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Hierarchic defensive system in mice: role of the corticotrophin-releasing factor (CRF)


Threatening situations elicit defense responses such as fight/flight and freezing behaviors, autonomic activation and antinociception. These reactions are orchestrated by limbic structures of the brain defensive system [e.g., medial prefrontal cortex (mPFC), hypothalamus (Hyp), amygdala (Amy) and periaqueductal gray matter (PAG)]. Recent results have shown that intra-PAG injections of corticotrophin-releasing factor (CRF) produce anxiogenic-like effects via activation of CRF1 (but not CRF2) receptors. Interestingly, the blockade of CRF1 receptors within the PAG also attenuates the pro-aversive effects (e.g., jumping and running) induced by local infusion of NOC-9, a nitric oxide (NO) donor, suggesting an interaction between the nitrergic and CRFergic systems in the modulation of defense reactions. Here, we will also investigate the role played by the CRF system (as well as its likely interplay with the nitrergic system) in other limbic structures that belong to the hierarchic defensive system, namely: mPFC, Amy, Hyp and the bed nucleus of the stria terminalis (BNST). Preliminar results obtained with intracerebral injections of NOC-9, CRF and CRF receptor antagonists on defensive behavior in mice have indicated that: 1) While chemical stimulation of the PAG elicits jumps, running and freezing besides an anxiogenic-like effect in mice exposed to the elevated plus-maze (EPM) or to the rat exposure test (RET, a prey-predator interaction test), the activation of the BNST induces only freezing behavior and anxiogenesis observed in the EPM. In addition, intra-mPFC injections of NOC-9 do not elicit jumps, running and freezing, however this procedure induces anxiogenesis in mice exposed to the EPM (we do not investigated the RET yet); 2) While intra-PAG injections of CRF1 antagonists do not change per se the anxiety-like behavior in the EPM, the blockade of this CRF receptor subtype located within the Amy and mPFC produces anxiolysis, suggesting a tonic modulation of the neuropeptide at CRF1 receptors located within these forebrain areas. Thus it is our interest to investigate the role played by CRF and NO in the modulation of this apparently hierarchic defense system. The confirmation of the hypothesis that the defensive reactions induced by different threatening situations (i.e. the EPM and the RET) are mediated by distinct underlying mechanisms will be useful to the comprehension of the neurobiology of defense system and related emotional disorders such, as anxiety and fear. Finally, based on evidence showing that stress situations trigger the activation of CRFergic mechanisms in limbic structures, this study will also investigate the profile of neuronal activation (through double staining Fos/CRF) as well as the effects of CRF1 e CRF2 receptor ligands injected into the above mentioned areas on defensive behavior in mice exposed to a single or repetitive situations of social defeat stress. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GOUVEIA, MARIANNA K.; MIGUEL, TARCISO T.; BUSNARDO, CRISTIANE; SCOPINHO, AMERICA A.; CORREA, FERNANDO M. A.; NUNES-DE-SOUZA, RICARDO L.; CRESTANI, CARLOS C.. Dissociation in control of physiological and behavioral responses to emotional stress by cholinergic neurotransmission in the bed nucleus of the stria terminalis in rats. Neuropharmacology, v. 101, p. 379-388, . (12/14376-0, 13/01283-6, 15/05922-9)
MASCARENHAS, DIEGO CARDOZO; GOMES, KARINA SANTOS; NUNES-DE-SOUZA, RICARDO LUIZ. Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice. Behavioural Brain Research, v. 292, p. 547-554, . (13/06764-2, 13/03445-3, 13/01283-6)
VICTORIANO, GABRIEL; SANTOS-COSTA, NATHALIA; MASCARENHAS, DIEGO CARDOZO; NUNES-DE-SOUZA, RICARDO LUIZ. Inhibition of the left medial prefrontal cortex (mPFC) prolongs the social defeat-induced anxiogenesis in mice: Attenuation by NMDA receptor blockade in the right mPFC. Behavioural Brain Research, v. 378, . (16/24568-4, 17/25409-0, 13/01283-6)
SORREGOTTI, TATIANI; CIPRIANO, ANA CLAUDIA; CRUZ, FABIO CARDOSO; MASCARENHAS, DIEGO CARDOZO; RODGERS, ROBERT JOHN; NUNES-DE-SOUZA, RICARDO LUIZ. Amygdaloid involvement in the defensive behavior of mice exposed to the open elevated plus-maze. Behavioural Brain Research, v. 338, p. 159-165, . (13/06764-2, 13/24986-2, 13/01283-6, 11/04561-1, 14/02956-7)
MASCARENHAS, DIEGO C.; GOMES, KARINA S.; SORREGOTTI, TATIANI; NUNES-DE-SOUZA, RICARDO L.. Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice. FRONTIERS IN PHARMACOLOGY, v. 8, . (13/01283-6, 13/06764-2, 13/03445-3)

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