PMID- 24462725 OWN - NLM STAT- MEDLINE DCOM- 20141203 LR - 20220129 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 263 DP - 2014 Apr 15 TI - Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder. PG - 34-45 LID - S0166-4328(14)00015-1 [pii] LID - 10.1016/j.bbr.2014.01.012 [doi] AB - Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Dias, Gisele Pereira AU - Dias GP AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2); Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: giseledias@ufrj.br. FAU - Bevilaqua, Mario Cesar do Nascimento AU - Bevilaqua MC AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2); Health and Environment School, Universidade Castelo Branco, Av. de Santa Cruz, 1631 - Realengo, CEP: 21710-250 Rio de Janeiro, RJ, Brazil. Electronic address: mariobevilaqua@gmail.com. FAU - da Luz, Anna Claudia Domingos Silveira AU - da Luz AC AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: annadomluz@gmail.com. FAU - Fleming, Renata Lopes AU - Fleming RL AD - Laboratory of Neurochemistry, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP: 21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: renataf@biof.ufrj.br. FAU - de Carvalho, Litia Alves AU - de Carvalho LA AD - Laboratory of Comparative and Developmental Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G - Cidade Universitaria, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: litia.carvalho@gmail.com. FAU - Cocks, Graham AU - Cocks G AD - Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: graham.d.cocks@kcl.ac.uk. FAU - Beckman, Danielle AU - Beckman D AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Laboratory of Neurochemistry, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP: 21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: daniellebeckman@gmail.com. FAU - Hosken, Lucas Costa AU - Hosken LC AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: lchosken@hotmail.com. FAU - de Sant'Anna Machado, William AU - de Sant'Anna Machado W AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1); Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: williamdesantannamachado@yahoo.com.br. FAU - Correa-e-Castro, Ana Carolina AU - Correa-e-Castro AC AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: anacarolina_castro@yahoo.com.br. FAU - Mousovich-Neto, Felippe AU - Mousovich-Neto F AD - Laboratory of Endocrine Physiology, Program of Physiology and Biophysics, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G - Cidade Universitaria, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: felippeneto@hotmail.com. FAU - de Castro Gomes, Vitor AU - de Castro Gomes V AD - Laboratory of Behavioral Neuroscience (LANEC), Department of Psychology, Pontificia Universidade Catolica do Rio de Janeiro (PUC-Rio), R. Marques de Sao Vicente, 225 - Gavea, CEP: 22451-900 Rio de Janeiro, RJ, Brazil; Department of Psychiatry and Neuroscience, Uniformed Services, University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA. Electronic address: vitorcastrogomes@gmail.com. FAU - Bastos, Gilmara de Nazareth Tavares AU - Bastos Gde N AD - Laboratory of Neuroinflammation, Institute of Biological Sciences, Universidade Federal do Para (UFPA), Rua Augusto Correa 01, CEP: 66075-110 Belem, PA, Brazil. Electronic address: gbastos@ufpa.br. FAU - Kubrusly, Regina Celia Cussa AU - Kubrusly RC AD - Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedics Institute, Universidade Federal Fluminense, Rua Prof. Hernani Pires de Melo 101/213 - Sao Domingos, CEP: 24210-130 Niteroi, RJ, Brazil. Electronic address: kubrusly@vm.uff.br. FAU - da Costa, Vania Maria Correa AU - da Costa VM AD - Laboratory of Endocrine Physiology, Program of Physiology and Biophysics, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G - Cidade Universitaria, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: vmccosta@biof.ufrj.br. FAU - Srivastava, Deepak AU - Srivastava D AD - Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: deepak.srivastava@kcl.ac.uk. FAU - Landeira-Fernandez, Jesus AU - Landeira-Fernandez J AD - Laboratory of Behavioral Neuroscience (LANEC), Department of Psychology, Pontificia Universidade Catolica do Rio de Janeiro (PUC-Rio), R. Marques de Sao Vicente, 225 - Gavea, CEP: 22451-900 Rio de Janeiro, RJ, Brazil; Laboratory of Comparative Psychology, Department of Psychology, Universidade Estacio de Sa (UNESA), R. do Bispo, 83 - Rio Comprido, CEP: 20261-060 Rio de Janeiro, RJ, Brazil. Electronic address: landeira@puc-rio.br. FAU - Nardi, Antonio Egidio AU - Nardi AE AD - Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Bras, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: antonioenardi@gmail.com. FAU - Thuret, Sandrine AU - Thuret S AD - Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: sandrine.1.thuret@kcl.ac.uk. FAU - Gardino, Patricia Franca AU - Gardino PF AD - Laboratory of Neurobiology of the Retina, Program of Neurobiology, Institute of Biophysics, Universidade Federal do Rio de Janeiro (UFRJ), Av Carlos Chagas Filho, 373, CCS, Bloco G, Sala C-031 - Cidade Universitaria, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: gardino@biof.ufrj.br. LA - eng GR - MR/L021064/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140123 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Biomarkers) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Dcx protein, rat) RN - 0 (Doublecortin Protein) RN - 0 (Receptors, Glucocorticoid) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - W980KJ009P (Corticosterone) SB - IM MH - Animals MH - Anxiety Disorders/pathology/*physiopathology MH - Avoidance Learning/physiology MH - Biomarkers MH - Brain-Derived Neurotrophic Factor/metabolism MH - Corticosterone/blood MH - Dentate Gyrus/pathology/physiopathology MH - Disease Models, Animal MH - Doublecortin Protein MH - Fear/physiology MH - Hippocampus/pathology/*physiopathology MH - Male MH - Maze Learning/physiology MH - Memory/physiology MH - Neural Stem Cells/pathology/physiology MH - Neurons/pathology/*physiology MH - Rats MH - Rats, Wistar MH - Receptors, Glucocorticoid/metabolism MH - Space Perception/physiology MH - gamma-Aminobutyric Acid/metabolism OTO - NOTNLM OT - Adult hippocampal neurogenesis OT - Anxiety OT - BDNF OT - Dendritic arborization OT - Dendritic spines OT - Fear memory EDAT- 2014/01/28 06:00 MHDA- 2014/12/15 06:00 CRDT- 2014/01/28 06:00 PHST- 2013/12/26 00:00 [received] PHST- 2014/01/08 00:00 [revised] PHST- 2014/01/15 00:00 [accepted] PHST- 2014/01/28 06:00 [entrez] PHST- 2014/01/28 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - S0166-4328(14)00015-1 [pii] AID - 10.1016/j.bbr.2014.01.012 [doi] PST - ppublish SO - Behav Brain Res. 2014 Apr 15;263:34-45. doi: 10.1016/j.bbr.2014.01.012. Epub 2014 Jan 23.