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

Knaap, Noortje van der; Wiedermann, Dirk; Schubert, Dirk W.; Hoehn, Mathias; Homberg, Judith R.

doi:10.1038/s41598-021-81327-z

Cited by 12 publications

(8 citation statements)

References 76 publications

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“…Cortical regions of interest, including cortical volumes of frontal, cingulate, somatosensory (postcentral gyrus), and higher-order visual areas (fusiform gyrus, parahippocampal gyrus), were included in the second tier to investigate how frontolimbic systems could contribute to the observed global associations. 10,19,22,28,29 Exposure and confounder variables were included as fixed effects with a random intercept to allow for the repeated observations of participants. Main associations and interaction terms of the exposure and child age with the brain outcomes were included.…”

Section: Discussionmentioning

confidence: 99%

“…To minimize multiple testing, we conducted follow-up analyses only if associations with the primary outcomes (total gray and white matter and hippocampus and amygdala) were observed. Cortical regions of interest, including cortical volumes of frontal, cingulate, somatosensory (postcentral gyrus), and higher-order visual areas (fusiform gyrus, parahippocampal gyrus), were included in the second tier to investigate how frontolimbic systems could contribute to the observed global associations . Exposure and confounder variables were included as fixed effects with a random intercept to allow for the repeated observations of participants.…”

Section: Methodsmentioning

confidence: 99%

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Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory

Koc,

Tiemeier,

Stricker

et al. 2023

JAMA Psychiatry

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ImportanceClinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring.ObjectiveTo investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty.Design, Setting, and ParticipantsThis prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022.ExposureMaternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans).Main Outcomes and MeasuresThe main outcome was brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age.ResultsThe study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U–shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (β [SE], −20 212.2 [7285.6] mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: β [SE], 43.3 [13.4] mm3; P = .006) and fusiform gyrus (age interaction: β [SE], 168.3 [51.4] mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (β [SE], −166.3 [65.1] mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (β [SE], −480.5 [189.2] mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed.Conclusions and RelevanceThe results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved in emotional regulation in offspring. Further research on the functional implications of these findings is needed.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory

Koc,

Tiemeier,

Stricker

et al. 2023

JAMA Psychiatry

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“…Interestingly, one of the few DEGs identified in the dSERT TMKO day 0 dataset was dpr1 in KC_ABp1, a cell-adhesion molecule that may represent an adjustment to dysregulated circuit activity in the presence of aberrant serotonergic signaling. SERT is present in developing serotonergic neurons [77], and SSRIs can cause dysregulation of circuit wiring in mammals [78][79][80]. Additionally, Drosophila serotonergic neurons are remodeled and form new synapses in development [81].…”

Section: Scrna-seqmentioning

confidence: 99%

Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter

Krantz

Bonanno

2023

Preprint

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The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence activated cell sorting of Kenyon cells, followed by either or bulk or single cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalapram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other Drosophila circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.

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“…Since ACA has been closely involved in pupil dynamics, as well as arousal state regulation (89)(90)(91), the mapping of the ACA in awake mice during visual stimulation provides a meaningful way to validate the conscious state of the mouse during scanning. Similarly, there are extensive rodent fMRI studies of vibrissa stimulation (44,(92)(93)(94)(95)(96). In contrast to the anesthetized state, this awake mouse fMRI detected not only activated contralateral BC and VPM, but also spread activation in the motor cortex, and small portion of the ipsilateral BC with positive BOLD signals.…”

Section: Brain-wide Functional Mapping With Visual and Vibrissa Stimu...mentioning

confidence: 99%

High-resolution awake mouse fMRI at 14 Tesla

Hike,

Liu,

Xie

et al. 2023

Preprint

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High-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Using a 14T scanner, high-resolution fMRI enabled brain-wide functional mapping of visual and vibrissa stimulation at 100x100x200µm resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detectable with the randomized stimulation paradigm. This early BC activation indicated learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas.Significance StatementThis awake mouse fMRI platform was developed by implementing an advanced implantable radiofrequency (RF) coil scheme, which simultaneously served as a headpost to secure the mouse head during scanning. The ultra-high spatial resolution (100x100x200µm) BOLD fMRI enabled the brain-wide mapping of activated visual and vibrissa systems during sensory stimulation in awake mice, including association cortices, e.g. anterior cingulate cortex and retrosplenial cortex, for high order sensory processing. Also, the activation of barrel cortex at 2 s prior to the air-puff indicated a learned anticipation of awake mice under continuous training of the repetitive vibrissa stimulation.

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

Cited by 12 publications

References 76 publications

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory

Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter

High-resolution awake mouse fMRI at 14 Tesla

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