title: Medial prefrontal cortex serotonergic and GABAergic mechanisms modulate the expression of contextual fear: intratelencephalic pathways and differential involvement of cortical subregions.
abstract: Several lines of evidence indicate that the dorsal hippocampus (dH) and medial prefrontal cortex (mPFC) regulate contextual fear conditioning. The prelimbic (PrL), infralimbic (IL) and the anterior cingulate cortex (ACC) subregions of the mPFC likely play distinct roles in the expression of fear. Moreover, studies have highlighted the role of serotonin (5-hydroxytryptamine, 5-HT)- and γ-aminobutyric acid (GABA)-mediated mechanisms in the modulation of innate fear in the mPFC. The present study characterized dH-mPFC pathways and investigated the role of serotonergic and GABAergic mechanisms of the PrL, IL and ACC-area 1 (Cg1) in the elaboration of contextual fear conditioning using fear-potentiated startle (FPS) and freezing behavior in Rattus norvegicus. The results of neurotracing with microinjections of biotinylated dextran amine into the dH revealed a neural link of the dH with the PrL and ACC. Intra-PrL injections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the GABAA receptor-selective agonist muscimol reduced contextual FPS and freezing responses. Intra-Cg1 injections of muscimol but not 8-OH-DPAT decreased FPS and freezing responses. However, neither intra-IL injections of a 5-HT1A agonist nor of a GABAA agonist affected these defensive responses. Labeled neuronal fibers from the dH reached the superficial layers of the PrL cortex and spread to the inner layers of PrL and Cg1 cortices, supporting the pharmacological findings. The present results confirmed the involvement of PrL and Cg1 in the expression of FPS and freezing responses to aversive conditions. In addition, PrL serotoninergic mechanisms play a key role in contextual fear conditioning. This study suggests that PrL, IL and Cg1 distinctively contribute to the modulation of contextual fear conditioning.
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil; Institute of Neuroscience and Behaviour (INeC), Ribeirão Preto, São Paulo, Brazil.
authors.forename: R C
authors.initials: RC
authors.lastname: Almada
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil; Institute of Neuroscience and Behaviour (INeC), Ribeirão Preto, São Paulo, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: nccoimbr@fmrp.usp.br.
authors.forename: N C
authors.initials: NC
authors.lastname: Coimbra
authors.affiliation: Laboratory of Neuropsychopharmacology, School of Philosophy, Sciences and Literature of the University of São Paulo, Department of Psychology, Ribeirão Preto, São Paulo, Brazil; Institute of Neuroscience and Behaviour (INeC), Ribeirão Preto, São Paulo, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: mbrandao@usp.br.
authors.forename: M L
authors.initials: ML
authors.lastname: Brandão
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D003911:Dextrans; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D065726:Limbic Lobe / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009434:Neural Pathways / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D056347:Neuroanatomical Tract-Tracing Techniques; D056325:Neuronal Tract-Tracers; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D003911:Dextrans; D058785:GABA-A Receptor Agonists; D056325:Neuronal Tract-Tracers; D011963:Receptors, GABA-A; D058825:Serotonin 5-HT1 Receptor Agonists; C076397:biotinylated dextran amine; D044282:Receptor, Serotonin, 5-HT1A; D009118:Muscimol; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D001710:Biotin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: GABA; anterior cingulate cortex; contextual fear conditioning; infralimbic cortex; prelimbic cortex; serotonin