title: Unravelling cortico-hypothalamic pathways regulating unconditioned fear-induced antinociception and defensive behaviours.
abstract: The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine. We also investigated the involvement of PH ionotropic glutamate receptors in the defensive behaviours and fear-induced antinociception by microinjecting NBQX (an AMPA/kainate receptor antagonist) and LY235959 (a NMDA receptor antagonist) into the PH. ACC pretreatment with lidocaine decreased the proaversive effect and antinociception evoked by GABAAreceptor blockade in the PH, which suggests that there may be descending excitatory pathways from this cortical region to the PH. Microinjections of both NBQX and LY235959 into the PH also attenuated defensive and antinociceptive responses. This suggests that the blockade of AMPA/kainate and NMDA receptors reduces the activity of glutamatergic efferent pathways. Both inputs from the ACC to the PH and glutamatergic hypothalamic short links disinhibited by intra-hypothalamic GABAAreceptors blockade are potentially implicated. Microinjection of a bidirectional neurotracer in the PH showed a Cg1-PH pathway and PH neuronal reciprocal connections with the periaqueductal grey matter. Microinjections of an antegrade neurotracer into the Cg1 showed axonal fibres and glutamatergic vesicle-immunoreactive terminal boutons surrounding both mediorostral-lateroposterior thalamic nucleus and PH neuronal perikarya. These data suggest a critical role played by ACC-PH glutamatergic pathways and AMPA/kainate and NMDA receptors in the panic attack-like reactions and antinociception organised by PH neurons.
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Luiz Luciano
authors.initials: LL
authors.lastname: Falconi-Sobrinho
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Tayllon
authors.initials: T
authors.lastname: Dos Anjos-Garcia
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Daoud Hibrahim
authors.initials: DH
authors.lastname: Elias-Filho
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil; NAP-USP-Neurobiology of Emotions (NuPNE) Research Centre, FMRP-USP, Ribeirão Preto, São Paulo, Brazil. Electronic address: nccoimbr@fmrp.usp.br.
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005239:Fear / Q000187:drug effects / Q000502:physiology* / Q000523:psychology; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology*; D007034:Hypothalamus, Posterior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008845:Microinjections; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000517:prevention & control* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D011810:Quinoxalines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001640:Bicuculline
keywords: AMPA/kainate receptors; Anterior cingulate cortex; NMDA receptors; Panic attacks; Posterior hypothalamus; Unconditional fear-induced antinociception