Sniffing the human body volatile hexadecanal blocks aggression in men but triggers aggression in women; our results imply that sniffing babies may increase aggression in mothers but decrease aggression in fathers

Sniffing the human body volatile hexadecanal blocks aggression in men but triggers aggression in women. Eva Mishor et al. Science Advances, Vol 7, Issue 47. Nov 19 2021. DOI: 10.1126/sciadv.abg1530

Abstract: In terrestrial mammals, body volatiles can effectively trigger or block conspecific aggression. Here, we tested whether hexadecanal (HEX), a human body volatile implicated as a mammalian-wide social chemosignal, affects human aggression. Using validated behavioral paradigms, we observed a marked dissociation: Sniffing HEX blocked aggression in men but triggered aggression in women. Next, using functional brain imaging, we uncovered a pattern of brain activity mirroring behavior: In both men and women, HEX increased activity in the left angular gyrus, an area implicated in perception of social cues. HEX then modulated functional connectivity between the angular gyrus and a brain network implicated in social appraisal (temporal pole) and aggressive execution (amygdala and orbitofrontal cortex) in a sex-dependent manner consistent with behavior: increasing connectivity in men but decreasing connectivity in women. These findings implicate sex-specific social chemosignaling at the mechanistic heart of human aggressive behavior.

Discussion

Impulsive aggression is a major factor in the human condition, yet how exactly aggression is triggered or blocked in the human brain remains unclear (11, 12). Moreover, real-world human impulsive aggression is one of the most sexually dimorphic behaviors (40), yet what brain mechanisms underlie this dimorphism also remains unclear (12). In animals ranging from insects to rodents, aggression is sexually dimorphic at levels ranging from genes to cells, and this dimorphism in aggression has been linked to dimorphism in the olfactory system (41). Here, we find the same in humans. We observed that sniffing a body volatile, namely, HEX, significantly decreased aggression in men yet significantly increased aggression in women. In both men and women, HEX increased brain activity in the AG, a cross-modal integrating hub involved in social cognition (42). In other words, in humans, like in rodents, a “social odor” activates the “social brain.” Moreover, HEX modulated functional connectivity between these substrates of social appraisal (AG) and a network previously associated with aggression. This included modulation of functional connectivity with the temporal pole (TP), an area similarly implicated in social appraisal (43) and aggression (44), and modulation of functional connectivity with the amygdala and OFC, namely, substrates implicated in aggressive execution (10, 12). All this modulation occurred in a sex-dependent manner consistent with behavior: HEX increased connectivity in men but decreased it in women. Thus, HEX may lead to increased or decreased aggression through increased or decreased control by the AG over the amygdala through a circuit involving the TP and OFC. This modulation of social behavior through modulation of functional brain connectivity was similarly observed following intranasal administration of oxytocin, which reduced OFC connectivity with the amygdala, and in this may have reduced negative emotional arousal (45). This further points to what may be considered a physiological counterpart of this brain mechanism: As stress increases, men become more aggressive and women become less aggressive (46). As stress decreases, men become less aggressive and women become more aggressive (47). In this manner, a non–sex-specific effect of HEX on the stress response (always reducing stress) may evolve into a sex-specific effect of HEX on aggression (increased aggression in women yet decreased aggression in men).

The above detailed neuroanatomy and mechanism may underlie a direct circuit from reception to action without the mediation of conscious perception. This echoes rodent circuitry, where OR37B projections bypass the olfactory cortex and connect directly to the paraventricular nucleus of the hypothalamus, where HEX reduces activity in corticotrophin-releasing cells, thus reducing activation of the hypothalamus-pituitary-adrenal axis (16). Although we cannot trace connectivity of a single olfactory receptor subtype in humans, it is tempting to liken the downstream activation in the absence of olfactory cortex activation we observed in response to HEX to the circuit detailed in rodents.

