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• W2103704610 abstract "Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways. Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways. Instinctive and learned fear are essential for survival and are evolutionarily conserved in organisms ranging from simple invertebrates to mammals. In humans, pathological forms of learned fear are hallmarks of severe psychopathologies such as anxiety disorders, posttraumatic stress disorders, and depression. The fact that fear can be enhanced through learning and can become a symptom of psychopathology in humans suggests that this form of learning may not always be appropriate and might, in certain situations, lead to unfavorable consequences. Therefore, it seems likely that effective inhibitory constraints exist that prevent the inappropriate expression of learned fear. In search for such a mechanism, Robert Rescorla extended the early work of Ivan Pavlov and delineated “conditioned inhibition” as a learning paradigm whereby a neutral CS develops the ability to inhibit responses to learned predictors of aversive or rewarding stimuli (Pavlov, 1927Pavlov I.P. Conditioned Reflexes. Dover, New York1927Google Scholar, Rescorla, 1969Rescorla R.A. Conditioned inhibition of fear resulting from negative CS-US contingencies.J. Comp. Physiol. Psychol. 1969; 67: 504-509Crossref PubMed Scopus (133) Google Scholar). Fear conditioning results from a positive correlation (pairing) of a previously neutral CS and an aversive US. During conditioned inhibition, by contrast, a CS that is negatively correlated (explicitly unpaired) with an aversive US becomes a positive signal (predictor) for safety and reduces the expression of conditioned fear. Since the animal associates the target signal with protection from an impending aversive event, conditioned inhibition has been thought to represent a form of learned safety, a process by which the animal learns to take advantage of sources of safety and security in the environment (Candido et al., 2004Candido A. Gonzalez F. de Brugada I. Safety signals from avoidance learning but not from yoked classical conditioning training pass both summation and retardation tests for inhibition.Behav. Processes. 2004; 66: 153-160Crossref PubMed Scopus (19) Google Scholar, Dinsmoor, 2001Dinsmoor J.A. Stimuli inevitably generated by behavior that avoids electric shock are inherently reinforcing.J. Exp. Anal. Behav. 2001; 75: 311-333Crossref PubMed Scopus (114) Google Scholar, Wiertelak et al., 1992Wiertelak E.P. Maier S.F. Watkins L.R. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia.Science. 1992; 256: 830-833Crossref PubMed Scopus (116) Google Scholar). The term “safety signal” generally refers to a stimulus that is inversely or negatively correlated to an aversive event (Candido et al., 2004Candido A. Gonzalez F. de Brugada I. Safety signals from avoidance learning but not from yoked classical conditioning training pass both summation and retardation tests for inhibition.Behav. Processes. 2004; 66: 153-160Crossref PubMed Scopus (19) Google Scholar). In our previous study, we referred to learned safety as the learning and memory resulting from a conditioned inhibition training procedure (Rogan et al., 2005Rogan M.T. Leon K.S. Perez D.L. Kandel E.R. Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse.Neuron. 2005; 46: 309-320Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). We here attempt to first characterize some of the behavioral consequences of learned safety and then to go on to explore it at the molecular level. The ability to identify events that afford relief from ongoing strain is thought to be crucial for the prevention of chronic stress, a precipitating factor for the development of anxiety disorders and depression (Chan et al., 2001Chan K.H. Morell J.R. Jarrard L.E. Davidson T.L. Reconsideration of the role of the hippocampus in learned inhibition.Behav. Brain Res. 2001; 119: 111-130Crossref PubMed Scopus (87) Google Scholar, Davis and Shi, 1999Davis M. Shi C. The extended amygdala: are the central nucleus of the amygdala and the bed nucleus of the stria terminalis differentially involved in fear versus anxiety?.Ann. N Y Acad. Sci. 1999; 877: 281-291Crossref PubMed Scopus (263) Google Scholar, LeDoux, 1993LeDoux J.E. Emotional memory: in search of systems and synapses.Ann. N Y Acad. Sci. 1993; 702: 149-157Crossref PubMed Scopus (149) Google Scholar, Rogan et al., 2001Rogan M.T. Weisskopf M.G. Huang Y.Y. Kandel E.R. Le Doux J.E. Long-term potentiation in the amygdala: Implications for