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Neurobiology of fear and stress


A large body of literature has accumulated over the last half century on the anatomy, physiology and pharmacology of areas or projection systems in the CNS, which, when stimulated electrically or chemically result in physiological and behavioral changes indicative of states of agony or displeasure as expressed by vegetative nervous system indicators, attempts to escape, and displays of fear and aggressive behavior. lt is generally assumed that brain sites, which mediate such behavioral changes, integrate information of aversive nature into appropriate adaptive emotional and behavioral reactions, including fear-related behaviors. The medial hypothalamus, amygdale and dorsal periaqueductal gray (dPAG) have been traditionally grouped together as a "brain aversion system". More recently, a continuous strip of midbrain structures composed of superior and inferior colliculus have also been proposed as parts of this "system". In this project we will focus on the neural substrates of defensive behavior in the midbrain tectum (dPAG, superior and inferior colliculi), and their relevance for understanding fear and anxiety. The proposed link between the defense behavior, fear and anxiety is consistent with many behavioral, electrophysiological and immunohistochemical studies showing expressive activation of these regions by threatening stimuli or conditions. The periaqueductal gray matter participates in the expressions of major brain functions, such as pain processing and modulation, vocalization, autonomic regulation, fear and anxiety. lt has been proposed that neurons in the inferior colliculus are filters for sounds that require immediate action, such as certain sounds made by prey, predators and co specifics. The stimulation of the midbrain tectum may represent an animal model for all these situations, since a gradual increase in the intensity of the electrical stimulation of the midbrain tectum structures produce initially alertness, then freezing, and finally escape reactions. Furthermore, electrical stimulation of the dPAG and inferior colliculus has been consistently shown to induce aversive effects since it elicits defensive behaviors, sustains Iearned operant escape responses and also supports Iearning of conditioned emotional responses. Recent studies using c-ias immunoreactivity bring further support to the notion that amygdale, medial hypothalamus, dP AG, dlSC and inferior colliculus appear to be constituents of a neuronal system or systems that control defensive behavior in the brain by showing that these areas are labeled following exposure or the animals to aversive environmental stimulation… (AU)

Scientific publications (37)
(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)
SANTANA AMARAL, VANESSA CRISTIANE; GOMES, KARINA SANTOS; NUNES-DE-SOUZA, RICARDO LUIZ. Increased corticosterone levels in mice subjected to the rat exposure test. Hormones and Behavior, v. 57, n. 2, p. 128-133, FEB 2010. Web of Science Citations: 20.
GOMES, K. S.; NUNES-DE-SOUZA, R. L. Implication of the 5-HT2A and 5-HT2C (but not 5HT(1A)) receptors located within the periaqueductal gray in the elevated plus-maze test-retest paradigm in mice. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 33, n. 7, p. 1261-1269, OCT 1 2009. Web of Science Citations: 22.
GOMES, KARINA SANTOS; DE CARVALHO-NETTO, EDUARDO FERREIRA; DA SILVA MONTE, KATIA CRISTINA; ACCO, BRUNO; DE CAMPOS NOGUEIRA, PAULO JOSE; NUNES-DE-SOUZA, RICARDO LUIZ. Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze. Brain Research Bulletin, v. 78, n. 6, p. 323-327, MAR 30 2009. Web of Science Citations: 21.
RUIZ MARTINEZ, RAQUEL CHACON; OLIVEIRA, AMANDA RIBEIRO DE; BRANDÃO, MARCUS LIRA. Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray. European Neuropsychopharmacology, v. 17, n. 11, p. 717-724, Nov. 2007.
OLIVEIRA, LUCIANA CHRYSTINE; BROIZ, ANA CAROLINA; MACEDO, CARLOS EDUARDO DE; LANDEIRA-FERNANDEZ, J.; BRANDÃO, MARCUS LIRA. 5-HT2 receptor mechanisms of the dorsal periaqueductal gray in the conditioned and unconditioned fear in rats. Psychopharmacology, v. 191, n. 2, p. 253-262, Apr. 2007.
BASSI‚ G.S.; NOBRE‚ M.J.; CARVALHO‚ M.C.; BRANDÃO‚ M.L. Substance P injected into the dorsal periaqueductal gray causes anxiogenic effects similar to the long-term isolation as assessed by ultrasound vocalizations measurements. Behavioural Brain Research, v. 182, n. 2, p. 301-307, 2007.
CORNÉLIO‚ A.M.; NUNES-DE-SOUZA‚ R.L. Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze. Behavioural Brain Research, v. 178, n. 1, p. 82-89, 2007.
