Estrella R. Montoya

Testosterone, cortisol, and serotonin as key regulators of social aggression: A review and theoretical perspective

In human and non-human animals the steroid hormones cortisol and testosterone are involved in social aggression and recent studies suggest that these steroids might jointly regulate this behavior. It has been hypothesized that the imbalance between cortisol and testosterone levels is predictive for aggressive psychopathology, with high testosterone to cortisol ratio predisposing to a socially aggressive behavioral style. In this review, we focus on the effects of cortisol and testosterone on human social aggression, as well as on how they might modulate the aggression circuitry of the human brain. Recently, serotonin is hypothesized to differentiate between impulsive and instrumental aggression, and we will briefly review evidence on this hypothesis. The aim of this article is to provide a theoretical framework for the role of steroids and serotonin in impulsive social aggression in humans.

New evidence on testosterone and cooperation

arising from C. Eisenegger, M. Naef, R. Snozzi, M. Heinrichs & E. Fehr 463, 356–359 (2010)10.1038/nature08711; Eisenegger et al. replyIn February 2010, Eisenegger et al. reported increased fair bargaining behaviour after administration of testosterone in an ultimatum game. However, unfair offers in the ultimatum game typically are rejected; thus, not only the motives for social cooperation but also the threat of financial punishment may have accounted for these effects. Here, using the public goods game (PGG), we unambiguously show increased social cooperation after testosterone administration, but only among subjects with low levels of prenatal testosterone (measured by the right hand’s second-to-fourth-digit ratio (2D:4D)). This finding establishes positive effects of testosterone on social cooperation, with prenatal hormonal priming providing for important individual variability.

Testosterone administration modulates neural responses to crying infants in young females

Parental responsiveness to infant vocalizations is an essential mechanism to ensure parental care, and its importance is reflected in a specific neural substrate, the thalamocingulate circuit, which evolved through mammalian evolution subserving this responsiveness. Recent studies using functional Magnetic Resonance Imaging (fMRI) provide compelling evidence for a comparable mechanism in humans by showing thalamocingulate responses to infant crying. Furthermore, possibly acting on this common neural substrate, steroid hormones such as estradiol and testosterone, seem to mediate parental behavior both in humans and other animals. Estradiol unmistakably increases parental care, while data for testosterone are less unequivocal. In humans and several other animals, testosterone levels decrease both in mothers and fathers during parenthood. However, exogenous testosterone in mice seems to increase parenting, and infant crying leads to heightened testosterone levels in human males. Not only is the way in which testosterone is implicated in parental responsiveness unresolved, but the underlying mechanisms are fully unknown. Accordingly, using fMRI, we measured neural responses of 16 young women who were listening to crying infants in a double blind, placebo-controlled, counterbalanced, testosterone administration experiment. Crucially, heightened activation in the testosterone condition compared to placebo was shown in the thalamocingulate region, insula, and the cerebellum in response to crying. Our results by controlled hormonal manipulation confirm a role of the thalamocingulate circuit in infant cry perception. Furthermore, the data also suggest that exogenous testosterone, by itself or by way of its metabolite estradiol, in our group of young women acted on this thalamocinculate circuit to, provisionally, upregulate parental care.

Hypervigilance for fear after basolateral amygdala damage in humans

Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach–Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brains threat vigilance system, which has important implications for the understanding of the amygdalas role in the disorders of fear and anxiety.

Testosterone administration modulates moral judgments depending on second-to-fourth digit ratio

Moral judgment involves the interplay of emotions and social cognitions. The male sex-hormone testosterone might play a role in moral reasoning as males are more utilitarian than females in their moral decisions, and high salivary testosterone levels also are associated with utilitarian moral decisions. However, there is no direct evidence for a role of testosterone in moral reasoning. Recent testosterone administration studies show effects on cognitive empathy and social cooperation, which depend on right-hands second-to-fourth (2D:4D) digit ratio, a proxy for prenatal sex-hormone (testosterone-versus-estradiol) priming. Here, in a placebo-controlled within-subjects design using 20 young females we show that 2D:4D predicts 44% of the variance in the effects of testosterone administration on moral judgment. Subjects who show an increase in utilitarian judgments following testosterone administration have significantly higher than average 2D:4D (relatively high prenatal estradiol priming), while subjects showing more deontological judgments following testosterone administration have near-significantly lower 2D:4D (relatively high prenatal testosterone priming). We argue that prenatally-organized differences in aromatase, i.e. conversion from testosterone to estradiol in the brain, might underlie these effects. Our findings suggest that early neurodevelopmental effects of sex steroids play a crucial role in the activational effects of hormones on moral reasoning later in life.

