Abstract
Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague–Dawley rats were subjected to MS for 3 h daily during postnatal days 2–12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11–13 weeks) brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood.
Highlights
In the early postnatal period of the rat, the brain is thought to be a developmental equivalent to the last trimester in utero and the perinatal period of human brain development (Romijn et al, 1991; Watson et al, 2006; Goodfellow et al, 2009), allowing for the use of postnatal rodent models in the investigation of the early programing of stress-related psychiatric disorders
5-HT1A RECEPTOR mRNA EXPRESSION Early-life stress significantly increased the levels of 5-HT1A receptor mRNA in the basomedial amygdala (BMA; Figure 1A; NS vs. maternal separation (MS): 10.39 ± 0.49 vs. 13.58 ± 0.36; t(10) = 5.226, p < 0.001), basolateral amygdala (BLA; Figure 1B; NS vs. MS: 4.27 ± 0.18 vs. 5.55 ± 0.33; t(10) = 3.373, p < 0.01) and central amygdala (CeA; Figure 1C; NS vs. MS: 3.35 ± 0.14 vs. 4.86 ± 0.51; t(10) = 2.838, p < 0.05), and decreased the expression of this transcript in the dorsal raphé nucleus (DRN) (Figure 2A; NS vs. MS: 25.85 ± 1.49 vs. 18.87 ± 1.1; t(10) = 3.804, p < 0.01) when compared to NS controls
Similar alterations have been described for another neurotransmitter system (Bravo et al, 2010), which further suggest that early-life stress does affects central nervous system (CNS) function
Summary
In the early postnatal period of the rat, the brain is thought to be a developmental equivalent to the last trimester in utero and the perinatal period of human brain development (Romijn et al, 1991; Watson et al, 2006; Goodfellow et al, 2009), allowing for the use of postnatal rodent models in the investigation of the early programing of stress-related psychiatric disorders. There are 14 types of 5-HT receptors, divided into seven families, with different subtypes identified by letters (A–F in the case of 5-HT1 receptors; Hoyer et al, 1994; Barnes and Sharp, 1999; Bockaert et al, 2010) One of these receptors is 5-HT1A, a G protein-coupled receptor that has been described to play an important role in the development of psychiatric disorders (Bowen et al, 1989; López et al, 1998; Drevets et al, 1999; Gross et al, 2002; Savitz et al, 2009). 5-HT1A receptor expression has been described in forebrain areas (Chalmers and Watson, 1991; Pompeiano et al, 1992; Cryan et al, 2005; Savitz et al, 2009) including the hippocampus and amygdala, structures involved in learning, control of emotions, memory and fear related information (Vizi and Kiss, 1998; Nestler et al, 2002; LeDoux, 2007)
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