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Depression as an evolutionary adaptation: Implications for the development of preclinical models
Medical Hypotheses 72 (2009) 342–347
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Depression as an evolutionary adaptation: Implications for the development of preclinical models C.A. Hendrie a,*, A.R. Pickles b a b
Institute of Psychological Sciences, University of Leeds, Leeds LS2 9JT, UK School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
a r t i c l e
i n f o
Article history: Received 16 September 2008 Accepted 25 September 2008
s u m m a r y Several authors have suggested that rather than being a disease state, depression is an evolutionary adaptation to human social organization. Adaptations are produced in response to selection pressures and similar adaptations may easily have evolved in a range of other species. The current paper seeks to identify the social pressures that may lead to a species developing depression as an adaptation and the potential benefits that this may confer. It also examines whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression as an adaptation are likely to exist. It is proposed that depression is a useful adaptation in group-living animals, where there is competition for a social rank that gives reproductive advantage over others. The cluster of symptoms associated with depression include altered activity patterns, reduced sociability and appetite, and increased submissiveness. This combination strongly suggests that the function of depression is to reduce the likelihood of an individual being subject to further attack once they have lost social status and so increase their chances of survival in the period immediately following this. Successful transition from high to low status may provide further opportunities to reproduce. Hence, animals that become depressed during this critical period gain a reproductive advantage over those that do not, as these are either killed or expelled from the group. Wild mice do not have social hierarchies and are highly territorial. Wild rats do have social hierarchies however these only compete for reproductive advantage at the level of the sperm, and social status does not translate into significantly greater access to mates. Therefore, there are no selection pressures in these species towards the development of depression and so it is most unlikely that rats and mice have this adaptation. It is concluded that current models of depression based on rats and mice are in reality models of monoamine activity and that progression beyond this tautology requires future models to be developed using species selected on the basis of their social organizations in the wild. Hendrie and Pickles, Medical Hypotheses. Ó 2008 Elsevier Ltd. All rights reserved.
Introduction Depression has a clear genetic component [59] and in recent years serious consideration has been given to the view that this is because it is not a disease state but an evolutionary adaptation to situations that arise as a result of human social organization [60,68,70,89]. In evolutionary terms, there are selection pressures towards the development of adaptations and as adaptations are not endpoints in themselves, these must confer benefit to individuals that show these responses. The same evolutionary pressures may produce similar adaptations in a range of species. Therefore, whilst there is no A priori reason to suppose that depression is a response uniquely seen in humans, there are strong reasons to suppose that this will not be seen in all species. This latter point has important consequences for the modeling of depression in the lab-
* Corresponding author. Tel.: +44 1133435736; fax: +44 1133435749. E-mail address: [email protected] (C.A. Hendrie). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.09.053
oratory as, in the same way that flight cannot be studied in animals that do not fly, depression cannot be modeled in species that are not adapted to show this response. The current paper proposes that depression is not a response uniquely seen in humans and seeks (i) to identify the social pressures that may lead to a species developing this adaptation and the advantages it may confer and (ii) to examine whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression are likely to exist.
Animal modeling and general mammalian features Laboratory rats and mice have been used since very early in the modern scientific epoch [52,58] and findings from these have formed the basis of many significant advances in our understanding and treatment of human organic diseases over the last hundred years and more. The main reason for the extensive use of these
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species is because of their general characteristics as mammals and their high fecundity, relatively small size and comparative docility [76] rather than any special features that they share with humans. As a class, mammals are remarkably similar and although there are over 4000 species (of which nearly half are rodents) in 20 orders, over 130 families and around 1000 genera, with birth weights ranging from 3 g to 6500 kg and adult lengths varying from 4 cm to more than 30 m, these are all clearly derived from a common ancestral stock [45]. Therefore, the morphology and physiology of all mammals are recognizably similar, and so rats and mice may usefully be used as models for human organic diseases. However, mammals are also to some extent social animals for at least some part of their lives. This arises in consequence of their need to suckle their young. These social organizations may be very simple, involving only a very few animals in transient groupings or they may be very complex, involving animals living permanently in very large groups made up of several generations and both sexes. The social organizations of mammals include all variations between these possibilities and individuals are adapted to meet the demands of their own particular social environment. Therefore, whilst mammalian morphology and physiology are recognizably similar across these species, their social adaptations are specialized and to a large extent species-specific. At the beginning of the 21st Century, drug treatments for depression remain only marginally different from those discovered by serendipity more than 50 years ago (c.f. imipramine and fluoxetine). If the reasons for this relatively slow progress lie within the animals that are used to model depression, then this is most likely to be due to their social rather than physiological characteristics.
