Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. Studies in humans and experimental animal models shows that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can lead to abnormal emotional behaviors in adulthood, with a majority of the studies focusing on male offspring behavior. In this dissertation, we assessed whether SSRI-induced neurobiological and behavior changes occur in both sexes and whether these changes emerge in the juvenile period. In addition, we observed gene expression changes in the hippocampus related to metabolism and synaptogenesis. Given that, we hypothesized that the behavioral impacts following SSRI exposure may be driven, in part, by these processes.
Juvenile offspring exposed to SSRIs in early life, regardless of sex, displayed increased anxiety-like behavior and altered social play. In adulthood, perinatal SSRI-exposed male and female offspring displayed increased passive coping in the Forced Swim Test but showed no differences in anxiety-like behavior. In addition to emotional behaviors, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency.
Alongside these behavioral changes, during infancy, we observed increased metabolic activity in the dentate gyrus of the hippocampus and decreased activity in the basolateral amygdala. During adulthood, the CA and dentate gyrus of the hippocampus in both sexes and the paraventricular nucleus of the hypothalamus in female offspring were more metabolically active in exposed offspring. We also observed differences in inter-correlations of limbic region COX activity in perinatal SSRI exposed and control offspring.
Finally, a major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). As a G-protein coupled receptor (GPCR), it is an interesting potential therapeutic target, since most recently approved drugs in the central nervous system act on GPCRs. Data present here show that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls.
Together, these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms and metabolic changes that drive adverse effects of perinatal SSRI exposure and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia. Therefore, these data suggest that investigate the Bai3 network may be an exciting route as a potential therapeutic target for depression. / Doctor of Philosophy / Environmental factors during development play an important role in shaping the growth, structure, and function of the brain and as well behavior of an organism. Some of these factors that alter development which can negatively impact behavior include early life exposure to stress, toxins, or drugs. In this dissertation, we will discuss the impact of early life exposure to antidepressants. Many people take selective serotonin reuptake inhibitor (SSRI) antidepressants as a way to treat their depression during pregnancy. It is important to note that is it essential to treat depression during pregnancy, since depression can drastically impact the behavior of the offspring. However, while considering this, it is also critical to understand how exposure to SSRI antidepressants influences behavior of the offspring. SSRI antidepressants work by increasing the neurotransmitter serotonin in the brain and body. Previous work has demonstrated that early life exposure to SSRIs can alter the way the serotonin system develops in the brain and also increases the chance of children to develop emotional disorders (e.g., depression and anxiety). The same is true in rodents, a model organism in research, since we see an increase in depression-related behavior in our rats that are exposed to SSRI antidepressants in early life.
Data shown in this dissertation support this claim, as we see altered behavior not only in adult but juvenile male and female rodent offspring. In adults, we found increased depression-related behavior and social deficits (e.g., maternal care). In the juvenile offspring, we saw alterations of social play behaviors and increase in anxiety-related behavior. Given this observation, we were interested in determining what occurs in the brain that alters these emotional and social behavior. To do this, we observed gene changes in the brain following early life SSRI exposure. We found changes in genes related to metabolic activity and communication between neurons (i.e., synaptogenesis). As a follow up to this study, we next wanted to characterize the metabolic and morphological (i.e., structural) changes that as a result of early life SSRI exposure. We found increased activity in several regions of the brain associated with emotion, including the hippocampus, amygdala, and hypothalamus. In addition, we did not find any morphological changes in the hippocampus, although ongoing studies will continue to analyze other brain regions.
Lastly, when considering specific pathways whereby early life SSRI exposure can alter emotional and social behavior, we are interested in identifying potential therapeutic targets. One set of proteins (G-coupled protein receptors; GPCRs) are interesting targets to investigate, since most FDA approved medications in the central nervous system target these GPCRs. Interestingly, one GPCR stood out in our gene studies: Bai3. In this dissertation, we present data to show that the Bai3 network is altered in rodents exposed to SSRIs in early life. In addition, we show that manipulating Bai3 in early life can help to improve depression-related behavior. Lastly, to understand if Bai3 could play a role in depression, we assessed human postmortem samples to see if Bai3 alterations occur in the depressed human condition. In this study, we found increased Bai3 levels in human male sample relative to healthy patients. Overall, the work presented here shows that early life SSRI exposure negatively impacts emotional and social behaviors in rodents. Coinciding with these behavior changes, we find differences in gene expression and metabolic activity, thus providing us with a potential mechanism whereby early life SSRI exposure influences behavior. It is possible that by manipulating these aspects of brain function represent fruitful options for therapeutic targets for depression and other mood disorders.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/111646 |
| Date | 26 August 2022 |
| Creators | Unroe, Keaton Andrew |
| Contributors | Graduate School, Clinton, Sarah, Kerman, Ilan, Sewall, Kendra, Thompson, Christopher, Buczynski, Matthew |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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