Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats

Noortje Van Der Knaap,Judith R Homberg,Dirk Wiedermann,Dirk Schubert,Mathias Hoehn

doi:10.1038/s41598-021-81327-z

Abstract

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.

Highlights

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy
In this study we set out to test how perinatal exposure to the SSRI fluoxetine affects large-scale functional brain activity associated with tactile sensory activation
Rodents show large scale activation of the barrel cortex upon whisker stimulation, but no differences in the Blood Oxygen Level Dependent (BOLD) response in the barrel field were found between the control and perinatally SSRI exposed groups

Summary

Introduction

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring This likely results from developmental changes in brain function. Rodent models fill this gap, giving us the opportunity to closely investigate the consequences of developmental SSRI exposure These preclinical studies have suggested differences in social behaviour, learning and memory, anxiety and sensory functions, alterations in neuronal organization, differences in hippocampal neurogenesis and epigenetic changes after SSRI exposure during pregnancy and the early postnatal phase[16,17,18,19,20,21,22,23,24,25,26,27,28]. Since there are similarities in the developmental consequences of SERT knockout and perinatal SSRI exposure[35,36], and perinatal SSRI exposure affects sensory functions as well as behaviours dependent on sensory processing (see above), we hypothesize that perinatal SSRI exposure affects the activity of brain areas associated with the somatosensory system later in life

Methods

Results

Conclusion