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

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.

Figure 1

Model of the experimental timeline and set-up. GD gestational days, PND postnatal days.

Figure 2

The effect of whisker stimulation block > control block over all subject groups. In both the perinatally SSRI exposed and control groups whisker stimulation to the left side is associated with increased activation of the barrel cortex at the contralateral side (5 weeks: z-max = 6.43, p < 0.001; 10 weeks: z-max is 6.25; p < 0.001). Additionally, there is strong activation in thalamic projection sides and sensory relay regions like the ventral posteromedial nucleus and posteromedial complex region. Cluster activation is shown on an in-house rat template and z-scores are depicted on the scale bar.

Figure 3

Results of the contrast perinatal SSRI exposure > control for the 5 weeks old rats. Whisker stimulation was given on the left side of the animal. Increased activity is observed in the hippocampal CA3 and dentate gyrus regions stretching to the mammillary body in the thalamus (cluster size = 72 voxels, z-max 1.9 p = 0.012). Significant clusters are shown upon an in-house rat template and z-scores are depicted in the scale-bar.

Figure 4

Results of the activated brain clusters in the 10-week old rats. The contrast for perinatal SSRI exposure over the control condition is shown. Whisker stimulation was given on the left side of the animal. Six different significant clusters are shown. The yellow square shows the contralateral activation of the piriform cortex (cluster size = 54 voxels, z-max = 3.81, p = 0.003). In both the yellow and red squares, the activation of the cluster encompassing the motor cortex and primary sensory cortex is shown (cluster size = 38 voxels, z-max = 3.0, p = 0.02). In the blue square the activation of the cluster in the retrosplenal granular and agranular cortex is shown (cluster size = 38 voxels, z-max = 3.2, p = 0.03). In the green square the activation of three clusters is shown: Ipsilateral to the stimulation side and most dorsal the secondary visual cortex (cluster size = 35 voxels, z-max = 3.63 p = 0.04), and the CA2 of the hippocampus (cluster size = 87 voxels, z-max = 4.93 and p < 0.001). Lastly, a cluster covering the perirhinal and entorhinal cortex stretching into the hippocampal CA2 region is activated (cluster size = 60 voxels, z-max = 4.07, p = 0.002). All clusters shown survived whole brain cluster correction and are laid over an in-house rat template. Value-bar depicts the z-value range.