Role of the Amygdala in Antidepressant Effects on Hippocampal Cell Proliferation and Survival and on Depression-like Behavior in the Rat Jorge E. Castro, Emilio Varea, Cristina Ma´ rquez, Maria Isabel Cordero, Guillaume Poirier, Carmen Sandi* Laboratory of Behavioral Genetics, Brain Mind Institute, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne, Switzerland Abstract The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA- dependent and –independent mechanisms. Our findings underscore the amygdala as a potential target to modulate antidepressants’ action in hippocampal neurogenesis and in their link to depression-like behaviors. Citation: Castro JE, Varea E, Ma´rquez C, Cordero MI, Poirier G, et al. (2010) Role of the Amygdala in Antidepressant Effects on Hippocampal Cell Proliferation and Survival and on Depression-like Behavior in the Rat. PLoS ONE 5(1): e8618. doi:10.1371/journal.pone.0008618 Editor: Martin Giurfa, Centre de Recherches su la Cognition Animale - Centre National de la Recherche Scientifique and Universite´ Paul Sabatier, France Received November 19, 2009; Accepted December 13, 2009; Published January 8, 2010 Copyright: 2010 Castro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the European Union 7th Framework Programme (FP7-HEALTH-F2M-2007-201600; MemStick) and the Swiss National Science Foundation (310000-120791). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: carmen.sandi@epfl.ch Introduction The enhancement of adult hippocampal neurogenesis induced by a wide variety of antidepressant treatments has attracted a great deal of attention [1,2,3]. In rodents, chronic antidepressant administration has been shown to increase both the proliferation of neural progenitors in the subgranular zone of the dentate gyrus (DG) [4] and the survival of these newborn neurons [5]. Intensive research is devoted to unravel the neurobiological mechanisms involved in the effects of antidepressants [6,7], and to disentangle how antidepressant effects on depression-like behavior may be mediated by hippocampal neurogenesis [8,9]. The search for mechanisms of action has mostly focused on the involvement of molecular pathways, including the activation of specific serotonin receptors [9,10,11], the cAMP-CREB signaling pathway [12], and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) [13]. Although less explored, network activity also seems to be critical for the neurogenic effects of antidepressants [3]. Local hippocampal activity has been shown to affect adult hippocampal neurogenesis at different phases, from cell proliferation to cell maturation and integration [14,15,16]. However, the possibility that antidepressant effects on adult hippocampal neurogenesis are influenced by the concerted action of other brain regions has not been, to our knowledge, as yet explored. The amygdala appears to be an excellent candidate to modulate antidepressant-related hippocampal neurogenesis. Substantial evidence indicates that the amygdala is a site of action of antidepressants [17,18,19,20,21,22]. Selective serotonin reuptake inhibitors (SSRI) antidepressant treatment was shown to modulate amygdala responses directly in humans without requiring a clinical change in mood or initial amygdala pathology, while diminishing the perception of fear [23,24]. In depressed subjects, decreased amygdala volume [25] and increased amygdala response to masked emotional faces [26,27] were normalized after chronic antidepressant (in particular, SSRI) treatment. In rodents, SSRI treatment resulted in reduced levels of fear conditioning, which depends critically on amygdala function [28]. In addition to its well known role in the mediation of emotions [29,30], the amygdala [particularly its basolateral division (BLA)] has been critically implicated in the emotional potentiation of memory by facilitating information processing and storage in other structures, notably the hippocampus [31,32,33]. Moreover, activation of the BLA was shown to regulate neural plasticity in the DG [34,35], the former being also associated with stress-induced deficits in PLoS ONE | www.plosone.org 1 January 2010 | Volume 5 | Issue 1 | e8618