Periodic Reporting for period 4 - SocioSmell (Social Chemosignaling as a Factor in Human Behavior in both Health and Disease)
Berichtszeitraum: 2020-03-01 bis 2021-01-31
The issue being addressed
We humans trust our nose over our eyes and ears in two of the most critical decisions we make: what we eat, and with whom we mate. Our reliance on our nose for key survival-related decisions such as eating and mating is subserved by an astonishingly keen olfactory system. We have in our nose ~6 million olfactory receptors, that as far as we know, are not different in their design and function from those of a rat or a dog. These receptors feed into olfactory bulbs that are, in proportion to the rest of our brain, much smaller than those of rodents, but in absolute terms, bigger than even the entire brain of some rodents. These bulbs then convey information to a human cortical olfactory and limbic system that is fully intact. Indeed, using this system, humans can detect odorants at parts-per-trillion dilution, they can discriminate between a huge number of molecules that differ by the smallest of molecular perturbations, and they can learn to achieve olfactory feats as unlikely as scent-tracking. One of the major uses of olfaction by macrosmatic mammals is in chemical communication. Mammals emit bodily-sourced odorants through urine and other secretions, and these odorants signal meaningful information to conspecifics. Some mammalian chemosignals induce effects that are nothing less than dramatic. For example, the Bruce effect describes the phenomena whereby a pregnant rodent will miscarry if exposed to the odorant of a non-fathering male within a critical early stage of pregnancy. It is hard to imagine a decision with greater evolutionary cost than a voluntary miscarriage, and this "decision" is made based on a chemosignal.
With the above in mind, the major objective of this proposal is to test the hypothesis that like all mammals, humans constantly exchange chemosignals that influence brain activity, hormonal state, and behavior.
Importance for society
Understanding the mechanisms of human chemosignaling will provide a better understanding of the link between brain and behavior, and may uncover specific chemosignaling molecules with important pharmacological implications.
Overall objectives
In Aim 1 we will ask what else do human social chemosignals signal? We will test the novel hypotheses that human social chemosignals communicate social status (dominance/submissiveness).
In Aim 2 we will ask how do humans exchange social chemosignals? We will test the novel hypotheses that handshaking is a chemosignaling mechanism, and that humans constantly chemo-investigate each other.
In Aim 3 we will ask what are the brain mechanisms that subserve human social chemosignaling? We will test the hypothesis that human social chemosignaling is independent of the main olfactory system.
In Aim 4 we will ask what happens when human social chemosignaling goes wrong? We will test the novel hypothesis that altered chemosignaling is a component of autism spectrum disorder.
Taken together, the answers to these questions promise to provide a novel framework for understanding human behavior in both health and disease.
We humans trust our nose over our eyes and ears in two of the most critical decisions we make: what we eat, and with whom we mate. Our reliance on our nose for key survival-related decisions such as eating and mating is subserved by an astonishingly keen olfactory system. We have in our nose ~6 million olfactory receptors, that as far as we know, are not different in their design and function from those of a rat or a dog. These receptors feed into olfactory bulbs that are, in proportion to the rest of our brain, much smaller than those of rodents, but in absolute terms, bigger than even the entire brain of some rodents. These bulbs then convey information to a human cortical olfactory and limbic system that is fully intact. Indeed, using this system, humans can detect odorants at parts-per-trillion dilution, they can discriminate between a huge number of molecules that differ by the smallest of molecular perturbations, and they can learn to achieve olfactory feats as unlikely as scent-tracking. One of the major uses of olfaction by macrosmatic mammals is in chemical communication. Mammals emit bodily-sourced odorants through urine and other secretions, and these odorants signal meaningful information to conspecifics. Some mammalian chemosignals induce effects that are nothing less than dramatic. For example, the Bruce effect describes the phenomena whereby a pregnant rodent will miscarry if exposed to the odorant of a non-fathering male within a critical early stage of pregnancy. It is hard to imagine a decision with greater evolutionary cost than a voluntary miscarriage, and this "decision" is made based on a chemosignal.
With the above in mind, the major objective of this proposal is to test the hypothesis that like all mammals, humans constantly exchange chemosignals that influence brain activity, hormonal state, and behavior.
Importance for society
Understanding the mechanisms of human chemosignaling will provide a better understanding of the link between brain and behavior, and may uncover specific chemosignaling molecules with important pharmacological implications.
Overall objectives
In Aim 1 we will ask what else do human social chemosignals signal? We will test the novel hypotheses that human social chemosignals communicate social status (dominance/submissiveness).
In Aim 2 we will ask how do humans exchange social chemosignals? We will test the novel hypotheses that handshaking is a chemosignaling mechanism, and that humans constantly chemo-investigate each other.
In Aim 3 we will ask what are the brain mechanisms that subserve human social chemosignaling? We will test the hypothesis that human social chemosignaling is independent of the main olfactory system.
In Aim 4 we will ask what happens when human social chemosignaling goes wrong? We will test the novel hypothesis that altered chemosignaling is a component of autism spectrum disorder.
Taken together, the answers to these questions promise to provide a novel framework for understanding human behavior in both health and disease.
This project has now ended, with significant progress at each of the above aims.
In Aim 1 we asked:"What do human chemosignals signal?"
In one key publication we identify a specific chemosignal, hexadecanal, that blocks aggression in men but triggers aggression in women. What might be the ecological significance of this? In all mammals, offspring benefit from maternal aggression but suffer from paternal aggression. This is because maternal aggression is typically directed at intruders, yet paternal aggression is often directed at the offspring themselves. Thus, if offspring have a tool to increase maternal aggression but decrease paternal aggression, their survival increases. Hexadecanal is just such a tool. With this hypothesis in mind, we measured body-odor emissions from baby heads, and found that hexadecanal is indeed one of the most abundant baby volatiles. These remarkable results constitute the first identified human pheromone, and can be seen at:https://www.biorxiv.org/content/10.1101/2020.09.29.318287v2.abstract.
