Article

Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
Brain research (Impact Factor: 2.83). 09/2009; 1305:47-63. DOI: 10.1016/j.brainres.2009.09.065
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ABSTRACT 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.
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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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    • "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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