Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder

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• 作者：Gisele Pereira Dias^a ; ^b ; ^c ; ^{giseledias@ufrj.br" class="auth_mail} ; ^{gisele.dias@kcl.ac.uk" class="auth_mail} ; Má ; rio Cesar do Nascimento Bevilaqua^a ; ^b ; ^d ; ^{mariobevilaqua@gmail.com" class="auth_mail} ; Anna Claudia Domingos Silveira da Luz^a ; ^b ; ^{annadomluz@gmail.com" class="auth_mail} ; Renata Lopes Fleming^e ; ^{renataf@biof.ufrj.br" class="auth_mail} ; Lí ; tia Alves de Carvalho^f ; ^{litia.carvalho@gmail.com" class="auth_mail} ; Graham Cocks^c ; ^{graham.d.cocks@kcl.ac.uk" class="auth_mail} ; Danielle Beckman^a ; ^e ; ^{daniellebeckman@gmail.com" class="auth_mail} ; Lucas Costa Hosken^a ; ^b ; ^{lchosken@hotmail.com" class="auth_mail} ; William de Sant&rsquo ; Anna Machado^a ; ^b ; ^{williamdesantannamachado@yahoo.com.br" class="auth_mail} ; Ana Carolina Corrê ; a-e-Castro^a ; ^{anacarolina_castro@yahoo.com.br" class="auth_mail} ; Felippe Mousovich-Neto^g ; ^{felippeneto@hotmail.com" class="auth_mail} ; Ví ; tor de Castro Gomes^h ; ⁱ ; ^{vitorcastrogomes@gmail.com" class="auth_mail} ; Gilmara de Nazareth Tavares Bastos^j ; ^{gbastos@ufpa.br" class="auth_mail} ; Regina Cé ; lia Cussa Kubrusly^l ; ^{kubrusly@vm.uff.br" class="auth_mail} ; Vâ ; nia Maria Corrê ; a da Costa^g ; ^{vmccosta@biof.ufrj.br" class="auth_mail} ; Deepak Srivastava^c ; ^{deepak.srivastava@kcl.ac.uk" class="auth_mail} ; Jesus Landeira-Fernandez^h ; ^m ; ^{landeira@puc-rio.br" class="auth_mail} ; Antonio Egidio Nardi^b ; ^{antonioenardi@gmail.com" class="auth_mail} ; Sandrine Thuret^c ; ^{sandrine.1.thuret@kcl.ac.uk" class="auth_mail} ; Patricia Franca Gardino^a ; ^{gardino@biof.ufrj.br" class="auth_mail}
• 关键词：Fear memory ; Anxiety ; Adult hippocampal neurogenesis ; BDNF ; Dendritic arborization ; Dendritic spines
• 刊名：Behavioural Brain Research
• 出版年：15 April, 2014
• 年：2014
• 卷：263
• 期：Complete
• 页码：34-45
• 全文大小：2082 K

文摘

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.