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

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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Available from: Paul M Plotsky, Sep 28, 2015
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    • "Due to a long term of perinatal mother-infant interaction in mammals, the growth and development of offspring are likely to be impacted by maternal influences, with psychological and physiological health left as long-term consequences (Simpson and Kelly, 2011). Convincingly, prenatal stress has been demonstrated able to affect pregnancy outcome and lead to early programming of brain functions leaving permanent changes in neuroendocrine regulation, gene expression and behavior of offspring in animal experiments (Gao et al., 2011; Belay et al., 2011; Gardner et al., 2009). "
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    ABSTRACT: Prenatal environmental enrichment (EE) has been proven to positively affect but prenatal stress negatively influence the physiological and psychological processes in animals, whose trans-generational genetic mechanism remains unclearly defined. We aimed to investigate and find out key genes underlying the positive-negative effects derived from prenatal interventions. Pregnant rats were randomized into EE group (EEG), earthquake simulation group (ESG), herbal group (HG) received herbal supplements in feed after earthquake simulation, and control group (CG). Light Box Defecation Test (LBDT) showed EEG offspring presented less fecal pellets than CG offspring, ESG's more than CG's, and HG's less than ESG (p's<0.05). Open-field Test (OFT) score of EEG was higher than CG offspring, of ESG's was lower than CG's, and HG's higher than ESG's. Irf7 and Ninj were screened, which were up-regulated in EEG, down-regulated in ESG (FC<0.5), and were neutralized in HG. Prenatal EE could positively promote the nervous system development, prenatal earthquake simulation could retard the nervous system development and Chinese herbal remedy (JKSQW) which could correct the retardation. The negative-positive prenatal effect could contribute to altered gene expression of Irf7 and Ninj2 which also could play a key role in the improving function of JKSQW for the kidneys.
    African Journal of Traditional, Complementary and Alternative Medicines 07/2014; 11(2):367-76. DOI:10.4314/ajtcam.v11i2.24 · 0.56 Impact Factor
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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.
    Journal of Neurochemistry 10/2012; 123(6). DOI:10.1111/jnc.12055 · 4.28 Impact Factor
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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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