Sweet Mother Monkey Milk Cortisol Reloaded

Mother’s milk is more than a food full of essential nutrients and more than a medicine packed with protective immunofactors. Mother’s milk contains signals- hormones of maternal origin- that influence infant metabolism, neurobiology, and behavior. Profs Frank “Skip” Bartol and Carol Bagnell coined the term “lactocrine programming” to describe the effects of these hormones in the baby.

Wonderfully covered by Carl Zimmer for the NYT, is the sequel to our 2011 monkey milk cortisol paper. 

And like all self-respecting sequels, we had to pack in more special effects (new predictors & outcomes!), an expanded cast of characters (N>100!), and an extended run-time (longitudinal data!).

Monkey Milk Cortisol Reloaded original photo by Alex Georgiev

In other words, we collected milk at multiple time-points across lactation, measured FOOD & SIGNAL in milk (available milk energy AND cortisol) and correlated these milk features with infant growth AND temperament. And the story just got a LOT more complicated. That’s biology for you.

Life history tradeoffs, sex differences, MONKEYS!

Subtle Differences for Sons and Daughters

Monkey mothers who had higher concentrations of cortisol in their milk had daughters who were more “nervous” and less “confident.” For sons, though, how much cortisol increased across time that was correlated with being more “nervous” and less “confident.” Nervous was a temperament score that combined ratings by a trained observer on how “nervous, fearful, timid, NOT calm, and NOT confident” the infant was after a 25-hour assessment during peak lactation. Confidence was the temperament score combining “confident, bold, active, curious, playful” traits. 

Daughters’ temperaments were also correlated with maternal social rank. Which makes a lot of sense given that daughters inherit rank directly from their mother in rhesus monkeys. The temperament of sons, who kick up their heels for the open road and greener, sexier patches at reproductive maturity, were not attuned to mom’s social rank, rather their temperament was correlated with available milk energy, their own growth, and how many kids their mother had previously produced.

Here is a fancy pants set of graph of the relationships with temperament and milk cortisol measures after controlling for other important variables…

All the pretty data (Hinde et al. 2014)

And given that daughters were sensitive at different time-points and in subtly different ways than sons, suggest compellingly that the windows of sensitivity to mother’s milk cortisol were different for sons and daughters. The levels of cortisol in milk for sons and daughters were the same. When the same amount of signal is going from mom to baby, but the effects are different this means that HOW THE BABY IS USING THE SIGNAL IS DIFFERENT!

Not a mammal but so awesome I have to use it.

So what does explain the difference in cortisol concentrations in milk?

I know what you are thinking… must be social rank? Because macaques are a bunch of A-holes, right? NOPE! Cortisol in milk was not explained by differences in maternal social rank.

Cortisol in mother’s milk was best predicted by how many kids the mom had (aka parity). The fewer kids she had, the higher her cortisol in milk and the more it was likely to increase across lactation. And this effect was not just for first-time moms, but really showed a systematic decrease with each additional kiddo up until kid 10, then the change from parity to parity was much much much smaller.

Life History Theory and Tradeoffs

The evolutionary explanation is that natural selection has shaped adaptations in mothers that maximize their production of offspring across an entire reproductive career. Theorists explain that is moms invest too much in reproduction early on there is less available for later on, they leave fewer kiddos in the next generation and they are less-favored by natural selection than a mom that adjusts care and milk across a series of kids. Young mammalian moms have a lot of handicaps. They are still growing and developing when they begin to reproduce so they have to invest in the kiddo and their own growth. Since they are still growing they have fewer resources available for pregnancy and lactation. AND since babies need to reach a certain threshold condition, they can be bigger compared to their mom than the babies of more prime aged females. So young mothers have more to pay for, with fewer bodily resources, that are relatively more costly.

And in rhesus monkeys, the available milk energy is sensitive to the number of offspring a mom has had. The more times she has been pregnant and lactated, the more her mammary glands are able to produce milk. So we know that younger mothers have less milk to transfer to kiddos. We think that cortisol in milk functions to tell kiddo “buddy, there is limited milk coming down this pipeline, you need to prioritize growing, not burning precious calories playing and exploring.” In this way babies are seemingly calibrating to expected resources from the mom across lactation, having a more nervous, less confident temperament but cortisol in milk was correlated with better growth.

