Abstract
The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.
Highlights
Acute stressors such as unexpected and potentially threatening changes of an individual’s environment usually provoke immediate stress responses to adapt, which are accompanied by and actuating a number of physiological processes [1]
Elevated Plus-maze (EPM) General activity in the Elevated Plus-maze Test (EPM) measured as total number of arm entries and path length differed between WT and KO mice with the latter being less active (Wilcoxon Test, path length: W = 20, P,0.0001, Fig. 1a; total arm entries: W = 31, P = 0.0008)
ANOVA revealed a trend for increased stress hormone concentrations in mice subjected to acute stress (F1,26 = 3.21, P = 0.085) but no effect of genotype (F1,26 = 2.36, P = 0.14) and there was no significant interaction of genotype by stress (F1,26 = 0.68, P = 0.42)
Summary
Acute stressors such as unexpected and potentially threatening changes of an individual’s environment usually provoke immediate stress responses to adapt, which are accompanied by and actuating a number of physiological processes [1]. A key regulator of serotonergic activity in the central nervous system is the serotonin transporter (5-HTT) that has been linked to inappropriate regulation of the stress response, for example in anxiety- and stress-related personality traits and neuropsychiatric disorders [2,3]. The evidence of a connection between mood disorders and genetic variation of the 5-HTT led to the generation of 5-HTT knockout mice with a targeted inactivation of 5-HTT function [11]. This genetic modification led to the identification of fundamental phenotypic changes, ranging from increased anxiety- and depression-related behaviors, gene expression differences to altered dendritic morphology (reviewed by [12]).
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