Serotonin transporter genotype modulates resting state and predator stress-induced amygdala perfusion in mice in a sex-dependent manner

Abstract

The serotonin transporter (5-HTT) is a key molecule of serotoninergic neurotransmission and target of many anxiolytics and antidepressants. In humans, 5-HTT gene variants resulting in lower expression levels are associated with behavioral traits of anxiety. Furthermore, functional magnetic resonance imaging (fMRI) studies reported increased cerebral blood flow (CBF) during resting state (RS) and amygdala hyperreactivity. 5-HTT deficient mice as an established animal model for anxiety disorders seem to be well suited for investigating amygdala (re-)activity in an fMRI study. We investigated wildtype (5-HTT+/+), heterozygous (5-HTT+/-), and homozygous 5-HTT-knockout mice (5-HTT-/-) of both sexes in an ultra-high-field 17.6 Tesla magnetic resonance scanner. CBF was measured with continuous arterial spin labeling during RS, stimulation state (SS; with odor of rats as aversive stimulus), and post-stimulation state (PS). Subsequently, post mortem c-Fos immunohistochemistry elucidated neural activation on cellular level. The results showed that in reaction to the aversive odor CBF in total brain and amygdala of all mice significantly increased. In male 5-HTT+/+ mice amygdala RS CBF levels were found to be significantly lower than in 5-HTT+/- mice. From RS to SS 5-HTT+/+ amygdala perfusion significantly increased compared to both 5-HTT+/- and 5-HTT-/- mice. Perfusion level changes of male mice correlated with the density of c-Fos-immunoreactive cells in the amygdaloid nuclei. In female mice the perfusion was not modulated by the 5-Htt-genotype, but by estrous cycle stages. We conclude that amygdala reactivity is modulated by the 5-Htt genotype in males. In females, gonadal hormones have an impact which might have obscured genotype effects. Furthermore, our results demonstrate experimental support for the tonic model of 5-HTTLPR function.

Sex-specific effects of psychedelic drug exposure on central amygdala reactivity and behavioral responding

“…3 B, D, E, G). A recent study looking at cerebral blood flow and the expression of the serotonin transporter (5-HTT) showed that, in response to an aversive predator odor, there were increases in blood flow and c-Fos expression in the CeA that were related to 5-HTT expression in males but not females [ 71 ]. These findings suggest potential sex-specific expression of serotonin receptors within the amygdala.…”

Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding

“…3B, 3D, 3E, 3G). A recent study looking at cerebral blood flow and the expression of the serotonin transporter (5-HTT) showed that, in response to an aversive predator odor, there were increases in blood flow and expression of the immediate early gene c-Fos in the CeA that were related to 5-HTT expression in males but not females [44]. These findings suggest potential sex-specific expression of serotonin receptors within the amygdala.…”

Sex differences in chronic pain-induced mental disorders: Mechanisms of cerebral circuitry

“…Moreover, the serotonin transporter protein is also worthy of investigation as a target for many anxiolytic and antidepressant drugs. Using 5-HT transporter (5-HTT) gene-deficient mice as an anxiety animal model, researchers examined cerebral blood flow during resting and amygdala hyperresponsiveness periods using resting-state functional magnetic resonance imaging (rs-fMRI) (Kolter et al, 2021 ). The results indicated that amygdala reactivity in 5-HTT-deficient mice is regulated by the 5-HTT genotype in males.…”

“…The results indicated that amygdala reactivity in 5-HTT-deficient mice is regulated by the 5-HTT genotype in males. Whereas, in females it is regulated by the estrous cycle and the predominant influence of gonadotropins may mask genotypic effects (Kolter et al, 2021 ).…”