Quick Guide to Evolutionary Medicine in Neuroimmunomodulation: Why "Evolved for the Benefit of the Species" Is Not a Valid Argument.

BACKGROUND: Evolutionary medicine builds on evolutionary biology and explains why natural selection has left us vulnerable to disease. Unfortunately, several misunderstandings exist in the medical literature about the levels and mechanisms of evolution. Reasons for these problems start from the lack of teaching evolutionary biology in medical schools. A common mistake is to assume that "traits must benefit the species, as otherwise the species would have gone extinct in the past" confusing evolutionary history (phylogeny) with evolutionary function (fitness). SUMMARY: Here we summarise some basic aspects of evolutionary medicine by pointing out: (1) Evolution has no aim. (2) For adaptive evolution to occur, a trait does not have to be beneficial to its carrier throughout its entire life. (3) Not every single individual carrying an adaptive trait needs to have higher than average fitness. (4) Traits do not evolve for the benefit of the species. Using examples from the field of neuroimmunomodulation like sickness behaviour (nervous system), testosterone (hormones), and cytokines (immunity), we show how misconceptions arise from not differentiating between the explanatory categories of phylogeny (evolutionary history) and evolutionary function (fitness). KEY MESSAGES: Evolution has no aim but is an automatism that does not function for the benefit of the species. In evolution, successful individuals are those that maximise the transmission of their genes, and health and survival are just strategies to have the opportunity to do so. Thus, a trait enabling survival of the individual until reproductive age will spread even if at later age the same trait leads to disease and death. Natural and sexual selection do not select for traits that benefit the health or happiness of the individual, but for traits that increase inclusive fitness even if this increases human suffering. In contrast, our humane aim is to increase individual well-being. Evolutionary medicine can help us achieve this aim against evolutionary constraints.

Cognitive performance is linked to survival in free-living African striped mice.

Cognition is shaped by evolution and is predicted to increase fitness. However, the link between cognition and fitness in free-living animals is unresolved. We studied the correlates of cognition and survival in a free-living rodent inhabiting an arid environment. We tested 143 striped mice (Rhabdomys pumilio) using a battery of cognitive tests, including: (i) an attention task, (ii) two problem-solving tasks, (iii) a learning and reversal learning task, and (iv) an inhibitory control task. We related cognitive performance with days of survival. Better problem-solving and inhibitory control performance were significant correlates of survival. Surviving males showed greater reversal learning which may be related to sex-specific behavioural and life-history characteristics. Specific cognitive traits and not a composite measure of general intelligence underpins fitness in this free-living rodent population, enhancing our understanding of the evolution of cognition in non-human animals.

Seasonal changes in problem-solving in wild African striped mice.

Innovative problem-solving ability is a predictor of whether animals can successfully cope with environmental changes. These environmental changes can test the limits of animals, for example when energy availability decreases seasonally and, hence, problem-solving performance decreases because less energy is available for cognitive processes. Here, we investigated: (1) how problem-solving performance changed between seasons that differed significantly in food availability; (2) whether these changes were related to environmentally induced physiological changes in blood glucose and ketone levels, indicators of energy availability; and (3) whether individual variation in problem-solving was related to sex differences. We studied 99 free-ranging African striped mice, Rhabdomys pumilio, in the Succulent Karoo, South Africa, 55 during the hot dry summer with low food availability and 44 during the cold wet winter with higher food availability. We measured their problem-solving abilities using a food extraction task and found no seasonal differences in problem-solving success. However, mice solved the problem faster in summer versus winter. In summer, food availability was reduced and blood ketones increased but there was no seasonal difference in blood glucose levels. There were no correlation between problem-solving performance and blood glucose or ketone levels. Overall, more males solved the task than females. It appears that in striped mice cognitive functions can be maintained under harsh environmental conditions.

Developmental mechanisms of stripe patterns in rodents.

