Diversity in animal models is key to advancing human health: A commentary on Blanchard, Carter, and Lambert’s reviews

In this special issue on its 30^th Anniversary, past presidents of the International Behavioral Neuroscience Society (IBNS) detail trends in behavioral neuroscience. A notable trend is translational research, which aims to take research findings from non-human animals and translate them into breakthroughs that improve human brain health. Yet efforts to advance translation are hampered by the overreliance on mice and rats, which are used in about 93% of non-human animal studies (Carbone, 2021). Moreover, these species have been selectively bred and are housed in sterile, artificial, sparse environments with limited conspecifics for interaction. Three reviews from past IBNS presidents’ Drs. Sue Carter (Presidential Year, 2004), Kelly Lambert (Presidential Years, 2009 – 2011), and Caroline Blanchard (Presidential Years, 2011 – 2013) highlight that diversity in the animal models is needed in order for preclinical studies to result in improved treatments for mental illness. Dr. Lambert’s review quotes Stanford neurobiologist Dr. Joe Garner who sums up the problem with the current approach clearly:

We would never perform a human drug trial in 42-year-old white males with identical educational levels, identical socioeconomic statuses, identical jobs, identical houses with identical (locked) thermostats, identical wives, identical diets, identical exercise regimes, in the same small town in Wisconsin, who all incidentally had the same grandfather. So can we realistically expect mice in exactly this kind of Stepford experiment to tell us anything about humans in general, or variability in risk or response in particular? (Garner, 2014), p. 442.

An excellent example of leveraging non-traditional rodent species comes from the pioneering work of Dr. Carter on the monogamous, wild caught, prairie vole (Carter, 2023). Dr. Carter and her lab discovered that the naturally selected, life-long monogamy in the prairie vole was driven by social preferences, but not sexual preferences. This monogamous behavior was leveraged to study the neuropeptides that drive social behavior, including oxytocin. The capacity of prairie voles to form lasting bonds has many parallels to motherhood, including high levels of oxytocin and low levels of gonadal steroids. Dr. Carter also describes the concept of sociostasis, which is the reciprocal influence of individuals to regulate homeostasis and allostasis, and she argues that humans are in pursuit of sociostasis. Thus, understanding the mechanisms underlying this key aspect of human behavior could have huge impacts on human health. To elucidate the neurobiological underpinnings of sociostasis, the field will need studies in model animals that form pair bonds – it is important to note that such bonds are not formed by laboratory mice and rats.

In her review, Dr. Lambert (2023) describes pivoting from a laboratory animal model exclusive (L.A.M.E.) approach to an ethoexperimental approach, a strategy that emphasizes studying the behavior of animals in natural contexts described by the Blanchards (Blanchard et al., 1989). Dr. Lambert explains the differences in brains and behavior between rats, Rattus norvegicus, in the laboratory versus natural environments. Wild caught rats have higher stress hormone levels, heavier brains, larger visual cortical areas, and greater activation of regions involved in emotional processing than laboratory rats. These differences suggest that the selective breeding of laboratory rats has changed their brains perhaps helping them adapt to a monotonous, predictable environment at the expense of allowing them the flexibility needed to adapt to a dynamic environment experienced by their wild rat counterparts. Although there are practical challenges in moving away from the L.A.M.E. approach, increasing neuroscience studies in natural settings will improve the likelihood of identifying translational treatments for humans, who live in a variety of environments that typically are not sterile, monotonous, and with limited social interaction.

Dr. Blanchard pioneered the ethoexperimental approach with a focus on understanding defensive behavior in wild-trapped rats, as well as laboratory rats and mice (Blanchard, 2023). How an animal responds to a threat (e.g., avoid/evade vs. attack) depends on relevant features of the situation (e.g., hiding place vs. no escape route). Although this work was originally motivated by the tradition of conducting scientific studies because the questions are interesting, Dr. Blanchard notes a needed shift of the field towards translational work due to the staggering impact of mental illness across the globe. Dr. Blanchard and her team moved their basic work on defensive behavior in rodents to human populations by developing scenarios for human participants that create situations of either a clear and immediate threat or an ambiguous, but potentially imminent, threat. Interestingly, humans respond to threatening situations with a similar pattern to rodents. For example, defensive attack is negatively correlated with threat escapability and threat distance across species. Dr. Blanchard’s work highlights how ethologically relevant basic research can be leveraged to understanding normal and pathological threat behaviors in humans such as fear and violence.

It is noteworthy that appeals to include diverse animal species to improve translational research are being made here by scientists who themselves increased the diversity of the field of behavioral neuroscience. Drs. Carter, Lambert, and Blanchard were IBNS presidents at a time when most presidents of scientific organizations were men. In some cases, they share how their personal experiences have influenced their research. Dr. Carter details how motherhood influenced her understanding of and desire to pursue mechanisms underlying bonding, while Dr. Blanchard discusses how her partnership with her husband, Dr. Bob Blanchard, enriched her science. Additionally, these women leaders have influenced the work of many others the field. For example, in her review, Dr. Lambert acknowledges Drs. Blanchard and Carter’s impact on her own research program. Collectively, their scientific and personal journeys underscore that diversity in all aspects of behavioral neuroscience, from the models studied to the people conducting the research, is necessary if we hope to leverage findings from animal models to meaningful improvements in human brain health.