memory.in: Holscher C. Neural Mechanisms of Memory Formation: Concepts of Long-Term Potention and Beyond. Cambridge University Press, Cambridge2001: 58-76Google Scholar). This led us to investigate whether learned safety, as a predictor of a break from continuously imminent, stress-producing danger, may have antidepressant effects. We tested this idea in mice using the forced-swim test and the unpredictable chronic mild stress (UCMS) paradigm. We then assessed whether learned safety could also share some major neuronal characteristics of pharmacological antidepressant treatments, specifically modulation of neurogenesis and the expression of BDNF in the dentate gyrus of the hippocampus (Warner-Schmidt and Duman, 2006Warner-Schmidt J.L. Duman R.S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment.Hippocampus. 2006; 16: 239-249Crossref PubMed Scopus (610) Google Scholar, Dranovsky and Hen, 2006Dranovsky A. Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants.Biol. Psychiatry. 2006; 59: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, Malberg and Duman, 2003Malberg J.E. Duman R.S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment.Neuropsychopharmacology. 2003; 28: 1562-1571Crossref PubMed Scopus (658) Google Scholar). The amygdala is a key structure for the pathogenesis of the dominant emotional symptoms in major depression. To examine the molecular mechanisms contributing to learned safety using Affymetrix high-density oligonucleotide arrays, we focused on the basolateral nucleus, the subregion of the amygdala where we have previously described distinct electrophysiological features of learned safety (Rogan et al., 2005Rogan M.T. Leon K.S. Perez D.L. Kandel E.R. Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse.Neuron. 2005; 46: 309-320Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Safety conditioning is carried out over 3 days, one session per day, and comprises a simple conditioned inhibition of fear paradigm consisting of several explicitly unpaired presentations of the aversive US and the tone CS (see Figure 1A). After safety training, freezing (the endogenous defense response of rodents) to the experimental context in the presence of the CS is significantly reduced in safety-trained mice and significantly increased in fear-conditioned mice, while remaining unchanged in tone controls (Figure 1B). This observation provides evidence for summation, one of the two defining criteria of a conditioned inhibitor (Rescorla, 1971Rescorla R.A. Summation and retardation tests of latent inhibition.J. Comp. Physiol. Psychol. 1971; 75: 77-81Crossref PubMed Scopus (155) Google Scholar). The second test that a true conditioned inhibitor needs to pass is retardation. Indeed, we found that, when mice were fear conditioned to the same CS used beforehand in safety training, they do not show freezing to the tone after 1 day of fear training (Figure 1C). However, with an additional day of fear training, previously safety-conditioned animals also learn to freeze to the CS (Figure 1D). To further rule out nonspecific excitatory effects of the safety signal, we tested whether a different tone (CS∗) that has not been explicitly unpaired with the US would reduce freezing to the context in the memory recall test. We found that the CS, but not the CS∗, reduced contextual freezing in safety-trained mice (Figure 1E). Using a within-subject control design, we tested whether the presence of the conditioned stimulus would act to modulate behavioral measures associated with reduced anxiety in the elevated plus maze. We found significantly increased numbers of open arm entries in safety-conditioned mice in the presence of the CS (Figure 2A). Closed arm entries were significantly decreased in safety-conditioned mice and increased in fear-conditioned mice during delivery of the CS (Figure 2B). Moreover, safety-conditioned mice spent significantly more time in the open arms in the CS than in the no-CS period, whereas the opposite effect was observed in fear-conditioned mice (Figure 2C). Immobility in the forced-swim test, interpreted as a form of behavioral despair, was significantly reduced in safety-conditioned mice in the presence of the safety signal (Figure 3A). We then evaluated, in safety-trained mice, the effect of fluoxetine on immobility in the forced-swim test, in order to validate the antidepressant activity of the safety signal with respect to a widely used pharmacological antidepressant. Vehicle- and fluoxetine-treated mice were either exposed to the safety signal during the forced-swim test (CS groups) or served