Testosterone in utero and at birth dictates how stressful experience will affect learning in adulthood

Abstract

Exposure to an acute stressful event can enhance learning in male rats, whereas exposure to the same event dramatically impairs performance in females. Here we tested whether the presence of sex hormones during early development organizes these opposite effects of stress on learning in males vs. females. In the first experiment, males were castrated at birth whereas females were injected with testosterone. Rats were trained as adults on the hippocampal-dependent learning task of trace eyeblink conditioning. Performance in adult males that had been castrated at birth was still enhanced by exposure to an acute stressful experience. However, adult females injected with testosterone at birth responded in the opposite direction, i.e., exposure to the stressor that typically reduces performance instead enhanced their levels of conditioning. In the second experiment, exposure to testosterone was manipulated in utero by injecting pregnant females with a testosterone antagonist. After foster rearing, adult offspring were exposed to the stressor and trained on the hippocampal-dependent learning task of trace conditioning. Although performance in adult females was unaffected by antagonizing testosterone in utero, i.e., stress still reduced performance, the enhancement of conditioning after stress in adult males was prevented. Thus, the presence of sex hormones during gestation and development organizes whether and how acute stressful experience will affect the ability to acquire new information in adulthood. As with many sexual behaviors, these cognitive responses to stress appear to be masculinized by exposure to testosterone and feminized by its absence during very early development.

Females do not Express Learned Helplessness like Males do

“…Therefore, we were surprised that learned helplessness behavior did not emerge in females that were masculinized at birth. In a previous study, masculinization of the female brain reversed the effects of uncontrollable stress on classical conditioning (Shors and Miesegeas, 2002). Instead of reducing classical eyeblink conditioning, exposure to the stressful event facilitated learning in females; they responded like intact males do.…”

“…Females from different litters were injected with 0.02 ml of sesame oil alone (n ¼ 14). This treatment has been used frequently to study the organizational effects of androgens on the brain and has been shown effective for masculinizing the female brain and many aspects of behavior (Barraclough and Gorski, 1961;Beatty and Beatty, 1970;Shors and Miesegeas, 2002).…”

“…Many sex differences in adult behaviors can be reversed or at least minimized by manipulation of sex steroids during development (Barraclough and Gorski, 1961;Beatty and Beatty, 1970;Shors and Miesegeas, 2002;Williams et al, 1990). Testosterone treatment of females at birth alters the phenotype of the hypothalamic-pituitary-adrenal axis (Seale et al, 2005), the morphology of sexually dimorphic brain regions (Han and De Vries, 2003;MacLusky et al, 1987;Morris et al, 2004;Roselli and Klosterman, 1998) and affects certain aspects of learning (Roof, 1993;Roof and Havens, 1992;Shors and Miesegeas, 2002;Williams and Meck, 1991).…”

“…Testosterone treatment of females at birth alters the phenotype of the hypothalamic-pituitary-adrenal axis (Seale et al, 2005), the morphology of sexually dimorphic brain regions (Han and De Vries, 2003;MacLusky et al, 1987;Morris et al, 2004;Roselli and Klosterman, 1998) and affects certain aspects of learning (Roof, 1993;Roof and Havens, 1992;Shors and Miesegeas, 2002;Williams and Meck, 1991). Therefore, we were surprised that learned helplessness behavior did not emerge in females that were masculinized at birth.…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…In rats, exposure to an acute stressful event can facilitate learning in males, but impairs performance in female rats. 311,312 Furthermore, exposure to an elevated plusmaze, a rodent anxiety test, leads to decreased 5-HTergic activity in the dorsal raphe nuclei in female rats, but to decreased 5-HTergic activity in the medial raphe nuclei in males. 101 There is also data to indicate that male rats may adapt better to stress than females.…”