo hormônios e circuitos neurais. A perda de água ou de volume pode ocorrer no compartimento intracelular (desidratação intracelular), do compartimento extracelular (desidratação extracelular) ou de ambos (desidratação absoluta ou mista). Estudo do nosso laboratório mostrou em animais não anestesiados que a desidratação extracelular produzida pela injeção de furosemida seguida da manutenção dos animais com uma dieta deficiente em sódio não altera os parâmetros cardiovasculares basais, mas altera a ventilação basal. Assim, os objetivos do nosso estudo em animais não anestesiados submetidos à desidratação intracelular ou mista foram: 1) caracterizar as respostas cardiorrespiratórias basais; 2) avaliar os parâmetros gasométricos arteriais; 3) avaliar as concentrações plasmáticas de sódio, potássio e osmolaridade plasmática; 4) avaliar as respostas cardiorrespiratórias à ativação de receptores glutamatérgicos NMDA no NTS de ratos submetidos à desidratação mista. Foram utilizados ratos Holtzman com cânulas implantadas no NTS e com cateteres inseridos na aorta abdominal através da artéria e na veia femoral. As medidas de ventilação (VE) foram obtidas pelo método de pletismografia de corpo inteiro. Os protocolos foram realizados em ratos normohidratados (antes da desidratação), desidratados (após a metodologia para induzir a desidratação) e/ou em ratos repletos (2 h após o livre acesso a NaCl 0,3 M e água). A desidratação intracelular induzida pela sobrecarga intragástrica de NaCl 2 M (2 mL), produziu um aumento da pressão arterial média (PAM), sem modificar a frequência cardíaca (FC), o volume corrente (VC), a frequência respiratória (fR) e a VE. A desidratação mista (intracelular e extracelular combinadas), induzida por 24 h de privação hídrica, produziu um aumento da PAM e do VC, sem modificar a FC, a fR e a VE. Nos ratos reidratados a PAM e o VC retornaram aos valores basais. Injeções unilaterais de L-glutamato e do agonista de receptor glutamatérgico NMDA no NTS de ratos normohidratados produziram respostas pressoras e bradicardicas. Após 24 h de privação hídrica essas respostas pressoras foram reduzidas, assim como a bradicardia produzida por injeção de NMDA no NTS e sem alteração na bradicardia produzida por L-glutamato no NTS. Após a reidratação, as respostas pressoras do Lglutamato e NMDA no NTS permaneceram reduzidas, bem como a bradicardia produzida pela injeção de NMDA no NTS. Além disso, os objetivos do nosso estudo em animais anestesiados submetidos à desidratação extracelular foram: 1) caracterizar as respostas cardiorrespiratórias basais e a atividade do nervo simpático renal (ANSR); 2) avaliar o efeito do bloqueio periférico dos receptores angiotensinérgicos AT1 sobre as respostas cardiorrespiratórias basais e sobre a ANSR; 3) avaliar os parâmetros gasométricos arteriais; 4) avaliar as concentrações plasmáticas de sódio e potássio. A desidratação extracelular induzida pela injeção subcutânea do diurético furosemida não alterou a PAM e a FC basais, não alterou a atividade do nervo frênico (ANF) e a ANSR. A desidratação extracelular não alterou a resposta pressora produzida pela injeção intravenosa (iv) de ANG II, nem a queda na ASNR e não promoveu alterações na FC e na ANF. A injeção iv de losartan (antagonista dos receptores AT1, 1 mg/kg de peso corporal) promoveu queda na PAM sem alterar a FC, a ANSR e a ANF. A resposta hipotensora após a injeção iv de losartan foi maior nos animais com desidratação extracelular. A desidratação extracelular não alterou a resposta da ANSR e ANF após o bloqueio com losartan. Os resultados sugerem que alterações na composição e no volume dos líquidos corporais modificam o controle cardiovascular em animais com desidratação intracelular. Além disso, altera o controle cardiorrespiratório em animais com desidratação mista, bem como a neurotransmissão glutamatérgica no NTS. E ainda, em animais anestesiados com desidratação extracelular não apresentaram alterações cardiorrespiratórias basais e nem na ANSR.