as control (no-CS groups). We found that the percentage of time spent immobile in the vehicle-treated CS group and the fluoxetine-treated no-CS group was not different, suggesting that the reduction in immobility induced by the safety signal is comparable to the effect seen with the antidepressant fluoxetine. Immobility was even further decreased in the presence of the safety signal in fluoxetine-treated safety-trained mice (Figure 3B). (A) Immobility in the presence of the CS (n = 10 per group) (main effect of phase of testing F(1,30) = 10.076: p < 0.01; interaction between phase of testing and type of training F(1,30) = 27.243: p < 0.001). Tukey-Kramer post hoc test for type of training (CS phase): safety versus tone p < 0.05 and versus fear p < 0.001; fear versus tone p > 0.05). “CS effect” (learned safety, p < 0.001; learned fear and tone alone, p > 0.05). (B) Immobility during the CS delivery period and the corresponding time period in the no-CS groups (n = 8–9 per group) in fluoxetine- and vehicle-treated groups (main effect of phase of testing F(1,33) = 61.190: p < 0.001; main effect of drug F(1,33) = 154.928: p < 0.001; main effect of CS delivery F(1,33) = 32.696: p < 0.001); effect of interaction between phase of testing and drug F(1,33) = 3.859: p < 0.05; effect of interaction between phase of testing and CS delivery F(1,33) = 142.242: p < 0.001; effect of interaction between phase of testing and drug and CS delivery F(1,33) = 5.791: p < 0.05. “CS effect” (vehicle CS and fluoxetine CS, p < 0.001; vehicle no-CS and fluoxetine no-CS, p > 0.05). Student's t test between CS phases of vehicle CS and fluoxetine no-CS p > 0.05. (C) Safety response in the memory recall test following 4 weeks of unpredictable chronic mild stress (UCMS) (n = 9–10 per group) (main effect of phase of testing F(1,19) = 135.903: p < 0.001; effect of interaction with UCMS exposure F(1,19) = 10.057: p < 0.01). “CS effect” (learned safety unstressed and learned safety UCMS: p < 0.001). Student's t test between CS phases of learned safety unstressed and learned safety UCMS p < 0.05). (D) Sucrose preference 24 hr after the last day of training (values above 50% [horizontal line] indicate sucrose preference above chance) in the presence of the CS (n = 7 per group) (main effect of UCMS exposure F(1,28) = 20.085: p < 0.001; main effect of type of training F(1,28) = 5.356: p < 0.05; effect of interaction between UCMS exposure and type of training F(1,28) = 6.663: p < 0.05). Tukey-Kramer post hoc test: tone control UCMS versus all other groups: p < 0.01). Data are depicted as mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.0001, n.s. (not significant) p > 0.05. We found that a 4 week exposure to unpredictable chronic mild stress induced a significantly increased response for learned safety in the memory recall test (Figure 3C). The depressive state induced by UCMS is associated with anhedonic behavior that can be assessed in the sucrose preference test. As expected, all mice showed abolished sucrose preference following UCMS treatment. In UCMS-treated safety-trained mice, sucrose preference was restored to levels of unstressed controls when assessed in the presence of the safety signal. The safety signal had no effect on sucrose preference in tone-alone controls (Figure 3D). To determine whether safety learning has an effect on adult-generated hippocampal neurons, we examined the number and the fate of newborn cells using labeling with the thymidine analog bromodeoxyuridine (BrdU). We employed two paradigms: the “survival paradigm” and the “proliferation paradigm” (Figure 4A) (Gould et al., 1999Gould E. Beylin A. Tanapat P. Reeves A. Shors T.J. Learning enhances adult neurogenesis in the hippocampal formation.Nat. Neurosci. 1999; 2: 260-265Crossref PubMed Scopus (1708) Google Scholar, Malberg et al., 2000Malberg J.E. Eisch A.J. Nestler E.J. Duman R.S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.J. Neurosci. 