Gardner KL, Hale MW, Lightman SL, Plotsky PM, Lowry CA. Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. Brain Res 1305: 47-63

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
Brain research (Impact Factor: 2.84). 09/2009; 1305:47-63. DOI: 10.1016/j.brainres.2009.09.065
Source: PubMed


Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of serotonergic systems in the brain. To evaluate the effects of early life experience, adverse experiences during adulthood, and potential interactions between these factors on serotonin transporter (slc6a4) mRNA expression, we investigated in rats the effects of maternal separation (180 min/day from days 2 to 14 of life; MS180), neonatal handing (15 min/day from days 2 to 14 of life; MS15), or normal animal facility rearing (AFR) control conditions with or without subsequent exposure to adult social defeat on slc6a4 mRNA expression in the dorsal raphe nucleus (DR) and caudal linear nucleus. At the level of specific subdivisions of the DR, there were no differences in slc6a4 mRNA expression between MS15 and AFR rats. Among rats exposed to a novel cage control condition, increased slc6a4 mRNA expression was observed in the dorsal part of the DR in MS180 rats, relative to AFR control rats. In contrast, MS180 rats exposed to social defeat as adults had increased slc6a4 mRNA expression throughout the DR compared to both MS15 and AFR controls. Social defeat increased slc6a4 mRNA expression, but only in MS180 rats and only in the "lateral wings" of the DR. Overall these data demonstrate that early life experience and stressful experience during adulthood interact to determine slc6a4 mRNA expression. These data support the hypothesis that early life experience and major stressful life events contribute to dysregulation of serotonergic systems in stress-related neuropsychiatric disorders.

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    • "This indicates that CORT released during chronic stress plays a large role for the up-regulated SERT protein levels in the DRN. This is consistent with other animal studies reported previously (Pare et al. 1999; Filipenko et al. 2002; Gardner et al. 2009). So far, we do not have satisfactory explanation for the mechanism underlying CORT-induced up-regulation of SERT proteins in the DRN. "
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    ABSTRACT: Chronic stress and dysfunction of the serotonergic system in the brain have been considered as two of the major risks for development of depression. In the present study, adult Fischer 344 rats were subjected to a regimen of chronic social defeat (CSD). To mimic stressful conditions some rats were not exposed to CSD but instead treated with corticosterone (CORT) in oral solution while maintained in their home cage. Protein levels of the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN), hippocampus, frontal cortex and amygdala were examined by western blotting or immunofluorescence staining. The results showed that CSD up-regulated SERT protein levels in the DRN, hippocampus, frontal cortex and amygdala regions. This upregulation was abolished or prevented by adrenalectomy, or treatment with antagonists of corticosteroid receptors mifepristone and spironolactone, alone or in combination. Similarly, up-regulated SERT protein levels in these brain regions were also observed in rats treated with oral CORT ingestion, which was analogously prevented by treatment with mifepristone and spironolactone. Furthermore, both CSD- and CORT-induced upregulation of SERT protein levels in the DRN and three brain regions were attenuated by simultaneous treatment with fluoxetine, an antidepressant that specifically inhibits serotonin reuptake. The results indicate that upregulation in SERT protein levels in the DRN and forebrain limbic structures caused by CSD regimen was mainly motivated by CORT through corticosteroid receptors. The present findings demonstrate that chronic stress is closely correlated with the serotonergic system by acting on the regulation of the SERT expression in the DRN and its projection regions, which may contribute to the development of depression. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12055.
    Full-text · Article · Oct 2012 · Journal of Neurochemistry
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    • "Moreover, humans with one or two copies of the short 5-HTTLPR allele have been reported to exhibit more depressive symptoms and suicidality than individuals homozygous for the high expressing long allele, but only in consequence of stressful life events [39] [40] (but see [41]). Recently, it was documented that an interaction between adverse early life experience and a stressful social defeat encounter during adulthood in rats increased 5-Htt mRNA expression in subpopulations of serotonergic dorsal raphe neurons [31]. The findings support the hypothesis that stressful life events and genetic dispositions contribute to dysregulation of the serotonergic system, possibly via inducing alterations in 5-Htt expression, and, in humans, interact in enhancing vulnerability to stress-related psychiatric disorders [28]. "
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    ABSTRACT: Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype-dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi-Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice.
    Full-text · Article · Jun 2011 · Behavioural brain research
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    • "These data are consistent with the effects of inescapable shock on caudal DRN activation; however, in hamsters, social defeat selectively increases c-Fos expression in rostral portions of the ventral DRN (Cooper et al., 2009). Similarly, social defeat interacts with maternal separation in rats to increase tryptophan hydroxylase mRNA (Gardner et al., 2009b) and serotonin transporter mRNA (Gardner et al., 2009a) in rostral portions of the ventral DRN. Although the mid and caudal DRN are well-known for reciprocal connections with limbic structures, the rostral DRN may also have connections with the amygdala and BNST (Commons et al., 2003; Imai et al., 1986; Rizvi et al., 1991). "
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    ABSTRACT: Exposure to traumatic events can increase the risk for major depressive disorder (MDD) as well as posttraumatic stress disorder (PTSD), and pharmacological treatments for these disorders often involve the modulation of serotonergic (5-HT) systems. Several behavioral paradigms in rodents produce changes in behavior that resemble symptoms of MDD and these behavioral changes are sensitive to antidepressant treatments. Here we review two animal models in which MDD-like behavioral changes are elicited by exposure to an acute traumatic event during adulthood, learned helplessness (LH) and conditioned defeat. In LH, exposure of rats to inescapable, but not escapable, tailshock produces a constellation of behavioral changes that include deficits in fight/flight responding and enhanced anxiety-like behavior. In conditioned defeat, exposure of Syrian hamsters to a social defeat by a more aggressive animal leads to a loss of territorial aggression and an increase in submissive and defensive behaviors in subsequent encounters with non-aggressive conspecifics. Investigations into the neural substrates that control LH and conditioned defeat revealed that increased 5-HT activity in the dorsal raphe nucleus (DRN) is critical for both models. Other key brain regions that regulate the acquisition and/or expression of behavior in these two paradigms include the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this review, we compare and contrast the role of each of these neural structures in mediating LH and conditioned defeat, and discuss the relevance of these data in developing a better understanding of the mechanisms underlying trauma-related depression. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
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