Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine
Introduction
Major depression is a common mental disorder, however, its pathophysiology remains poorly understood. Stress, the main cause of depression, most severely affects hippocampal formation (McEwen et al., 2012), while hippocampal subgranular zone (SGZ) of the dentate gyrus (DG) is a region where new neurons originate throughout mammalian adulthood. Moreover, stress leads to significant decrease of adult neurogenesis (for review see Warner-Schmidt and Duman, 2006), implicating a role of this decrease in the onset of depression-like symptoms, however, this notion remains controversial (for reviews see Sahay and Hen, 2007, Balu and Lucki, 2009, Eisch and Petrik, 2012).
Hippocampal neurogenesis has also been proposed as a crucial process involved in the therapeutic efficacy of chronic antidepressants (ADs) treatment (e.g., Santarelli et al., 2003). This hypothesis is supported by the fact that recovery from depression requires several weeks – the timescale that overlaps with the time-course of AD-stimulated neurogenesis and is also paralleled with the time needed for differentiation and incorporation of newborn neurons into existing neuronal hippocampal networks (Sahay and Hen, 2007, Balu and Lucki, 2009). Moreover, majority of the antidepressant approaches elevate neurogenesis by increasing proliferation rate and/or by enhancing newborn cells survival (for review see Samuels and Hen, 2011). Indeed, it was shown that animals with blocked adult neurogenesis do not recover from depression-like behavior when chronically administered with ADs (Santarelli et al., 2003, Surget et al., 2008, David et al., 2009, Onksen et al., 2011, Perera et al., 2011). However, recent studies suggest both neurogenesis-dependent and independent mechanisms underlying ADs action, as more studies show none or only partial effect of reducing neurogenesis on restoration of behavioral homeostasis by ADs (Meshi et al., 2006, David et al., 2007, Holick et al., 2008, Surget et al., 2008, Bessa et al., 2009a, David et al., 2009, Singer et al., 2009, Nollet et al., 2012).
Herein, we have employed cyclin D2 knockout (cD2 KO) mice showing lack of adult brain neurogenesis. We showed before that mice with mutated cyclin D2 gene display largely impaired proliferation of neuronal precursors in SGZ (Kowalczyk et al., 2004, Jaholkowski et al., 2009, Jedynak et al., 2012). Notably, cyclin D2 mutant mice show deficits in some hippocampal-dependent behaviors (Jedynak et al., 2012), but not in learning in general (Jaholkowski et al., 2009, Jedynak et al., 2012, Urbach et al., 2013), while selected cognitive functions are impaired (Ben Abdallah et al., 2013, Garthe et al., 2014).
In the present study, we set out to test the reaction of cD2 KO mice to chronic fluoxetine administration following chronic stress. We have chosen unpredictable chronic mild stress (UCMS) as known to cause ADs-reversible behavioral changes in rodents that parallel symptoms of major depression (Willner, 2005). This paradigm was also used in the original study suggesting a causal link between ADs efficacy and adult neurogenesis (Santarelli et al., 2003). Also, we have chosen forced swim test (FST) as one of the most widely used test of ADs action (Petit-Demouliere et al., 2005, Krishnan and Nestler, 2011), which results in reduced immobility following their acute (Porsolt et al., 1977a, Porsolt et al., 1977b) and chronic delivery (e.g., Detke et al., 1997, Dulawa et al., 2004, Holick et al., 2008, Lin and Wang, 2014) as well as in reversal of increased immobility following UCMS (Willner, 2005). Finally, we have used fluoxetine as most commonly used AD in adult neurogenesis-depression studies, e.g., in the original Santarelli et al. (2003) publication.
Section snippets
General experimental design
A cohort of animals (cD2 KO, n = 30; WT, n = 30) was subjected to unpredictable chronic mild stress (UCMS) and chronically administered with fluoxetine. When stress and fluoxetine administration ended, all animals were tested behaviorally in the forced swim test (FST) and cell proliferation was assessed in DG using bromodeoxyuridine (BrdU) injection and immunocytochemistry. There was also an open field control test performed 24 h after the last fluoxetine administration. The overall design of
Mutant cD2 KO mice did not show increased immobility
Basal depression-like behavior, behavioral response to UCMS as well as chronic fluoxetine treatment were assessed in FST (Fig. 2A). Two-way ANOVA of no stress and stress-vehicle groups revealed effect of both the stress (p < 0.001, F(1,39) = 24.0) and genotype (p < 0.01, F(1,39) = 9.3). The latter effect was confirmed by one-way ANOVA: cD2 KO mice showed decreased time [%] spent immobile compared to WT animals (cD2 KO mice, 38.6 ± 3.4; WT mice, 51.5 ± 3.5; F(1,19) = 6.9, p < 0.05). We further
Discussion
Despite numerous publications, the exact function of new neurons in the etiology and treatment of mood disorders remains elusive. In the present study, we used cD2 KO mice with ablated adult neurogenesis to investigate the role of this process in ADs action. We have found that fluoxetine treatment was efficient in the FST independently of the presence of newborn cells in the SGZ of mice. These data suggest that neurogenesis-independent mechanisms underlie, at least in some specific
Conflict of interest
All authors declare that they have no conflicts of interest.
Contributors
LK, RKF, and PJ designed the study. TK and CS introduced FST and UCMS techniques, respectively, into the laboratory. PJ performed the experiments and undertook the statistical analysis. PJ and RKF wrote the manuscript and prepared the figures. All authors contributed to and have approved the final manuscript.
Role of funding sources
This work was supported by the European Union structural funds Innovative Economy Operational Program, project no. POIG.01.01.02-00-109/09 and by statutory funds of the University of Finance and Management in Warsaw. PJ was supported by FEBS Short-Term Collaborative Experimental Scholarship for Central & Eastern Europe. The funding sources had no role in the study design; collection, analysis or interpretation of data; writing of the report; or decision to submit the paper for publication.
Acknowledgments
None.
References (54)
- et al.
Adult hippocampal neurogenesis: regulation, functional implications, and contribution to disease pathology
Neurosci Biobehav Rev
(2009) - et al.
Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice
Behav Brain Res
(2013) - et al.
Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression
Neuron
(2009) - et al.
Lack of cyclin D2 impairing adult brain neurogenesis alters hippocampal-dependent behavioral tasks without reducing learning ability
Behav Brain Res
(2012) - et al.
Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats
Behav Brain Res
(2014) - et al.
Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress
Neuropharmacology
(2012) - et al.
Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta
Neuroscience
(2008) - et al.
Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal
Biol Psychiat
(2008) - et al.
Hypogonadism predisposes males to the development of behavioural and neuroplastic depressive phenotypes
Psychoneuroendocrinology
(2011) - et al.
LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats
Prog Neuropsychopharmacol Biol Psychiatry
(2011)
The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling
Mol Psychiatr
A trans-dimensional approach to the behavioral aspects of depression
Front Behav Neurosci
Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations
Stress
Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments
Hippocampus
Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat
PloS One
Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors
Mol Psychiatr
Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-m ethylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis
J Pharmacol Exp Ther
Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression
Exp Clin Psychopharm
Effects of chronic fluoxetine in animal models of anxiety and depression
Neuropsychopharmacol
Depression and hippocampal neurogenesis: a road to remission?
Science
Neurogenic evangelism: comment on Urbach et al. (2013)
Behav Neurosci
Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits
Genes Brain Behav
Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3beta/beta-catenin signaling
Mol Psychiatr
Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor
Neuropsychopharmacology
New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning
Learn Mem
Increased ethanol intake and preference in cyclin D2 knockout mice
Genes Brain Behav
Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus
Brit J Pharmacol
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