2000; 20: 9104-9110Crossref PubMed Google Scholar). We found that learned safety significantly enhanced the number of newborn cells surviving 2 weeks after BrdU administration (Figures 4B–4E). Results from the proliferation paradigm indicate that learned safety did not affect the rate of neurogenesis. We used x-irradiation of the dentate gyrus to ablate hippocampal neurogenesis in mice and verified the absence of newly generated cells by doublecortin immunohistochemistry (a marker for neurons younger than 1 month of age) 6 weeks later (Figure S1 available online). We then tested the effect of ablated hippocampal neurogenesis on learned safety and found that x-irradiated mice showed no evidence of safety learning after 1 day of training, in contrast to sham-irradiated control mice (Figure 5A). However, after an additional 2 days of training, both x-irradiated and sham mice displayed significant reduction of contextual freezing when exposed to the safety signal (Figure 5B). In contrast to learned safety, fear conditioning was not affected by ablation of hippocampal neurogenesis on either day. When evaluating the potential of learned safety to reduce depression-like behaviors, we found that safety trained x-irradiated mice did not show reduced immobility in the presence of the safety signal, which was observed in the controls (Figure 5C). Moreover, UCMS-induced enhancement of the safety response was absent (Figure 5D), and the ability of learned safety to rescue the UCMS-induced reduction of sucrose preference was abolished in x-irradiated safety-trained mice (Figure 5E). BDNF is known to be induced by antidepressant treatment in the hippocampus, particularly in the dentate gyrus (Nibuya et al., 1995Nibuya M. Morinobu S. Duman R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.J. Neurosci. 1995; 15: 7539-7547Crossref PubMed Google Scholar, Russo-Neustadt et al., 2004Russo-Neustadt A.A. Alejandre H. Garcia C. Ivy A.S. Chen M.J. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise.Neuropsychopharmacology. 2004; 29: 2189-2199Crossref PubMed Scopus (144) Google Scholar), and could be responsible for the increase in and survival of hippocampal neurons following antidepressant drug treatment (Duman, 2004aDuman R.S. Depression: a case of neuronal life and death?.Biol. Psychiatry. 2004; 56: 140-145Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar, Duman, 2004bDuman R.S. Role of neurotrophic factors in the etiology and treatment of mood disorders.Neuromolecular Med. 2004; 5: 11-25Crossref PubMed Google Scholar). This led us to analyze the expression of BDNF in the dentate gyrus in mice following safety and fear training together with tone-alone controls. Using immunohistochemical analysis, we found increased BDNF expression in safety-conditioned mice, whereas the expression of BDNF in fear-conditioned mice was reduced as compared to tone-alone controls (Figure 6). To characterize the molecular mechanisms involved in safety learning, we searched for genes whose mRNAs were differentially regulated in safety- and fear-conditioned mice in the basolateral nucleus of the amygdala. We isolated the basolateral nucleus of the amygdala using laser-capture microdissection (LCM), which permits for rigorously controlled and precise isolation of the target nucleus without contamination from surrounding areas (Figure 7A). Using a combination of hypothesis-free and hypothesis-driven approaches, we examined all significant changes (80 specific probe sets) (Figure 7B and Table S1) but thereafter also focused on certain candidate genes that have been implicated in the literature to be involved in stress, anxiety, and depression (Table S2). We found differential regulation of four genes (dopamine D2 receptor, substance P, prodynorphin, and preproenkephalin 1) that have been highly implicated in the response to endogenous and exogenous stressors and depression (McLaughlin et al., 2003McLaughlin J.P. Marton-Popovici M. Chavkin C. Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses.J. Neurosci. 2003; 23: 5674-5683Crossref PubMed Google Scholar, Sinchak et al., 2000Sinchak K. Eckersell C. Quezada V. Norell A. Micevych P. Preproenkephalin mRNA levels are regulated by acute stress and estrogen stimulation.Physiol. Behav. 2000; 69: 425-432Crossref PubMed Scopus (32) Google Scholar). To independently verify the observed changes and to relate them to benchmark values, we carried out RT-PCR analyses for two of these genes—dopamine D2 receptor (D2R) and substance P (SP)—those on which we focused more in subsequent experiments. In addition, RNA isolated from LCM samples of handled-only mice as naive baseline controls was included (Figures 7C and 7D). To evaluate the importance of the gene expression findings in vivo, we examined the effects of blockade of D2R on the memory for learned safety. We found that the treatment with the D2R antagonist sulpiride before the memory recall test led to a significant enhancement of the safety response (Figure 8A). When sulpiride was administered before the training sessions and mice were tested drug free, no effect in either safety- or fear-trained mice was observed (Figure S2A). Application of the D2R agonist quinprinole before