This generates a hierarchy of biological imperatives for the growing kiddo. First order of business: STAY ALIVE! aka “maintenance.”  Resources on top of that? GROW! Even more resources? Get your behavioral activity on!

Working Hypothesis: 

Milk Cortisol Orchestrates Infant Developmental Priorities 

in a Hierarchy of Biological Imperatives

Getting Down to Brass Tacks

Now, some folks may be inclined to think being more nervous, less confident is bad while being more confident, less nervous is good. And that high/increasing cortisol in milk is bad and low/decreasing cortisol in milk is good. 

BUT THOSE ARE NOT THE TAKEAWAYS! Because infants at both ends of this distribution are seemingly calibrating to the mom’s resources and environment. And generally speaking calibration is a good thing.

Our environmental experiences shape our gene expression that influences our behavioral biology. That capacity for developmental plasticity is, to me, the exquisite loveliness of biological systems. Contingent, cascading responses in these baby monkeys have the signature of adaptation because calibrating to mom can be essential for surviving the period of maternal dependence… even if it means that you are not “optimized” for adulthood.

Mortality in wild living animals is generally greatest during development. Although natural selection favors individuals that produce the most offspring (or help their relatives produce the most offspring) in order to produce offspring, an organism has to reach sexual maturity! So traits that help you make it to adulthood will be favored by natural selection too. 

What does this mean for humans?

Human milk contains cortisol and has been linked to temperament. Breast-fed human babies have increased expression of cortisol receptors in their intestinal tract (kickass work by Sharon Donovan & colleagues). And in humans cortisol concentrations in milk are correlated with circulating cortisol in the mother’s bloodstream. 

Taken together, these suggest to me that babies are like other mammalian young, they have physiology specifically to use hormonal signals from mom ingested via milk to influence their daily functioning and shape their development. But we know hardly anything about this biobehavioral system in humans. Monkeys and humans share many features relative to other mammals- we typically produce socially complex, large-brained, singleton infants upon whom we lavish care, so the monkey results are informative for motivating more human research.

What does it mean when cortisol is missing (formula) or cortisol in milk is turned to 11 with the knob broken off? We don’t know. Do we expect it to necessarily be catastrophic in typically developing kiddos? No, we don’t… because this one hormone, in one aspect of parenting, is just one of the rivets holding the plane wing on. One rivet can break, and the plane still flies… even two or three and the plane can get off the ground. Development is a multi-factorial system, and rarely is any one single aspect the linchpin.

So moms, don’t let these findings stress you out.

Kathy West/CNPRC

The OPEN ACCESS article: Hinde K,  Skibiel AL,  Foster AB, Del Rosso L, Mendoza SP, & Capitanio JP. 2014. Cortisol in mother’s milk across lactation reflects maternal life history and predicts infant temperament. Behavioral Ecology. Advance Access.

And science is necessarily collaborative & the most exciting research happens at the intersections of academic fields so…

Collaborators: Roll Call!

Amy Skibiel, previously a post-doc in the Comparative Lactation Lab, who did groundbreaking research in ground squirrel lactation and is a Lecturer at Auburn University. She also did a mega-mammal-milk analysis.

Sally Mendoza & John Capitanio, UC Davis Department of Psychology and the California National Primate Research Center are epically awesome in all ways. Since they will likely gut me if I continue rhapsodizing publicly, I will just direct you to this recent paper on paternal care and this one on monkey loneliness.

Alison Foster was an undergraduate student in the lab who did initial analyses on a subset of these data and presented them at the UC Davis undergraduate research symposium. She is now doing graduate work for Early Childhood Special Education Certification.

Last but not least: Laura Del Rosso has been the day-to-day operations manager of the BBA program since the beginning in 2001. She worked tirelessly to juggle the to schedule the infants from the Mother’s Milk Study for BioBehavioral Assessment, anticipated and neutralized potential hiccups, and basically facilitated this research study coming together so smoothly. I am forever in her debt.