Mammalian colour patterns are among the most recognizable characteristics found in nature and can have a profound impact on fitness. However, little is known about the mechanisms underlying the formation and subsequent evolution of these patterns. Here we show that, in the African striped mouse (Rhabdomys pumilio), periodic dorsal stripes result from underlying differences in melanocyte maturation, which give rise to spatial variation in hair colour. We identify the transcription factor ALX3 as a regulator of this process. In embryonic dorsal skin, patterned expression of Alx3 precedes pigment stripes and acts to directly repress Mitf, a master regulator of melanocyte differentiation, thereby giving rise to light-coloured hair. Moreover, Alx3 is upregulated in the light stripes of chipmunks, which have independently evolved a similar dorsal pattern. Our results show a previously undescribed mechanism for modulating spatial variation in hair colour and provide insights into how phenotypic novelty evolves.

Do alternative reproductive tactics predict problem-solving performance in African striped mice?

In changing environments, animals face unexpected problems to solve. Not all individuals in a population are equally able to solve new problems. It still remains unclear what factors (e.g. age and body condition) influence the propensity of problem solving. We investigated variation in problem-solving performance among males following alternative reproductive tactics (ARTs). We studied a free-ranging population of the African striped mouse (Rhabdomys pumilio). Adult male striped mice can employ 3 ARTs: (1) dominant group-living breeders, (2) philopatric living in their natal group, and (3) solitary-living roamers. ARTs in male striped mice reflect differences in competitiveness, sociality and physiology which could influence their problem-solving performance. We tested a total of 48 males in 2 years with two tasks: a string-pulling task to reach food and a door-opening task to reach the nest. Since male striped mice differ in personality traits independent of ARTs, we also measured activity, boldness and exploration. In addition, we assessed the association of body condition and age with problem solving. Problem solving was related the interaction of age and ARTs. The younger philopatrics had better performance in a food-extraction task whereas the older breeders were faster at solving the door-opening task. Individual differences in traits related to personality were significant correlates of problem-solving performance: pro-active mice (i.e. more active and explorative and bolder) performed better in both tasks. Finally, problem-solving performance was not consistent between the two tasks. Our study provides evidence of correlates of ARTs, age and personality on problem-solving abilities.

Seasonal variation in telomere dynamics in African striped mice.

Telomere shortening has been used as an indicator of aging and is believed to accelerate under harsh environmental conditions. This can be attributed to the fact that telomere shortening has often been regarded as non-reversible and negatively impacting fitness. However, studies of laboratory mice indicate that they may be able to repair telomere loss to recover from environmental harshness, as indicated by recent studies in hibernating rodents. We studied seasonal variation in telomere dynamics in African striped mice (Rhabdomys pumilio) living in a highly seasonal environment. In our annual species, individuals born in the moist spring (high food availability) need to survive the harsh dry summer (low food availability) to be able to reproduce in the following spring. We studied the effect of the harsh dry vs. the benign moist season on telomere dynamics. We also tested if telomere length or the rate of change in telomere length over the dry season predicted the probablity of dissapearance from the population at the same time. Male, but not female, stripped mice showed age-related telomere erosion. Telomeres were longer at the beginning of the dry season compared to the rest of the year. Telomeres increased significantly in length during the moist season. Neither telomere length at the onset of the dry season nor telomere loss over the dry season predicted whether or not individuals disappeared. In conclusion, our data suggest that seasonal attrition and restoring of telomeres also occurs in non-hibernating wild rodents living in hot food restricted environments.

Elevated basal corticosterone levels increase disappearance risk of light but not heavy individuals in a long-term monitored rodent population.