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2018-08-09T11:39:12Z No. of bitstreams: 2 Dissertaçao - Lara Marques Naves - 2018.pdf: 4245553 bytes, checksum: 32754e93d07b1f96bc7f0b9a2bc618ff (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-08-09T12:20:22Z (GMT) No. of bitstreams: 2 Dissertaçao - Lara Marques Naves - 2018.pdf: 4245553 bytes, checksum: 32754e93d07b1f96bc7f0b9a2bc618ff (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-08-09T12:20:22Z (GMT). No. of bitstreams: 2 Dissertaçao - Lara Marques Naves - 2018.pdf: 4245553 bytes, checksum: 32754e93d07b1f96bc7f0b9a2bc618ff (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-03-02 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Hemodynamic and cardiovascular benefits from the hypertonic saline solution (HS) use in the hypotensive hemorrhage (HH) treatment have been reported for several years. Recent investigations have shown the participation of central nervous system (CNS) regions, such as A1 neuronal clusters (located in the caudal ventrolateral medulla; CVLM), A2 neuronal clusters (located in the nucleus of the solitary tract; NTS) and the Median Preoptic Nucleus (MnPO) on hemodynamic responses induced by sodium chloride overload in normovolemic animals. However, the role of the above structures in cardiovascular recovery and autonomic changes induced by HS solution administration in animals submitted to HH has not yet been evaluated. Thus, the present study evaluated the A1, A2 neuronal clusters and MnPO nucleus involvement in the cardiovascular and autonomic responses promoted by HS solution infusion in hypovolemic animals. For this, wistar rats (280-320 g) were separated into four protocols: I. A2 neuronal cluster lesion (A2 Sham: n = 6; A2 Experimental: n = 6); II. A1 neuronal cluster lesion (A1 Sham: n = 6; A1 Experimental: n = 6); III. A1 and A2 neural clusters concomitant lesions (A1 + A2 Sham: n = 6; A1 + A2 Experimental: n = 6) and IV. Pharmacological inhibition of MnPO (MnPO Sham: n = 6; MnPO Experimental: n = 6). The animals of the first three protocols were anesthetized and subjected to saporin-anti-DβH nanoinjections for neuronal lesion (100 nL, 0.105 ng/nl) in experimental groups and Saporin nanoinjections (100 nL, 0.022 ng/nL) in sham groups for fictitious neuronal lesion, respectively, in the NTS, CVLM or simultaneously in the NTS and CVLM regions. After 20 days of recovery, the animals were anesthetized and instrumented to mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nervous activity (RSNA) recordings. Then, HH was performed by blood withdrawal until MAP reached approximately 60 mmHg. After 20 min of HH, sodium overload (3M NaCl, 1.8 mL/g, 90 seconds of infusion, i.v) was conducted. In another series of experiments, MnPO Sham and MnPO Experimental groups were anesthetized and instrumented for MAP, HR and RSNA recordings. Then, the animals were submitted to HH and HS infusion at the end of the hemorrhage. GABAergic agonist Muscimol (4 mM, 100 nL, MnPO Experimental group) or saline nanoinjections (0.15 M, 100 nL, MnPO Sham group) were performed in the MnPO after 10 min from the start of HH. HH-induced hypotension, bradycardia and renal sympathoinhibition in the animals of the A2 Sham, A1 Sham, A1 + A2 Sham and MnPO Sham groups. In the sham groups, HS infusion after HH reestablished MAP, HR, and did not alter the renal sympathoinhibition generated during hypovolemia. In the A2 Experimental and A1 Experimental groups, the specific lesion of A1 or A2 neurons did not alter the hypotension, bradycardia and renal sympathoinhibition caused during HH. In addition, the A1 or A2 neurons specific lesion did not alter the reestablishment of MAP, HR and the RSNA reduction after HS solution infusion. However, in the animals of the A1 + A2 experimental group, the simultaneous A1 and A2 neurons lesion did not alter the decrease in MAP and HR observed during HH, but abolished renal sympathoinhibition. In addition, simultaneous A1 and A2 neurons lesion abolished MAP restoration and ANSR reduction after HS infusion, while HR restoration was not modified. In the MnPO experimental animals, MnPO nucleus inhibition did not alter the decrease in MAP and HR observed during HH, but abolished renal sympathoinhibition. However, MnPO inhibition abolished the MAP restoration and promoted strong sympathetic activation in the renal bed after HS infusion, while HR restoration was not modified. These results suggest that the A1, A2 neuronal clusters and MnPO nucleus are part of the integration and transmission information circuits about changes in plasma osmolarity, participating in cardiovascular and autonomic recovery induced by sodium chloride overload in animals submitted to HH. / Os benefícios hemodinâmicos e cardiovasculares provenientes do uso de solução salina hipertônica (SH) no tratamento da hemorragia hipotensiva (HH) são relatados há vários anos. Recentes investigações mostraram a participação de regiões do sistema nervoso central (SNC), como os grupamentos neuronais A1 (localizado na região caudoventrolateral do bulbo; CVLM), A2 (localizado no núcleo do tracto solitário; NTS) e do núcleo Pré-óptico mediano (MnPO) nas respostas hemodinâmicas