In a second key publication we find that humans unconsciously compare their own body-odor to conspecific body-odor to guide decisions on social interaction. Humans interact better with other humans who smell like them. The strength of this link was such that we could predict the quality of future social interactions between strangers by smelling them with an electronic nose. These results can be seen at: https://www.biorxiv.org/content/10.1101/2021.06.14.448352v2.abstract.
In Aim 2 we asked: “How do humans exchange social chemosignals?”
In a series of studies we found that humans use a host of mechanisms to constantly but mostly subconsciously sniff themselves and each-other. For example, humans use hand-shake to smell other humans. These results can be seen at: 1.https://elifesciences.org/articles/05154.pdf. 2. https://academic.oup.com/chemse/article/39/4/277/318577. 3. https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2019.0372.
In Aim 3 we asked: "What are the brain mechanisms that subserve human social chemosignaling?"
We developed novel methods for fMRI of olfaction and chemosignaling (https://academic.oup.com/chemse/advance-article/doi/10.1093/chemse/bjaa085/6060058) and using these methods in each of the above and below reported studies, we uncovered how social odors are processed in the social brain, namely, in brain substrates of sociality rather than in primary or secondary olfactory cortex alone. Additionally, we serendipitously found that humans can maintain normal olfaction without olfactory bulbs, a finding that challenges our current understanding of how olfaction works (https://www.sciencedirect.com/science/article/pii/S0896627319308542).
In Aim 4 we asked:“What happens when social chemosignaling goes wrong?”
In a series of studies we found that impaired social chemosignaling may be associated with autism spectrum disorder (1.https://www.sciencedirect.com/science/article/pii/S096098221500651X. 2.https://www.nature.com/articles/s41593-017-0024-x) and in a second line of investigation we provide circumstantial evidence for altered chemosignaling in unexplained repeated pregnancy loss, or in other words, we raise the possibility of a human Bruce-like effect (https://elifesciences.org/articles/55305.pdf).
In combination, we have achieved most of the goals of this project.
In Aim 1 we asked:"What do human chemosignals signal?"
In one key publication we identify a specific chemosignal, hexadecanal, that blocks aggression in men but triggers aggression in women. What might be the ecological significance of this? In all mammals, offspring benefit from maternal aggression but suffer from paternal aggression. This is because maternal aggression is typically directed at intruders, yet paternal aggression is often directed at the offspring themselves. Thus, if offspring have a tool to increase maternal aggression but decrease paternal aggression, their survival increases. Hexadecanal is just such a tool. With this hypothesis in mind, we measured body-odor emissions from baby heads, and found that hexadecanal is indeed one of the most abundant baby volatiles. These remarkable results constitute the first identified human pheromone, and can be seen at:https://www.biorxiv.org/content/10.1101/2020.09.29.318287v2.abstract.
In a second key publication we find that humans unconsciously compare their own body-odor to conspecific body-odor to guide decisions on social interaction. Humans interact better with other humans who smell like them. The strength of this link was such that we could predict the quality of future social interactions between strangers by smelling them with an electronic nose. These results can be seen at: https://www.biorxiv.org/content/10.1101/2021.06.14.448352v2.abstract.
In Aim 2 we asked: “How do humans exchange social chemosignals?”
In a series of studies we found that humans use a host of mechanisms to constantly but mostly subconsciously sniff themselves and each-other. For example, humans use hand-shake to smell other humans. These results can be seen at: 1.https://elifesciences.org/articles/05154.pdf. 2. https://academic.oup.com/chemse/article/39/4/277/318577. 3. https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2019.0372.
In Aim 3 we asked: "What are the brain mechanisms that subserve human social chemosignaling?"
We developed novel methods for fMRI of olfaction and chemosignaling (https://academic.oup.com/chemse/advance-article/doi/10.1093/chemse/bjaa085/6060058) and using these methods in each of the above and below reported studies, we uncovered how social odors are processed in the social brain, namely, in brain substrates of sociality rather than in primary or secondary olfactory cortex alone. Additionally, we serendipitously found that humans can maintain normal olfaction without olfactory bulbs, a finding that challenges our current understanding of how olfaction works (https://www.sciencedirect.com/science/article/pii/S0896627319308542).
In Aim 4 we asked:“What happens when social chemosignaling goes wrong?”
In a series of studies we found that impaired social chemosignaling may be associated with autism spectrum disorder (1.https://www.sciencedirect.com/science/article/pii/S096098221500651X. 2.https://www.nature.com/articles/s41593-017-0024-x) and in a second line of investigation we provide circumstantial evidence for altered chemosignaling in unexplained repeated pregnancy loss, or in other words, we raise the possibility of a human Bruce-like effect (https://elifesciences.org/articles/55305.pdf).
In combination, we have achieved most of the goals of this project.
The achievements have several areas of potential societal impact:
1. Hexadecanal has been licensed by a company that is testing it as an agent that may calm drivers in a manner that will reduce car accidents.
2. Our results with autism may point to novel paths for diagnosis and intervention.
3. Our results with spontaneous miscarriage point to a novel path of intervention.
1. Hexadecanal has been licensed by a company that is testing it as an agent that may calm drivers in a manner that will reduce car accidents.
2. Our results with autism may point to novel paths for diagnosis and intervention.
3. Our results with spontaneous miscarriage point to a novel path of intervention.