the memory recall test (Figure 8B) but not before the training sessions (Figure S2B) abolished the safety response in the memory recall test. Quinprinole treatment did not affect learned fear under either condition. A significant interaction between CS delivery and drug administration was revealed when we trained mice drug free in the learned safety paradigm and administered sulpiride before the forced-swim test. This result suggests that dopaminergic transmission is an important, although not the exclusive, mediator of learned safety (Figure 8C). To determine the importance of Substance P in vivo, we first tested the effect of blockade of the preferred receptor for Substance P, the NK-1 receptor, using L-703,606. We found that the response to the safety CS was not different in L-703,606-treated and vehicle-treated mice in both safety- and fear-conditioned mice when mice were trained drug free and NK-1 receptors were blocked only during the memory recall test (Figure S2C). However, when we trained mice under the influence of L-703,606 and then tested them drug free, we observed a significantly enhanced safety response in L-703,606-treated mice whereas the response to the CS was not altered in fear-conditioned mice. NK-1 inhibition during training did not affect the CS response in the memory recall test (Figure 8D). Application of the NK-1 agonist ([Sar9, Met(O2)11]-Substance P) before the memory recall test did not affect learned safety (Figure S2D). However, when we exposed the animals to the NK-1 agonist before each training session, we observed a reduced safety response during the memory recall test (Figure 8E). The learned fear response was not affected by drug treatment under either condition. Several lines of evidence support an important role of 5-HT1A receptors in depressive illness (Bowen et al., 1989Bowen D.M. Najlerahim A. Procter A.W. Francis P.T. Murphy E. Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life.Proc. Natl. Acad. Sci. USA. 1989; 86: 9504-9508Crossref PubMed Scopus (128) Google Scholar, Drevets et al., 1999Drevets W.C. Frank E. Price J.C. Kupfer D.J. Holt D. Greer P.J. Huang Y. Gautier C. Mathis C. PET imaging of serotonin 1A receptor binding in depression.Biol. Psychiatry. 1999; 46: 1375-1387Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar) and in the response to antidepressants (Li et al., 1998Li D.L. Simmons R.M. Iyengar S. 5HT1A receptor antagonists enhance the functional activity of fluoxetine in a mouse model of feeding.Brain Res. 1998; 781: 119-126Crossref Scopus (17) Google Scholar, Singh and Lucki, 1993Singh A. Lucki I. Antidepressant-like activity of compounds with varying efficacy at 5–HT1A receptors.Neuropharmacology. 1993; 32: 331-340Crossref PubMed Scopus (41) Google Scholar). However, blockade of 5-HT1A receptors affected learned safety neither in the acquisition nor in the memory recall phase (Figures 8F and 8G). We find that learned safety reduces depression-like behavior in mice. Consistent with its behavioral antidepressant effects, learned safety enhances the survival of newborn cells and leads to increased expression of BDNF in the hippocampal dentate gyrus. In the amygdala, learned safety strongly modulates the expression of key components of the dopaminergic and neuropeptidergic system while having no effect on elements of the serotonergic transmission. Learned safety thus exerts its antidepressant activity through cell-biological steps also recruited by conventional, serotonergically based antidepressants but triggers these through different molecular pathways. We produced learned safety by a conditioned inhibition of fear protocol in which the animal learns about a stimulus—the safety signal—that indicates the absence of impending aversive events. We and others have found that the behavioral response triggered by the safety signal can become independent from the context in which it has been acquired and might even be effective to control a different, unconditioned response (Denniston et al., 1998Denniston J.C. Cole R.P. Miller R.R. The role of temporal relationships in the transfer of conditioned inhibition.J. Exp. Psychol. Anim. Behav. Process. 1998; 24: 200-214Crossref PubMed Scopus (26) Google Scholar, Rogan et al., 2005Rogan M.T. Leon K.S. Perez D.L. Kandel E.R. Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse.Neuron. 