According to the cort-fitness hypothesis, glucocorticoid levels correlate negatively with fitness. However, field studies found mixed support for this hypothesis, potentially because the association between glucocorticoids and fitness might depend on prevailing environmental conditions. Based on the long-term monitoring of a natural rodent population, we tested whether individuals with elevated corticosterone levels were more likely to disappear, accounting for individual condition and among-year variation in food availability, population density and predation pressure. We used basal corticosterone levels measured at the onset of the pre-breeding season in 331 African striped mice from six generations. While basal corticosterone levels were highly repeatable within individuals, between-individual variation was large. Survival analysis revealed that disappearance risk over the pre-breeding season increased with elevated basal corticosterone levels for light but not for heavy individuals. High levels of corticosterone may be more deleterious to smaller individuals (i.e. through allostatic overload), eventually increasing their mortality risk, and disappearance would represent actual death. An alternative non-exclusive explanation could be that high levels of corticosterone selectively trigger dispersal in light individuals, and disappearance would rather reflect their departure from the population. Although environmental conditions varied considerably among generations, none of the interactions between corticosterone and environmental variables were significant. Disappearance probability was positively correlated with both predation pressure and with food availability, a factor favoring dispersal. In sum, elevated basal corticosterone levels increased disappearance in light striped mice, either directly via reduced survival prospects and/or indirectly via dispersal.

Fat content of striped mice decreases during the breeding season but not during the food-restricted dry season.

Individuals that are capable of accumulating appropriate fat stores are assumed to have selective advantages when food becomes scarce. Similarly to species from temperate zones, some species inhabiting arid areas accumulate fat stores prior to periods of food limitation. Yet, we have little knowledge concerning seasonal variation in body composition and the relationship between fat store size and disappearance risk in species from arid habitats. Using the water dilution method, we examined the body composition of African striped mice (Rhabdomys pumilio) living in a seasonal habitat with a long food-restricted dry season. We tested for seasonal changes in body composition (N=159 measurements of 113 individuals) and whether dry season survival was related to fat mass (N=66 individuals). Fat stores were similar in size at the onset and the end of the dry season, but surprisingly smaller at the onset of the moist breeding season. Fat stores showed a negative relationship with food availability. Individual variation in fat stores was not associated with disappearance risk, but there was a positive association of disappearance risk with body mass. Increased disappearance risk of heavy individuals suggests elevated dispersal rates in competitive individuals. This study suggests that non-breeding philopatric striped mice do not accumulate large fat stores prior to the food-limited dry season but that they might mobilize fat stores at the onset of the breeding season to satisfy the energetic demands of reproduction and/or to decrease costs associated with larger fat stores, such as increased predation risk.

Density feedbacks mediate effects of environmental change on population dynamics of a semidesert rodent.

Population dynamics are the result of an interplay between extrinsic and intrinsic environmental drivers. Predicting the effects of environmental change on wildlife populations therefore requires a thorough understanding of the mechanisms through which different environmental drivers interact to generate changes in population size and structure. In this study, we disentangled the roles of temperature, food availability and population density in shaping short- and long-term population dynamics of the African striped mouse, a small rodent inhabiting a semidesert with high intra- and interannual variation in environmental conditions. We parameterized a female-only stage-structured matrix population model with vital rates depending on temperature, food availability and population density, using monthly mark-recapture data from 1609 mice trapped over 9 years (2005-2014). We then applied perturbation analyses to determine relative strengths and demographic pathways of these drivers in affecting population dynamics. Furthermore, we used stochastic population projections to gain insights into how three different climate change scenarios might affect size, structure and persistence of this population. We identified food availability, acting through reproduction, as the main driver of changes in both short- and long-term population dynamics. This mechanism was mediated by strong density feedbacks, which stabilized the population after high peaks and allowed it to recover from detrimental crashes. Density dependence thus buffered the population against environmental change, and even adverse climate change scenarios were predicted to have little effect on population persistence (extinction risk over 100 years <5%) despite leading to overall lower abundances. Explicitly linking environment-demography relationships to population dynamics allowed us to accurately capture past population dynamics. It further enabled establishing the roles and relative importances of extrinsic and intrinsic environmental drivers, and we conclude that doing this is essential when investigating impacts of climate change on wildlife populations.

