Effect of Acute Stressor and Serotonin Transporter Genotype on Amygdala First Wave Transcriptome in Mice

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.

5-HTT Deficiency Affects Neuroplasticity and Increases Stress Sensitivity Resulting in Altered Spatial Learning Performance in the Morris Water Maze but Not in the Barnes Maze

“…Thus, floating in the WM could reflect a state of despair indicating that 5-HTT-/- mice gave up active coping with the challenging situation earlier than both other genotypes. This is in line with a recent study with 5-HTT deficient mice suggesting that different coping styles of stressor processing seemed dependent upon the availability of 5-HTT protein [26]. …”

“…This lifelong reduced or absent 5-HTT function is associated with many changes at the neurochemical level such as the compensatory increased expression of the organic cationic transporter 3 in the hippocampus of 5-HTT-/- mice and various neuroplasticity phenomena such as higher spinogenesis in the amygdala of 5-HTT-/- compared to 5-HTT+/+ mice [18-22], for review see 23,24. In addition to differential gene expression of undisturbed 5-HTT-/- mice both genotypes also react differently to acute stress: While 5-HTT+/+ mice immediately after being exposed to forced swimming for one minute were found to express genes in the amygdala that are related to neuroplasticity and adaptation to stressors 5-HTT-/- express genes more related to chronic stress and pathophysiology [25,26]. Furthermore, 5-HTT deficient mice exhibit a changed behavioral phenotype, especially regarding increased anxiety- and depression-like behavior [5,15,24,27-29].…”

“…A brain region-specific increase of cFos expression is rapidly induced following various types of stimulations such as exercise [23,24], electroconvulsive seizures [25,26] the exposure to physical and psychological stressors [5,15,24,27-29], or spatial exploration and the consolidation of recognition memory [5,30-34], only to name a few. Moreover, cFos expression can be modulated by different drug classes such as anxiolytics and antidepressants as well as hormones (e.g., glucocorticoids) and neurotrophins [35-42].…”

Serotonin and stress coping

“…5-HTT variants have been shown to modulate the response to stress in humans or in mice in terms of behavior and gene expression in specific brain areas [33,[76][77][78][79].…”

Interação genético-ambiental nos estados depressivos periparto

“…Com esta falha de modulação, mulheres carreadoras de dois braços curtos apresentam uma associação positiva entre sintomas ansiosos e o tamanho da amigdala, enquanto a relação entre sintomas ansiosos e tamanho da amigdala é inversa em portadoras de braços longos (Cerasa et al, 2013). Animais com alterações neste polimorfismo específico apresentam alterações na sinalização, expressão e função do receptor de serotonina, tornando a recaptação de serotonina menos eficiente (Caspi et al, 2010;Hohoff et al, 2013;Beach et al, 2014;Wankerl et al, 2014;Duman e Canli, 2015). Além disso, quando submetidos a ambientes estressores, demonstram modificações na expressão de genes que codificam receptores mineralocorticoides e glicocorticoides (Van Der Doelen, Calabrese, et al, 2014).…”