The sex dimorphism in our behavioral and brain results dovetails with previous findings obtained using functional brain imaging (48) and EEG (15) to depict a level of functional brain sex dimorphism in response to social odors that is not matched by any other sensory stimulus that we are aware of. Human functional brain responses to basic auditory and visual cues are generally nondissociable by sex (49), yet here, we could use them alone to discriminate men from women at 79.6% accuracy. This begs the question: what behavioral setting could underlie selection for a body volatile that increases aggression in women but decreases it in men? Or in other words, what could be the ecological relevance of these results? In this respect, we call attention to the setting of infant rearing. Parents across cultures are encouraged to sniff their babies (50), an action that activates brain reward circuits in women (51). Our results imply that sniffing babies may increase aggression in mothers but decrease aggression in fathers. Whereas maternal aggression has a direct positive impact on offspring survival in the animal world (52), paternal aggression has a negative impact on offspring survival (53). This is because maternal aggression (also termed maternal defense behavior) is typically directed at intruders, yet paternal aggression, and more so nonpaternal male aggression, is often directed at the offspring themselves (54, 55). If babies had a mechanism at their disposal that increased aggression in women but decreased it in men, this would likely increase their survival. With the hypothesis in mind that HEX provides babies with exactly such a mechanism, we first note that infant rearing is the one social setting where humans have extensive exposure to conspecific feces, a rich source of HEX (22). We also turned to a recently published analysis of baby-head volatiles (56), yet in contrast to our hypothesis, this report did not mention HEX. We turned to the authors of that report, who explained that the published analysis was not tuned to the near semivolatile range of HEX. With our question in mind, they (now coauthors T.U. and M.O.) sampled an additional 19 babies (fig. S10A), using gas chromatography (GC) × GC–mass spectrometry, and observed that HEX is one of the most abundant baby-head volatiles, evident in 17 of the 19 babies (fig. S10, B and C). Moreover, they also searched for the two additional known ligands of OR37, namely, pentadecanal and heptadecanal, and found both, albeit at levels much lower than HEX. Pentadecanal was evident in 15 babies but only at an average peak area of 56% that of HEX, and heptadecanal was evident in 16 babies but only at average peak area of 45.5% that of HEX (HEX greater than pentadecanal and peptadecanal: Kruskal-Wallis χ2 = 7.65, df = 2, P = 0.02) (fig. S10C). This outcome renders our overall ecological hypothesis plausible and retrospectively supports our selection of HEX as a testing target. In summary, babies emit HEX from their head. This is expected to trigger aggression in women but block aggression in men, and both of these impacts are expected to increase baby survival.

Given all the above, should we label HEX as a human pheromone? Sniffing human bodily secretions such as sweat and tears drives assorted behavioral and physiological effects (7, 24), and body odors may reflect assorted emotional states (57), including aggression (13, 14), but the identity of specific molecular components involved in human social chemosignaling has remained elusive (58). Moreover, the current view on human social chemosignals is that, to the extent that they exist, they likely entail alterations in the ratios of components in complex body odor bouquets and not single molecular species (59). Yet, here, we identify one component, namely, HEX, whose effects can be seen as consistent with those of a mammalian pheromone (60). Previously, the steroidal molecules estratetraenol (EST) and androstadienone (AND) had been proposed as human pheromones, yet this labeling was often rejected, primarily because EST and AND do not clearly trigger or block behavior, nor do they have obvious ecological relevance (59, 61). Here, HEX had a pronounced effect on behavior and, moreover, on the behavior of aggression, a domain dominated by pheromonal communication in most mammals (3). The notion of pheromonal communication was once considered dependent on a functional vomeronasal system, a system that humans may not have (62). More recent views, however, blur this distinction and highlight pheromonal communication through the main olfactory system as well (63–65). Given all this, we think that had we presented an equivalent set of results obtained from mice, very few would argue the pheromone label. In turn, if HEX is a human pheromone, is it a cuing pheromone that is emitted consistently by the sender or a signaling pheromone that is emitted only during appropriate behavioral context (61)? Here, we reach at the primary limitation of this study: Although we think of HEX as a signal, we did not measure its emission as a function of behavior. Had we measured HEX emission under different conditions and found that its emission increased under the endurance of aggression, this would have closed the loop of a signaling pheromone. Such an effort, however, was far beyond the scope of the current study and remains the key missing component for labeling HEX a human signaling pheromone.

Beyond this, we would like to acknowledge several additional limitations in this study: First, although we used various control conditions across experiments (eugenol, mineral oil, and blank air), we did not test any other potential OR37 ligands. The rationale for selecting HEX was detailed in Introduction, but future testing of additional potential ligands remains an important question. Second, we do not know whether the concentrations of HEX that we used were physiological. This is because we do not know the concentrations that humans emit (the existing reports are relative), and we do not know the concentration that actually reached our participants using the current paradigms (e.g., experiment 1 sniff-jar versus experiment 2 olfactometer). Third, regarding our imaging results, we reiterate that correlation is not causation. We identify a brain pattern associated with HEX, and it is tempting to suggest that this pattern is responsible for the observed effects, yet this can only be proven by experiments where the brain mechanism is perturbed, experiments that are very difficult to conduct in human participants. Last, we also acknowledge that our suggested ecological relevance in infant rearing was not directly tested in this study. One may note that there are various forms of aggression, and whereas our tasks measured interpersonal aggression, our infant-rearing hypothesis alludes to paternal/maternal aggression. Thus, although we think it is a plausible hypothesis, it remains to be experimentally verified, and here serves only as an example of possible ecological relevance for our results.

Despite the above limitations, we conclude in stating that sniffing the body odor constituent HEX blocks aggression in men but triggers aggression in women. HEX may exert its effects by modulating functional connectivity between the brain substrates of social appraisal and the brain substrates of aggressive execution. This places chemosignaling at the mechanistic heart of human aggression and poses but one added example to the rapidly growing body of evidence implicating social chemosignaling as a major, albeit mostly subconscious, power in human behavior.