Intra-specific variation in social organization of Strepsirrhines.

Strepsirrhines, that is, lemurs, galagos, and lorises, are considered basal primates, making them important to understand the evolution of primate sociality. Apart from some lemurs, they are nocturnal and solitary living, though the view of their sociality nature has changed with field studies being completed. We conducted a review of the primary literature about the social organization (group composition) of strepsirrhines, with the aim to determine whether intra-specific variation in social organization (IVSO) occurs and to determine how many species are pair-living, group-living, or solitary living. We found data in 83 peer-reviewed studies for 43 of the 132 strepsirrhine species and compared our results using two databases on social systems of mammals published in 2011 and 2013. While it is often assumed that primates show relatively fixed social organizations, we found that 60.5% of species for which data exist have IVSO. We found only 7% of the species to be truly solitary living (with 34.9% additional species to be sometimes solitary living), which is in contrast to the other databases, which had reported 60.9% and 37.7% of species to be solitary. We further explored group compositions by designating "functional groups" (e.g., foraging, breeding, and infant care groups). While functional groups might explain IVSO within a single species, this was not consistent over species with IVSO, such that IVSO was poorly explained by functional groups. Our study supports the view that most strepsirrhines are social (58.1% of species with another 34.9% of species sometimes living in pairs or groups) and show complex and often variable social organizations; reinforcing the assumption that the ancestor of all primates was social and not solitary.

Both thyroid hormone levels and resting metabolic rate decrease in African striped mice when food availability decreases.

In response to variation in food availability and ambient temperature (Ta), many animals show seasonal adaptations in their physiology. Laboratory studies showed that thyroid hormones are involved in the regulation of metabolism, and their regulatory function is especially important when the energy balance of an individual is compromised. However, little is known about the relationship between thyroid hormones and metabolism in free-living animals and animals inhabiting seasonal environments. Here, we studied seasonal changes in triiodothyronine (T3) levels, resting metabolic rate (RMR) and two physiological markers of energy balance (blood glucose and ketone bodies) in 61 free-living African striped mice (Rhabdomys pumilio) that live in an semi-arid environment with food shortage during the dry season. We predicted a positive relationship between T3 levels and RMR. Further, we predicted higher T3 levels, blood glucose levels and RMR, but lower ketone body concentrations, during the moist season when food availability is high compared with summer when food availability is low. RMR and T3 levels were negatively related in the moist season but not in the dry season. Both RMR and T3 levels were higher in the moist than in the dry season, and T3 levels increased with increasing food availability. In the dry season, blood glucose levels were lower but ketone body concentrations were higher, indicating a change in substrate use. Seasonal adjustments in RMR and T3 levels permit a reduction of energy expenditure when food is scarce, and reflect an adaptive response to reduced food availability in the dry season.

Survival is linked with reaction time and spatial memory in African striped mice.

Studying the association between fitness and cognition in free-living animals is a fundamental step in the elucidation of the evolution of cognition. We assessed whether survival until the onset of the breeding season was related to reaction time or spatial memory in the African striped mouse Rhabdomys pumilio, a rodent that has to survive summer drought before breeding. We tested a total of 90 individuals at the beginning of summer. Female survival was related to a faster response to predation stimuli. Male survival increased with greater spatial memory, possibly because it is important for males to remember the configuration of the environment during dispersal. This study revealed that individual variation in reaction time and spatial memory can be related to survival probability, which is important for understanding the selection pressures acting on basic cognitive traits.

Alternative reproductive tactics in female striped mice: Solitary breeders have lower corticosterone levels than communal breeders.

