Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep

Abstract

Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesized to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep with higher numbers of tyrosine hydroxylase (TH)-immunoreactive cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30–90 or 60–90 resulted in increased numbers of VTA TH- immunoreactive cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T-treated ewes, which was primarily accounted for by greater numbers of TH-immunoreactive cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T-treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH as well as the protein levels with dopamine cells. Sex differences were also noted in numbers of TH-immunoreactive cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH-immunoreactive cells in the substantia nigra, suggesting that this sex difference is organized independently from prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T.

Digit ratio (2D:4D) in relation to substance and computer use: a meta-analysis

“…Translational evidence indicates that intrauterine androgen priming organizes the brain with lasting structural and molecular alterations and influences substance use and addictive behaviors in adulthood. In female sheep, prenatal exposure to excess testosterone increases the number of tyrosine hydroxylase-immunoreactive cells in the ventral tegmental area (VTA) of adult sheep (Brown et al 2015 ). The VTA is a part of the mesolimbic system, which is an area of the brain that is related to motivation and addictive behaviors.…”

Lower Digit Ratio (2D:4D) Indicative of Excess Prenatal Androgen Is Associated With Increased Sociability and Greater Social Capital

“…Prenatal stress relates to increased androgen load; accordingly, intervention programs to reduce maternal stress during pregnancy are being developed (Lenz et al, 2018b). Animal models (mice, sheep) have shown permanent organizational effects of prenatal testosterone on the brain (Brown et al, 2015; Huber et al, 2018). These early effects also contribute to sex differences in adult behavior.…”

Mindfulness-based Stress Reduction in Pregnancy: an App-Based Programme to Improve the Health of Mothers and Children (MINDFUL/PMI Study)

“…Parallel ist bekannt, dass erhöhte vorgeburtliche Testosteronexposition mit Erkrankungen über die Lebensspanne assoziiert ist. Im Tiermodell verursacht vorgeburtliche Testosteronexposition bis ins Erwachsenenalter anhaltende Gehirnveränderungen und erhöht den Alkoholkonsum 31 , 32 . Es verwundert daher nicht, dass eine hohe vorgeburtliche Testosteronlast (beim Menschen u. a. erfasst mit Biomarkern wie dem 2D : 4D-Verhältnis) mit einer ganzen Reihe von Beeinträchtigungen über die Lebensspanne assoziiert ist.…”

“…At the same time, it is known that elevated antenatal testosterone exposure is associated with illnesses throughout life. In the animal model, antenatal testosterone exposure causes brain changes which persist into adulthood and increases alcohol consumption 31 , 32 . It is therefore not surprising that a high antenatal testosterone load (recorded in humans using biomarkers, such as the 2D:4D ratio, among others) is associated with a whole range of impairments throughout life.…”