FERREIRA-NETTO‚ C.; BORELLI‚ K.G.; BRANDÃO‚ M.L. Distinct Fos expression in the brain following freezing behavior elicited by stimulation with NMDA of the ventral or dorsal inferior colliculus. Experimental Neurology, v. 204, n. 2, p. 693-704, 2007.
FRANCOLIN-SILVA‚ AL; BRANDÃO‚ ML; ALMEIDA‚ SS. Early postnatal protein malnutrition causes resistance to the anxiolytic effects of diazepam as assessed by the fear-potentiated startle test. NUTRITIONAL NEUROSCIENCE, v. 10, n. 1-2, p. 1-2, 2007.
MACEDO‚ C.E.; MARTINEZ‚ R.C.R.; ALBRECHET-SOUZA‚ L.; MOLINA‚ V.A.; BRANDÃO‚ M.L. 5-HT2-and D1-mechanisms of the basolateral nucleus of the amygdala enhance conditioned fear and impair unconditioned fear. Behavioural Brain Research, v. 177, n. 1, p. 100-108, 2007.
MOREIRA‚ C.M.; MASSON‚ S.; CARVALHO‚ M.C.; BRANDÃO‚ M.L. Exploratory behaviour of rats in the elevated plus-maze is differentially sensitive to inactivation of the basolateral and central amygdaloid nuclei. Brain Research Bulletin, v. 71, n. 5, p. 466-474, 2007.
CABRAL‚ A.; ISOARDI‚ N.; SALUM‚ C.; MACEDO‚ CE; NOBRE‚ MJ; MOLINA‚ VA; BRANDÃO‚ ML. Fear state induced by ethanol withdrawal may be due to the sensitization of the neural substrates of aversion in the dPAG. Experimental Neurology, v. 200, n. 1, p. 200-208, 2006.
COIMBRA‚ NC; DE OLIVEIRA‚ R.; FREITAS‚ RL; RIBEIRO‚ SJ; BORELLI‚ KG; PACAGNELLA‚ RC; MOREIRA‚ JE; DA SILVA‚ LA; MELO‚ LL; LUNARDI‚ LO; OTHERS. Neuroanatomical approaches of the tectum-reticular pathways and immunohistochemical evidence for serotonin-positive perikarya on neuronal substrates of the superior colliculus and periaqueductal gray matter involved in the elaboration of the defensive behavior and fear-induced analgesia. Experimental Neurology, v. 197, n. 1, p. 93-112, 2006.
MIYASE, CÁTIA ISUMI; KISHI, RENATO; PAZ, DENISE AMORIM; COIMBRA, NORBERTO CYSNE; FREITAS, RENATO LEONARDO DE. Involvement of pre- and post-synaptic serotonergic receptors of dorsal raphe nucleus neural network in the control of the sweet-substance-induced analgesia in adult Rattus norvegicus (Rodentia, Muridae). Neuroscience Letters, v. 379, n. 3, p. 169-173, May 2005.
REBOUÇAS, E. C. C.; SEGATO, E. N.; KISHI, R.; FREITAS, R. L.; SAVOLDI, M.; MORATO, S.; COIMBRA, N. C. Effect of the blockade of mu(1)-opioid and 5HT(2A)-serotonergic/alpha(1)-noradrenergic receptors on sweet-substance-induced analgesia. Psychopharmacology, v. 179, n. 2, p. 349-355, May 2005.
BORELLI‚ K.G.; GÁRGARO‚ A.C.; SANTOS‚ J.M.; BRANDÃO‚ M.L. Effects of inactivation of serotonergic neurons of the median raphe nucleus on learning and performance of contextual fear conditioning. Neuroscience Letters, v. 387, n. 2, p. 105-110, 2005.
M.C. CARVALHO; L. ALBRECHET-SOUZA; S. MASSON; M.L. BRANDÃO. Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test. Brazilian Journal of Medical and Biological Research, v. 38, n. 12, p. 1857-1866, Dez. 2005.
MENDES-GOMES‚ J.; NUNES-DE-SOUZA‚ R.L. Concurrent nociceptive stimulation impairs the anxiolytic effect of midazolam injected into the periaqueductal gray in mice. Brain Research, v. 1047, n. 1, p. 97-104, 2005.
NUNES MAMEDE ROSA‚ M.L.; NOBRE‚ M.J.; RIBEIRO OLIVEIRA‚ A.; BRANDÃO‚ M.L. Isolation-induced changes in ultrasonic vocalization‚ fear-potentiated startle and prepulse inhibition in rats. NEUROPSYCHOBIOLOGY, v. 51, n. 4, p. 248-255, 2005.