Alternative reproductive tactics (ARTs), where members of the same sex and population show distinct reproductive phenotypes governed by decision-rules, have been well-documented in males of many species, but are less well understood in females. The relative plasticity hypothesis (RPH) predicts that switches between plastic ARTs are mediated by changes in steroid hormones. This has received much support in males, but little is known about the endocrine control of female ARTs. Here, using a free-living population of African striped mice (Rhabdomys pumilio) over five breeding seasons, we tested whether females following different tactics differed in corticosterone and testosterone levels, as reported for male striped mice using ARTs, and in progesterone and oestrogen, which are important in female reproduction. Female striped mice employ three ARTs: communal breeders give birth in a shared nest and provide alloparental care, returners leave the group temporarily to give birth, and solitary breeders leave to give birth and do not return. We expected communal breeders and returners to have higher corticosterone, owing to the social stress of group-living, and lower testosterone than solitary breeders, which must defend territories alone. Solitary breeders had lower corticosterone than returners and communal breeders, as predicted, but testosterone and progesterone did not differ between ARTs. Oestrogen levels were higher in returners (measured before leaving the group) than in communal and solitary breeders, consistent with a modulatory role. Our study demonstrates hormonal differences between females following (or about to follow) different tactics, and provides the first support for the RPH in females.

Seasonal variation in attention and spatial performance in a wild population of the African striped mouse (Rhabdomys pumilio).

Cognitive flexibility describes the reversible changes of cognition in response to environmental changes. Although various environmental factors such as temperature, photoperiod and rainfall change seasonally, seasonal variation in cognitive performance has been reported in merely a few birds and mammals. We assessed whether cognitive performance in a wild population of African striped mice Rhabdomys pumilio, from the Succulent Karoo semidesert of South Africa, differed between summer and winter. In order to measure cognitive performance, striped mice were trapped in the field, tested under laboratory conditions at our research station and returned to the field within 5 h. We measured attention and spatial memory using the standardized orientation response test and the Barnes maze test. Males tested during summer oriented faster toward a predator-stimulus but made more errors and took longer to locate a shelter than males tested during winter. In contrast, females' performance did not differ between the two seasons. We discuss how the faster orientation in males during winter might be the consequence of lower temperatures and/or prolonged food restriction. We suggest that the enhancement of spatial performance during winter might be due to a greater motivation for future dispersal in male striped mice, as spring represents the breeding season.

Alternative reproductive tactics in female striped mice: heavier females are more likely to breed solitarily than communally.

Alternative reproductive tactics (ARTs) are discrete reproductive phenotypes governed by decision rules called strategies. ARTs are fixed for life in species with alternative strategies, while tactic expression is plastic in species with a single strategy. ARTs have been investigated in males of many species, but few studies have tested whether the same theoretical framework applies in females. Female striped mice (Rhabdomys pumilio) employ three ARTs: communal breeders give birth in a nest shared with female kin and a breeding male and show allo-parental care; returners give birth away from the shared nest and later return to it; and solitary breeders give birth away from the shared nest and do not return to the group. Here, studying free-living female striped mice over six breeding seasons, we tested whether ARTs arise from alternative strategies or a single strategy. We also asked to what extent stochastic extrinsic factors explain whether individuals become solitary rather than group living. Females switched tactics, consistent with a single strategy, so we tested whether this represented a mixed or conditional single strategy. Only the latter predicts differences between ARTs in traits indicating competitive ability, such as body mass or age, before individuals adopt a tactic. We weighed females at conception when they were still group living to eliminate potential confounding effects of gestation and subsequent social tactic (solitary versus group living) on body mass. Females that went on to use a solitary ART were heavier than those that became communal breeders and returners, in support of a conditional strategy. Solitary breeders also arose through extrinsic factors (mortality of all adult female group members). They weighed less than females that became solitary while relatives were alive, but did not differ in body mass from communal breeders and returners. We conclude that ART theory applies to both sexes, with female striped mice following a conditional single strategy. Future studies should consider the possibility that phenotypes that superficially resemble evolved tactics might also arise through non-adaptive extrinsic causes.

Basal blood glucose concentration in free-living striped mice is influenced by food availability, ambient temperature and social tactic.