Further Reading:

Bartol FF, Wiley AA, Bagnell CA.  Relaxin and maternal lactocrine programming of neonatal uterine development.  Annals of the New York Academy of Sciences  1160:158-163, 2009.

Donovan, S. M., Wang, M., Monaco, M. H., Martin, C. R., Davidson, L. A., Ivanov, I., & Chapkin, R. S. (2014). Noninvasive molecular fingerprinting of host–microbiome interactions in neonates. FEBS letters.

Glynn LM, Davis EP, Schetter CD, Chicz-Demet A, Hobel CJ, Sandman CA. 2007. Postnatal maternal cortisol levels predict temperament in healthy breastfed infants. Early Hum Dev. 83(10):675-81.

Grey KR, Davis EP, Sandman CA, Glynn LM. 2013. Human milk cortisol is associated with infant temperament. Psychoneuroendocrinology. pii: S0306-4530(12)00358-7. doi: 10.1016/j.psyneuen.2012.11.002.

Hinde K, Capitanio JP. 2010. Lactational programming? Mother’s milk predicts infant temperament and behavior. Am J Primatol. 72:522-529

Hinde K. 2013. Lactational programming of infant behavioral phenotype In: Primate Developmental Trajectories in Proximate and Ultimate Perspectives. Clancy KBH, Hinde K, Rutherford JN, eds.  Springer, New York. pp 187-207

Sullivan EC, Hinde K, Mendoza SP, Capitanio JP. 2011. Cortisol concentrations in the milk of rhesus monkey mothers are associated with confident temperament in sons, but not daughters. Dev Psychobiol 53: 96–104.

Yan, Wenbo, Anne A. Wiley, Ross AD Bathgate, Amy-Lynn Frankshun, Sally Lasano, Bethany D. Crean, Bernard G. Steinetz, Carol A. Bagnell, and Frank F. Bartol. "Expression of LGR7 and LGR8 by neonatal porcine uterine tissues and transmission of milk-borne relaxin into the neonatal circulation by suckling." Endocrinology 147, no. 9 (2006): 4303-4310.

____________________

Also check out these other anthropological new releases on breast milk!

EA Quinn's new paper on milk leptin!

Cecília Tomori's new book on Nighttime Breastfeeding!

Aunchalee Palmquist's paper on Breast Milk Sharing!

____________________

Additional thoughts that didn’t fit in the main body of text above, laid out in manufactured Q & A:

Every new study of course generates MOAR empirical questions:

Q: Two time points huh- pretty much locks you into a linear effect interpretation. Couldn’t there be other critical windows of sensitivity and sweet curvilinear effects of milk hormones across lactation?

A: Probably! Future research should definitely collect samples at more time points across lactation, especially if they can involve experimental manipulations that demonstrate causal arrow insights into health, cognition, growth, and behavior.

Q: What about the infant’s genotype? Couldn’t genotype influence how sensitive infants are to the variation in the maternal physiological investment?

A: Probably! Gene by environment (e.g. maternal behavioral care and physiological investment prenatally) interactions have been empirically demonstrated… these dynamics likely apply to mother’s milk too.

Q: Glucocorticoids are important for immune function- couldn’t glucocorticoids in milk interact with immune factors in milk and consequently affect immune function in the baby?

A: Probably!

Q: You only looked at cortisol, couldn’t lots of other hormones and additional milk constituents influence infant behavior & temperament? Couldn’t these milk bioactives be interacting in complex and variable ways across lactation and infant development?

A: Probably!

Q: Wow, that’s a lot of “probablies.” To think that this incredible adaptation has been shaped by natural selection for hundreds of millions of years such that there are thousands of constituents in milk! And we still don’t systematically know how they influence baby development?!! That’s Crazy Town! Aren’t these key topics to address global health goals for infant survival and thrival? Given such key questions remain unanswered, along with so many other research mandates, should Americans be freaked the eff out that the main funding source for health-related research, the National Institutes of Health, has been stalled and is now decreasing!

A: Probably. And by probably I mean DEFINITELY!!! Luckily, the incoming 114th United States Congress is looking forward to our calls and letters about the importance of improving research funding.