SANTOS‚ J.M.; GÁRGARO‚ A.C.; OLIVEIRA‚ A.R.; MASSON‚ S.; BRANDÃO‚ M.L. Pharmacological dissociation of moderate and high contextual fear as assessed by freezing behavior and fear-potentiated startle. European Neuropsychopharmacology, v. 15, n. 2, p. 239-246, 2005.
SEGATO‚ EN; REBOUÇAS‚ ECC; FREITAS‚ RL; CAIRES‚ MPT; CARDOSO‚ AV; RESENDE‚ GCC; SHIMIZU-BASSI‚ G.; ELIAS-FILHO‚ DH; COIMBRA‚ NC. Effect of chronic intake of sweet substance on nociceptive thresholds and feeding behavior of Rattus norvegicus (Rodentia‚ Muridae). NUTRITIONAL NEUROSCIENCE, v. 8, n. 2, p. 129-140, 2005.
BORELLI, KARINA GENARO; NOBRE, MANOEL JORGE; BRANDÃO, MARCUS LIRA; COIMBRA, NORBERTO CYSNE. Effects of acute and chronic fluoxetine and diazepam on freezing behavior induced by electrical stimulation of dorsolateral and lateral columns of the periaqueductal gray matter. Pharmacology Biochemistry and Behavior, v. 77, n. 3, p. 557-566, Mar. 2004.
OLIVEIRA, LUCIANA DE; CUNHA, ALEXANDRA OLIMPIO SIQUEIRA; MORTARI, MÁRCIA RENATA; PIZZO, ANDRÉA BALDOCCHI; MIRANDA, ANTONIO; COIMBRA, NORBERTO CYSNE; SANTOS, WAGNER FERREIRA DOS. Effects of microinjections of neurotoxin AvTx8, isolated from the social wasp Agelaia vicina (Hymenoptera, Vespidae) venom, on GABAergic nigrotectal pathways. Brain Research, v. 1031, n. 1, p. 74-81, Jan. 2004.
NOBRE‚ M.J.; LOPES‚ M.G.; BRANDÃO‚ M.L. Defense reaction mediated by NMDA mechanisms in the inferior colliculus is modulated by GABAergic nigro-collicular pathways. Brain Research, v. 999, n. 1, p. 124-131, 2004.
SILVA‚ RCB; GÁRGARO‚ A.C.; BRANDAO‚ ML. Differential regulation of the expression of contextual freezing and fear-potentiated startle by 5-HT mechanisms of the median raphe nucleus. Behavioural Brain Research, v. 151, n. 1, p. 93-101, 2004.
OSAKI, M. Y.; CASTELLAN-BALDAN, L.; CALVO, F.; CARVALHO, A. D.; FELIPPOTTI, T. T.; OLIVEIRA, R. DE; UBIALI, W. A.; PASCHOALIN-MAURIN, T.; ELIAS-FILHO, D. H.; MOTTA, V.; ET AL. Neuroanatomical and neuropharmacological study of opioid pathways in the mesencephalic tectum: effect of mu(1)- and kappa-opioid receptor blockade on escape behavior induced by electrical stimulation of the inferior colliculus. Brain Research, v. 992, n. 2, p. 179-192, Dec. 2003.
AVANZI‚ V.; SILVA‚ RCB; MACEDO‚ CE; BRANDÃO‚ ML. 5-HT mechanisms of median raphe nucleus in the conditioned freezing caused by light/foot-shock association. Physiology & Behavior, v. 78, n. 3, p. 471-477, 2003.
VIANNA‚ D.M.L.; BORELLI‚ K.G.; FERREIRA-NETTO‚ C.; MACEDO‚ C.E.; BRANDÃO‚ M.L. Fos-like immunoreactive neurons following electrical stimulation of the dorsal periaqueductal gray at freezing and escape thresholds. Brain Research Bulletin, v. 62, n. 3, p. 179-189, 2003.
LAMPREA‚ M.R.; CARDENAS‚ F.P.; VIANNA‚ D.M.; CASTILHO‚ V.M.; CRUZ-MORALES‚ S.E.; BRANDÃO‚ M.L. The distribution of fos immunoreactivity in rat brain following freezing and escape responses elicited by electrical stimulation of the inferior colliculus. Brain Research, v. 950, n. 1, p. 186-194, 2002.
MACEDO‚ C.E.; CASTILHO‚ V.M.; DE SOUZA E SILVA‚ M.A.; BRANDÃO‚ M.L. Dual 5-HT mechanisms in basolateral and central nuclei of amygdala in the regulation of the defensive behavior induced by electrical stimulation of the inferior colliculus. Brain Research Bulletin, v. 59, n. 3, p. 189-195, 2002.

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