Vertebrates obtain most of their energy through food, which they store mainly as body fat or glycogen, with glucose being the main energy source circulating in the blood. Basal blood glucose concentration (bBGC) is expected to remain in a narrow homeostatic range. We studied the extent to which bBGC in free-living African striped mice (Rhabdomys pumilio) is influenced by ecological factors with a bearing on energy regulation, i.e. food availability, abiotic environmental variation and social tactic. Striped mice typically form extended family groups that huddle together at night, reducing energetic costs of thermoregulation, but solitary individuals also occur in the population. We analysed 2827 blood samples from 1008 individuals of seven different social categories that experienced considerable variation in food supply and abiotic condition. Blood samples were taken from mice in the morning after the overnight fast and before foraging. bBGC increased significantly with food plant abundance and decreased significantly with minimum daily ambient temperature. Solitary striped mice had significantly higher bBGC than group-living striped mice. Our results suggest that adaptive responses of bBGC occur and we found large natural variation, indicating that bBGC spans a far greater homeostatic range than previously thought.

Arginine vasopressin plasma levels change seasonally in African striped mice but do not differ between alternative reproductive tactics.

Arginine vasopressin (AVP) is an important hormone for osmoregulation, while as a neuropeptide in the brain it plays an important role in the regulation of social behaviors. Dry habitats are often the home of obligately sociable species such as meerkats and Damaraland mole-rats, leading to the hypothesis that high plasma AVP levels needed for osmoregulation might be associated with the regulation of social behavior. We tested this in a facultative sociable species, the African striped mouse (Rhabdomys pumilio). During the moist breeding season, both solitary- and group-living reproductive tactics occur in this species, which is obligatory sociable in the dry season. We collected 196 plasma samples from striped mice following different reproductive tactics both during the moist and the dry season. Solitary mice did not have lower AVP levels than sociable mice, rejecting the hypothesis that peripheral AVP is involved in the regulation of alternative reproductive tactics. However, we found significantly higher AVP levels during the dry season, with AVP levels correlated with the abundance of food plants, the main source of water for striped mice. Plasma AVP levels were not correlated with testosterone or corticosterone levels. Our study underlines the important role that AVP plays in osmoregulation, particularly for a free ranging mammal living under harsh arid conditions.

Leptin levels in free ranging striped mice (Rhabdomys pumilio) increase when food decreases: the ecological leptin hypothesis.

Leptin is a hormone informing the body about its fat stores, reducing appetite and foraging and as such reducing fattening of individuals. In laboratory rodents, leptin secretion is highly correlated to the amount of adipose tissue. We compared this to the alternative ecological leptin hypothesis, which based on the behavioural effects of leptin predicts that leptin levels are disassociated from adipose tissue when fattening is of evolutionary advantage to survive coming periods of low food availability. Studying a species that has to survive a dry season with low food availability, we tested the ecological leptin hypothesis, predicting low leptin levels when food availability and thus adiposity is high promoting foraging and fattening, but high leptin levels in the seasons of low food availability, reducing energetic costs due to foraging. We measured leptin levels in 154 samples of free living African striped mice (Rhabdomys pumilio). Striped mice gain significant body mass during the moist season to survive the following dry season with low food availability. We found a strong seasonal effect, with higher leptin levels in the dry season with low food availability, which was in contrast to the hypothesis deriving from studies on laboratory rodents, but in agreement with ecological leptin hypothesis: leptin levels remained low in the period of high food availability, allowing fattening, but increased during periods of low food availability, possibly suppressing energetically costly foraging in an environment where foraging success would have been very low. Leptin correlated significantly and negatively with testosterone levels, and high testosterone levels in the moist season could explain why leptin levels were low even though food availability was high. However, analysing samples from an experimental laboratory study where testosterone levels were increased via implants found no support for a suppressive role of testosterone on leptin. In sum, our study indicates that in a species with seasonal fattening, leptin levels might be uncoupled from the amount of adipose tissue.