induzidas pela sobrecarga de cloreto de sódio em animais normovolêmicos. Entretanto, o papel das estruturas acima relacionadas na recuperação cardiovascular e nas alterações autonômicas induzidas pela administração de solução SH em animais submetidos à HH ainda não foi avaliado. Assim, o presente estudo buscou avaliar o envolvimento dos grupamentos neuronais A1, A2 e do núcleo MnPO nas respostas cardiovasculares e autonômicas promovidas pela infusão de solução SH em animais hipovolêmicos. Para isto, ratos Wistar (280-320 g) foram separados em quatro protocolos: I. Lesão do grupamento neuronal A2 (Controle A2: n=6; Experimental A2: n=6); II. Lesão do grupamento neuronal A1 (Controle A1: n=6; Experimental A1: n=6); III. Lesões concomitantes dos grupamentos neuronais A1 e A2 (Controle A1 + A2: n=6; Experimental A1 + A2: n=6) e IV. Inibição farmacológica do núcleo MnPO (Controle MnPO: n=6; Experimental MnPO: n=6). Os animais dos três primeiros protocolos foram anestesiados e submetidos a nanoinjeções de saporina-anti-DβH para lesão neuronal (100 nL, 0,105 ng/nL) nos grupos experimentais e Saporina (100 nL, 0,022 ng/nL) nos grupos controles para lesão neuronal fictícia, respectivamente, no NTS, na região CVLM ou conjuntamente no NTS e CVLM. Após 20 dias de recuperação, os animais foram novamente anestesiados e instrumentalizados para registro da pressão arterial média (PAM), frequência cardíaca (FC) e atividade nervosa simpática renal (ANSR). Em seguida, a HH foi realizada através da retirada de sangue até que a PAM atingisse aproximadamente 60 mmHg. Após 20 min de HH foi conduzida a sobrecarga de sódio (NaCl 3M, 1,8 mL/kg, 90 segundos de infusão, i.v). Em outra série de experimentos, os animais dos grupos controle MnPO e Experimental MnPO foram anestesiados e instrumentalizados para registro da PAM, FC, ANSR. Em seguida, foram submetidos à HH e a infusão de solução SH ao final da hemorragia. Nanoinjeções do agonista GABAérgico, muscimol (4 mM, 100 nL, grupo experimental MnPO) ou salina (0,15 M; 100 nL; grupo controle MnPO) foram realizadas no MnPO após 10 min do início da HH. A HH promoveu hipotensão, bradicardia e simpatoinibição no território renal nos animais dos grupos controle A2, controle A1, controle A1 + A2 e controle MnPO. Nos grupos controle, a infusão de solução SH após a HH reestabeleceu a PAM, FC e não alterou a simpatoinibição renal gerada durante a hipovolemia. Nos animais dos grupos experimental A2 e experimental A1, a lesão especifica dos neurônios A1 ou A2 não alterou a hipotensão, bradicardia e simpatoinibição provocados durante a HH. Em adição, a lesão especifica dos neurônios A1 ou A2 não alterou o reestabelecimento da PAM, FC e a queda da ANSR gerada após a infusão de solução SH. Entretanto, nos animais do grupo experimental A1 + A2, a lesão simultânea dos neurônios A1 e A2 não alterou a queda da PAM, da FC observada durante a HH, mas aboliu a simpatoinibição renal. Ademais, a lesão simultânea dos neurônios A1 e A2 aboliu a restauração da PAM e a redução da ANSR após a infusão de solução SH, enquanto a restauração da FC não foi modificada. Nos animais do grupo experimental MnPO, a inibição do MnPO não alterou a queda da PAM e da FC observadas durante a HH, entretanto aboliu a simpatoinibição renal. Porém, a inibição do núcleo MnPO aboliu a restauração da PAM e promoveu forte simpatoexcitação no leito renal após a infusão de solução SH, enquanto a restauração da FC não foi modificada. Esses resultados sugerem que os neurônios dos grupamentos A1, A2 e o núcleo MnPO fazem parte dos circuitos de integração e transmissão de informações a respeito de mudanças na osmolaridade plasmática, participando da recuperação cardiovascular e autonômica induzida pela sobrecarga de cloreto de sódio em animais submetidos à HH.

活動性拒食症(ABA)とは、食事時間の制限と過剰なランニングによって引き起こされる摂食障害である。本論文では、ABAモデルラットが示す摂食障害に、脳の孤束核がどう関わっているかを検証した。第一実験は、筆者の立てた仮説に基づき、オピオイドの役割が中枢性か末梢性かについて、孤束核にナロキソンを直接投与し、その影響を調べた。第二実験では、第一実験の結果を踏まえ、ABAラットの孤束核を破壊し、その影響を調べた。 / Active anorexia (ABA) is an eating disorder caused by restricted meal times and excessive running. This study examined the involvement of the nucleus of the solitary tract (NST) of the brain in ABA model rats. In the first experiment, based on the hypothesis previously formulated by the author, naloxone was microinjected into the NST. This was to determine whether the opioid worked in the central or peripheral mechanisms. In the second experiment, based on the results of the first experiment, the NSTs of rats were lesioned and the effects were examined. / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University