Cortisol administration induces global down-regulation of the brain's reward circuitry

Research in rodents and humans has shown divergent effects of the glucocorticoids corticosterone and cortisol (CRT) on reward processing. In rodents, administration of CRT increases reward drive by facilitating dopamine release in the ventral striatum. In humans, correspondingly, risky decision-making increases when CRT levels are elevated. Human stress studies contrariwise show that elevated CRT is accompanied by a decrease in reward-related brain activity. There are however no direct insights into how CRT acts on the reward system in the human brain. Accordingly, we used pharmacological functional magnetic resonance imaging (pharmaco-fMRI) to investigate the effects of CRT on the brains reward system. In a randomized within-subject design we administered a high dose of CRT (40 mg) and placebo to twenty healthy male volunteers on separate days, and used a monetary incentive delay task to assess the effects of the hormone on the striatum and the amygdala in anticipation of potential reward. In contrast to animal studies, we show that this high dose of CRT strongly decreases activity of the striatum in both reward and non-reward conditions. Furthermore, we observed reductions in activity in the basolateral amygdala, a key regulator of the brains reward system. Crucially, the overall down-regulation of the brains reward circuit was verified on the subjective level as subjects reported significantly reduced reward preference after CRT. In sum, we provide here direct evidence in humans that CRT acts on brain regions involved in reward-related behavior, that is, the basolateral amygdala and the striatum. Our findings suggest that CRT in the quantity and time course presently used globally down-regulates the reward system, and thereby decreases motivational processing in general.

Oxytocin reduces neural activity in the pain circuitry when seeing pain in others

Our empathetic abilities allow us to feel the pain of others. This phenomenon of vicarious feeling arises because the neural circuitry of feeling pain and seeing pain in others is shared. The neuropeptide oxytocin (OXT) is considered a robust facilitator of empathy, as intranasal OXT studies have repeatedly been shown to improve cognitive empathy (e.g. mind reading and emotion recognition). However, OXT has not yet been shown to increase neural empathic responses to pain in others, a core aspect of affective empathy. Effects of OXT on empathy for pain are difficult to predict, because OXT evidently has pain-reducing properties. Accordingly, OXT might paradoxically decrease empathy for pain. Here, using functional neuroimaging we show robust activation in the neural circuitry of pain (insula and sensorimotor regions) when subjects observe pain in others. Crucially, this empathy-related activation in the neural circuitry of pain is strongly reduced after intranasal OXT, specifically in the left insula. OXT on the basis of our neuroimaging data thus remarkably decreases empathy for pain, but further research including behavioral measures is necessary to draw definite conclusions.

Testosterone Administration Moderates Effect of Social Environment on Trust in Women Depending on Second-to-Fourth Digit Ratio.

Animal research has established that effects of hormones on social behaviour depend on characteristics of both individual and environment. Insight from research on humans into this interdependence is limited, though. Specifically, hardly any prior testosterone experiments in humans scrutinized the interdependency of testosterone with the social environment. Nonetheless, recent testosterone administration studies in humans repeatedly show that a proxy for individuals’ prenatal testosterone-to-estradiol ratio, second-to-fourth digit-ratio (2D:4D ratio), influences effects of testosterone administration on human social behaviour. Here, we systematically vary the characteristics of the social environment and show that, depending on prenatal sex hormone priming, testosterone administration in women moderates the effect of the social environment on trust. We use the economic trust game and compare one-shot games modelling trust problems in relations between strangers with repeated games modelling trust problems in ongoing relations between partners. As expected, subjects are more trustful in repeated than in one-shot games. In subjects prenatally relatively highly primed by testosterone, however, this effect disappears after testosterone administration. We argue that impairments in cognitive empathy may reduce the repeated game effect on trust after testosterone administration in subjects with relatively high prenatal testosterone exposure and propose a neurobiological explanation for this effect.

Improved memory for reward cues following acute buprenorphine administration in humans

In rodents, there is abundant evidence for the involvement of the opioid system in the processing of reward cues, but this system has remained understudied in humans. In humans, the happy facial expression is a pivotal reward cue. Happy facial expressions activate the brains reward system and are disregarded by subjects scoring high on depressive mood who are low in reward drive. We investigated whether a single 0.2mg administration of the mixed mu-opioid agonist/kappa-antagonist, buprenorphine, would influence short-term memory for happy, angry or fearful expressions relative to neutral faces. Healthy human subjects (n38) participated in a randomized placebo-controlled within-subject design, and performed an emotional face relocation task after administration of buprenorphine and placebo. We show that, compared to placebo, buprenorphine administration results in a significant improvement of memory for happy faces. Our data demonstrate that acute manipulation of the opioid system by buprenorphine increases short-term memory for social reward cues.

Dissociated neural effects of cortisol depending on threat escapability

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the “stress‐hormone”, is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brains fear systems when humans are under virtual‐predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear‐related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormones crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp 36:4304–4316, 2015.