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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2020.tde-12022020-170935
Document
Author
Full name
Luiz Luciano Falconi Sobrinho
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Coimbra, Norberto Cysne (President)
Rocha, Maria Jose Alves da
Zanoveli, Janaína Menezes
Oliveira, Leda Menescal de
 
Title in Portuguese
Influência dos receptores NMDA e de vias glutamatérgicas do córtex cingulado anterior na modulação do comportamento de defesa e da antinocicepção induzida pelo medo evocados por doador de óxido nítrico microinjetado no hipotálamo anterior
Keywords in Portuguese
Antinocicepção induzida pelo medo
Comportamento de defesa
Córtex cingulado anterior
Hipotálamo anterior
Óxido nítrico
Receptores NMDA
Abstract in Portuguese
Tem sido estabelecido que um desequilíbrio excitatório no hipotálamo de roedores, causado por estimulação química local, provoca respostas defensivas relacionadas com o medo, como reações de fuga e de "congelamento", e antinocicepção. No entanto, há uma escassez de estudos mostrando a participação do núcleo hipotalâmico anterior (HA) na geração dessas respostas defensivas. Há evidências de que doadores de óxido nítrico (NO), quando microinjetados em estruturas límbicas e paralímbicas, podem evocar respostas defensivas relacionadas com o medo, e essa neuromodulação nitrérgica envolvida na geração do medo pode ser mediada pelo sistema glutamatérgico. Além disso, recentes estudos realizados por nossa equipe demonstraram que respostas comportamentais e antinociceptivas organizadas no hipotálamo posterior podem ser moduladas por neurônios glutamatérgicos do córtex "pré-frontal" medial, como aqueles localizados no córtex cingulado anterior (CCA). No entanto, faltam estudos que demonstrem a participação do CCA no controle de respostas defensivas relacionadas com o medo incondicionado, organizadas pelo HA. Para investigar a influência do sistema glutamatérgico nos mecanismos nitrérgicos que geram as respostas defensivas relacionadas com o medo organizadas por neurônios do HA, o presente estudo avaliou os efeitos do doador de NO SIN-1 administrado no HA de camundongos em diferentes doses (75, 150 e 300 nmol/0,1 ?L). Em seguida, investigamos os efeitos do pré-tratamento no HA com o AP-7, um antagonista seletivo de receptores do tipo NMDA, nas doses de 0,02, 0,2 e 2,0 nmol/0,1 ?L, sobre os efeitos comportamentais e antinociceptivos evocados pela administração intra-HA de SIN-1. Além disso, para compreender melhor a mediação cortical das respostas defensivas organizadas no hipotálamo, foram realizados estudos morfológicos para revelar vias glutamatérgicas que conectem o CCA ao HA, e abordagens farmacológicas para investigar os efeitos da ativação de neurônios do CCA por microinjeções intra-Cg1 de NMDA em diferentes doses (0,1, 1,0 e 10 nmol). Nossos dados demonstraram que a dose de 300 nmol de SIN-1 foi a mais efetiva em causar comportamentos defensivos do tipo pânico, os quais foram seguidos por antinocicepção. Além disso, os comportamentos de defesa e a antinocicepção induzidos por SIN-1, foram inibidos pelo pré-tratamento do HA com AP-7, sugerindo que os efeitos panicogênicos e antinociceptivos evocados por microinjeções intra-HA de SIN-1 dependem da ativação do receptor NMDA. No estudo morfológico, microinjeções de um neurotraçador no Cg1 revelaram fibras axônicas marcadas com vesículas sinápticas glutamatérgicas no pericário do HA. E, por fim, a ativação do CCA com NMDA aumentou o comportamento de fuga não orientada e reduziu o "congelamento" e a antinocicepção organizados por neurônios do HA, sugerindo que vias glutamatérgicas do CCA modulam as reações defensivas do tipo pânico organizadas por neurônios do HA, e sua ativação promove pronocicepção.
 
Title in English
Influence of NMDA receptors and glutamatergic pathways from anterior cingulate cortex in the modulation of defensive behaviour and fear-induced antinociception evoked by nitric oxide donor microinjected into the anterior hypothalamus
Keywords in English
Anterior cingulate cortex
Anterior hypothalamus
Antinociception induced by fear
Defensive behaviour
Nitric oxide
NMDA receptors
Abstract in English
It has been established that an excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation provokes fear-related defensive responses, such as escape and freezing reactions, and antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic (AH) nucleus in the generation of these defensive responses. There is evidence that nitric oxide (NO) donors, when microinjected into limbic and paralimbic structures, may evoke fear-related defensive responses, and that nitrergic neuromodulation involved in genesis of fear can be mediated by the glutamatergic system. In addition, recent studies performed by our team have demonstrated that behavioural and antinociceptive responses organised in the posterior hypothalamus can be modulated by glutamatergic neurons of the medial "prefrontal" cortex, such as those located in the anterior cingulate cortex (ACC). However, there is a lack of studies showing the participation of the ACC in the control of uncondiotioned fear-related defensive responses organised in the AH. To investigate the influence of the glutamatergic system on the nitrergic mechanisms that generate the fear-related defensive responses organised by AH neurons, the present study investigated the effects of the NO donor SIN-1 administered in the AH of mice at different doses (75, 150 and 300 nmol/0.1 ?L). Then, we investigated the effects of AH pretreatment with the NMDA receptor selective antagonist AP-7 at different doses (0.02, 0.2 and 2.0 nmol/0.1) on behavioural and antinociceptive effects evoked by the intra-AH administration of SIN-1. In addition, to better understand cortical mediation of defensive responses organised by hypothalamic neurons, morphological studies have been performed to reveal glutamatergic pathways that connect ACC to AH and, through pharmacological approaches, to investigate the effects of ACC neurons activation by intra-Cg1 microinjections of NMDA at different doses (0.1, 1.0 and 10 nmol). Our findings demonstrated that the highest dose (300 nmol) of SIN-1 was the most effective in causing panic-like defensive behaviours, which were followed by antinociception. In addition, the SIN-1-induced antinociception and defensive behaviours were inhibited by pretreatment of AH with AP-7, suggesting that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on the activation of NMDA receptor. In the morphological study, microinjections of a neurotracer in the Cg1 of the ACC revealed axonal fibres labelled with glutamatergic synaptic vesicles in the AH perikarya. Finally, the activation of ACC neurons increased the non-oriented escape behaviour, and reduced the freezing and antinociception organised by HA neurons, suggesting that glutamatergic pathways of the ACC modulate panic-like defensive reactions organised by AH neurons, and its activation promotes pronociception.
 
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Publishing Date
2020-04-29
 
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