Date of Award

1-1-2024

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Psychology

Dissertation/Thesis Chair

Christine K Wagner

Committee Members

Damian G Zuloaga, Andrew M Poulos

Keywords

17-α-hydroxyprogesterone caproate, behavior, dopaminergic, neural development, progestins, serotonergic

Subject Categories

Developmental Biology

Abstract

The synthetic progestin, 17-α -hydroxyprogesterone caproate (17-OHPC) has beencommonly prescribed during gestation to reduce preterm delivery in individuals at risk (Meis et al., 2003). In singleton pregnancies, 17-OHPC treatment begins during the second trimester, around gestational weeks 16-20, and continues until the end of the third trimester, around week 37 (Berghella, 2012). Although the fetus is not directly administered 17-OHPC, previous research demonstrated that 17-OHPC was transferred from the maternal unit to the fetal unit of the placenta in situ, was detectable in maternal and fetal blood up to 44 days following the last injection (Caritis et al., 2012; Hemauer et al., 2008), and was detectable in vivo within cord plasma of neonates up to 44 days after the termination of treatment (Caritis et al., 2012). This suggests that the fetus is exposed to 17-OHPC during a period of critical development. Yet, information regarding the long-term effects of 17-OHPC on neural and behavioral development in children is lacking. This dissertation investigated the impact of developmental exposure to 17-OHPC on rodent neural and behavioral development throughout the lifespan. The effects of this clinically relevant synthetic progestin on neural development offer insights into the underlying mechanisms by which it may exert its effects, including the alteration of nuclear progesterone receptor (PR) expression in the neonatal somatosensory cortex and dentate gyrus. Additionally, the study explored the sensitivity of limbic targets to 17-OHPC-induced perturbations, specifically in dopaminergic and serotonergic innervation within the Nucleus Accumbens shell and hippocampus during adolescent males. Notably, microglia activational phenotype in the hippocampus showed sensitivity to developmental 17-OHPC exposure, generating the intriguing hypothesis that irregular microglia activational phenotype may be a potential mechanism contributing to disrupted serotonergic circuitry in hippocampus in adolescent male rats. Furthermore, the research indicated potential dysfunction within the dopaminergic system, particularly involving dopamine 2 receptors and/or dopamine 2 autoreceptors. This dissertation significantly expands the current literature by investigating the behavioral effects of 17-OHPC. The study examined sensorimotor behaviors, revealing a notable impact of developmental 17-OHPC exposure on behaviors indicative of cortical development in neonates. For example, 17-OHPC disrupted the developmental profile of numerous sensorimotor-dependent behaviors, including hindlimb and forelimb grasping, surface right, and cliff aversion. Additionally, it explored the influence on mesocorticolimbic mood-related behaviors across neonatal and adolescent stages, highlighting a pronounced effect in males. Specifically, developmental 17-OHPC exposure increased time spent in the periphery of the area, a well-established indicator of anxiety-like behavior, in male neonates and decreased latency to first bout of immobility in the Forced Swim Test, suggestive of a depressive-like phenotype, in adolescent males. Finally, the research delved into fundamental aspects of decision-making in adult rats, specifically addressing the phenomenon of omissions. Results from delay discounting testing show a consistent increase in omissions (i.e. failure to respond) at the longest delays (i.e. when choice becomes most difficult) in 17-OHPC exposed adult rats. This effect on omissions was in the absence of impairment in other aspects of v performance. Further, our data indicate that administration of the dopamine transporter inhibitor, Methylphenidate, and dopamine 2 receptor antagonist, Eticlopride, altered omissions in control rats. These effects were significantly attenuated in 17-OHPC exposed rats, suggesting a dopaminergic mechanism for omissions without other cognitive deficits in rats. Collectively, these results suggest that 17-OHPC exposure has differential effects in male and female rats across the lifespan. Findings from the present dissertation add to the growing body of research that demonstrates the potential effect of synthetic progestin exposure on neural and behavioral development in rodents. In conclusion, this dissertation provides insights into the potential risks and benefits of exogenous hormone use during critical periods of human fetal neural development. It highlights the need for further investigation into the impact of 17-OHPC on cognitive, mood-related, and sensorimotor behavior in exposed children, suggesting potential sex-specific effects. Finally, the findings from this dissertation emphasize the critical necessity for caution in utilizing exogenous hormones in development, highlighting the imperative of preventing unintended consequences in children.

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