Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder.
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.
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 Universitária, 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 Brás, 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.
Gisele Pereira
GP
Dias
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 Universitária, 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 Brás, 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.
Mário Cesar do Nascimento
MC
Bevilaqua
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 Universitária, 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 Brás, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: annadomluz@gmail.com.
Anna Claudia Domingos Silveira
AC
da Luz
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 Universitária, CEP: 21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: renataf@biof.ufrj.br.
Renata Lopes
RL
Fleming
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 Universitária, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: litia.carvalho@gmail.com.
Lítia Alves
LA
de Carvalho
Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: graham.d.cocks@kcl.ac.uk.
Graham
G
Cocks
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 Universitária, 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 Universitária, CEP: 21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: daniellebeckman@gmail.com.
Danielle
D
Beckman
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 Universitária, 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 Brás, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: lchosken@hotmail.com.
Lucas Costa
LC
Hosken
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 Universitária, 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 Brás, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: williamdesantannamachado@yahoo.com.br.
William
W
de Sant'Anna Machado
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 Universitária, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: anacarolina_castro@yahoo.com.br.
Ana Carolina
AC
Corrêa-e-Castro
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 Universitária, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: felippeneto@hotmail.com.
Felippe
F
Mousovich-Neto
Laboratory of Behavioral Neuroscience (LANEC), Department of Psychology, Pontifícia Universidade Católica do Rio de Janeiro (PUC-Rio), R. Marquês de São Vicente, 225 - Gávea, 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.
Vítor
V
de Castro Gomes
Laboratory of Neuroinflammation, Institute of Biological Sciences, Universidade Federal do Pará (UFPA), Rua Augusto Corrêa 01, CEP: 66075-110 Belém, PA, Brazil. Electronic address: gbastos@ufpa.br.
Gilmara de Nazareth Tavares
Gde N
Bastos
Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedics Institute, Universidade Federal Fluminense, Rua Prof. Hernani Pires de Melo 101/213 - São Domingos, CEP: 24210-130 Niterói, RJ, Brazil. Electronic address: kubrusly@vm.uff.br.
Regina Célia Cussa
RC
Kubrusly
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 Universitária, CEP: 21941-902 Rio de Janeiro, RJ, Brazil. Electronic address: vmccosta@biof.ufrj.br.
Vânia Maria Corrêa
VM
da Costa
Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: deepak.srivastava@kcl.ac.uk.
Deepak
D
Srivastava
Laboratory of Behavioral Neuroscience (LANEC), Department of Psychology, Pontifícia Universidade Católica do Rio de Janeiro (PUC-Rio), R. Marquês de São Vicente, 225 - Gávea, CEP: 22451-900 Rio de Janeiro, RJ, Brazil; Laboratory of Comparative Psychology, Department of Psychology, Universidade Estácio de Sá (UNESA), R. do Bispo, 83 - Rio Comprido, CEP: 20261-060 Rio de Janeiro, RJ, Brazil. Electronic address: landeira@puc-rio.br.
Jesus
J
Landeira-Fernandez
Translational Neurobiology Unit, Laboratory of Panic & Respiration, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Avenida Venceslau Brás, 71 Fundos - Botafogo, CEP: 22290-140 Rio de Janeiro, RJ, Brazil(2). Electronic address: antonioenardi@gmail.com.
Antonio Egidio
AE
Nardi
Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Electronic address: sandrine.1.thuret@kcl.ac.uk.
Sandrine
S
Thuret
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 Universitária, CEP:21941-902 Rio de Janeiro, RJ, Brazil(1). Electronic address: gardino@biof.ufrj.br.
Patricia Franca
PF
Gardino
D000818:Animals; D001008:Anxiety Disorders / Q000473:pathology / Q000503:physiopathology*; D001362:Avoidance Learning / Q000502:physiology; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013028:Space Perception / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D011965:Receptors, Glucocorticoid; D005680:gamma-Aminobutyric Acid; D003345:Corticosterone
Adult hippocampal neurogenesis; Anxiety; BDNF; Dendritic arborization; Dendritic spines; Fear memory