2005; 46: 309-320Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). We now find that the safety signal in itself contains an autonomous informational content that can be transferred and lead to reduction in unlearned, innate fear in the elevated plus maze. We used two animal models of depression to test the idea that the safety signal may come to indicate a general “relief period” from ongoing stress and thus may counteract depressive states. We found an antidepressant effect in the forced-swim test (similar and in magnitude comparable to pharmacological treatment with fluoxetine) and complemented this result by the rescue of chronic mild stress-induced reduction in sucrose preference by the safety signal, similar to that obtained with pharmacological antidepressants (Gittos and Papp, 2001Gittos M.W. Papp M. Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats.Eur. Neuropsychopharmacol. 2001; 11: 351-357Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, Moreau et al., 1996Moreau J.L. Bos M. Jenck F. Martin J.R. Mortas P. Wichmann J. 5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats.Eur. Neuropsychopharmacol. 1996; 6: 169-175Abstract Full Text PDF PubMed Scopus (107) Google Scholar). Antidepressant pharmacotherapy is more effective in patients with depressive disorders than in healthy controls. The enhancement of the learned safety response in mice, in which a depressive state has been induced by chronic mild stress, resembles this situation in humans and supports learned safety as an animal model of behavioral antidepressant treatment with good face and content validity. Many pharmacological antidepressants and other interventions achieving antidepressant effects increase neurogenesis, whereas, conversely, stress typically reduces neurogenesis (Warner-Schmidt and Duman, 2006Warner-Schmidt J.L. Duman R.S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment.Hippocampus. 2006; 16: 239-249Crossref PubMed Scopus (610) Google Scholar, Dranovsky and Hen, 2006Dranovsky A. Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants.Biol. Psychiatry. 2006; 59: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, Malberg and Duman, 2003Malberg J.E. Duman R.S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment.Neuropsychopharmacology. 2003; 28: 1562-1571Crossref PubMed Scopus (658) Google Scholar). We found that in the “survival paradigm” learned safety enhances the number of BrdU-positive cells in the dentate gyrus 14 days after BrdU labeling. The number of new cells in the dentate gyrus increases between 2 hr and 1 week after DNA synthesis and then declines rapidly by the 2 week time point (Cameron et al., 1993Cameron H.A. Woolley C.S. McEwen B.S. Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat.Neuroscience. 1993; 56: 337-344Crossref PubMed Scopus (1027) Google Scholar). The ability of learned safety to rescue cells that were generated shortly before the training procedure provides a direct link between newborn cells in the adult hippocampus and this behavioral paradigm. These results on neurogenesis add further significance to the behavioral results suggestive of an antidepressant activity of learned safety. The fact that we observed an enhanced survival of those cells that were generated before training but did not observe an effect when BrdU was injected after training suggests that the effect of learned safety on newborn cells may occur only during a specific “sensitive period” following the generation of these cells. Interestingly, it is precisely within this time frame (between 1 and 2 weeks after mitosis) that adult-generated granule cells of the dentate gyrus appear to be forming connections with the CA3 region (Gould et al., 1999Gould E. Beylin A. Tanapat P. Reeves A. Shors T.J. Learning enhances adult neurogenesis in the hippocampal formation.Nat. Neurosci. 1999; 2: 260-265Crossref PubMed Scopus (1708) Google Scholar). Learned safety, thus, may facilitate the integration of these cells into an established circuitry and promote their survival. Another factor potentially contributing to enhanced cell survival following learned safety may be the increased neurotrophic support by BDNF. BDNF has been shown to be regulated by antidepressant and is thought to oppose the effects of stress on neuronal cells (e.g., inhibiting excitotoxic damage, blocking neuronal atrophy, etc.) by helping to" @default.
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• W2103704610 date "2008-10-01" @default.
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• W2103704610 title "An Animal Model of a Behavioral Intervention for Depression" @default.
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• W2103704610 doi "https://doi.org/10.1016/j.neuron.2008.07.041" @default.
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