Sociobiological considerations The basic tenet of sociobiology is that individuals are carriers of genes and that the survival and ultimate reproduction of these genes is their primary goal [94]. There are various routes to reproductive success, however the two most important aspects of these are access to mates and survival rates of the offspring. In most mammalian species there is a male-biased operational sex ratio [39] that is the result of far fewer eggs being available than sperm [25,88]. Therefore, males compete amongst themselves for access to females. At its simplest this competition may be at the level of the sperm [8]. However, social hierarchies may also develop that give dominant animal’s preferential sexual access. For example, in chimpanzees, alpha males sire more than half of a colony’s offspring during their reign [47]. Consequently, securing a high rank in these hierarchies has a profound influence on a males’ ability to reproduce. As a general rule subordinate animals mate less often, less successfully and/or have access to lower quality gametes than their dominant counterparts [27,38,53,62,78,82], although this is not always the case [12]. Therefore, there is often intense competition for dominance [31,32,61,73]. Social rank is also important for females [5]. Males have a lower threshold to mate than females [24] and so females are almost always assured of opportunities to copulate. However, not all mates are equally desirable, as the social rank of an offspring is heavily influenced by the social status of its parents [20, p. 98]. Further, the major cost of reproduction almost always falls on females in terms of gestation, lactation and other aspects of postnatal care [3, p. 397]. Therefore, females may form their own dominance hierarchies [2,4] or adopt other strategies [17], in order to secure matings with high-ranking males and so ensure that their investment is made in offspring with the highest possible reproductive potential. In species that make a significant parental investment there is a trade-off between levels of parental care needed to increase
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survival rates and the number of offspring that are not produced because of the need to provide this care [3, p. 482]. Therefore, these species produce only a relatively few offspring over a lifetime and each of these is of enormous value as a mechanism by which the parents’ genes may continue to be reproduced. In sociobiological terms, loss of any one of these offspring is disastrous, as is the loss of access to mates in species where significant investment is made to procure these. Therefore, animals that make significant parental investment and make significant investment in procuring their mates are extremely vulnerable to damage to their reproductive potential. This damage may be caused by the loss of a previous investment (and an indirect future investment), such as the death of a child or it may be caused by damage to future investment, such as the loss of a high social rank that gives preferential access to mates.
Depression as an adaptation In species where there is competition for a rank that gives reproductive advantage over others, it is inevitable that this social status will at some point be lost, in view of increasing age, injury or simply facing bigger or more aggressive rivals. This may occur in both sexes. At its most punitive, all the previously high-ranking animals’ offspring may be killed or driven away by the newly dominant animal [15]. This infanticide may be perpetrated by both sexes on both sexes [33] and is a reproductive catastrophe for the victims. It is proposed that depression is an adaptation to situations such as these. That is, where there has been a loss of social status in species, where rank gives a reproductive advantage over others and where no or only very few offspring survive their parents loss of rank. Surviving a downward movement through a social hierarchy may give rise to opportunities to improve upon what is otherwise a very poor genetic legacy, and depression is the mechanism by which the chances of survival are increased during the transition to a lower social rank. For depression to be effective under these circumstances and hence to have adaptive significance, its core symptoms must serve to protect affected individuals from further attack and the increased vulnerability to disease that is associated with this period [26,57], which indeed appears to be the case. Sleep disturbances ensure that depressed individuals are active mainly at times when other animals are not [42]. Reduced appetite [77] and libido [83] means that the need for affected animals to compete for these resources is minimized [77]. Reduced sociability [37,46] places affected animals at the edge of social groupings and hence largely away from points of conflict. As a by-product this also reduces the risk of contagion from other animals. Where contact with other animals is unavoidable, submissive gestures such as a hunched posture, downward gaze and avoidance of eye contact [36,68] serve to reduce the probability of further attack and hence the likelihood of physical harm, as does the suppression of social signals through ‘arrested flight’ that is also seen in depression [35]. These core symptoms of human depression give strong indication that the behavioural consequences of the low mood that is associated with depression [6,74] and with losing in competitive situations [41] is the mechanism by which individuals survive a downward change in their status, rather than its product. Those with little or no chance of reproducing, such as the old or poorly fecund, are also those most likely to consider suicide [30]. Those that do not possess this adaptation leave or are driven from the group or die and so also forgo the opportunity to reproduce once they have lost social status. Therefore, although depression is associated with a negative mood state, there is clear indication that there is a positive selection pressure towards its development. The key social features required for its development as an adapta-
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tion are (i) that within a social hierarchy there is competition for high rank that gives reproductive advantage over others; (ii) that no, or only very few offspring survive the parents’ loss of rank and (iii) that previously high ranking animals’ only further opportunities for reproductive success come from remaining within these groups. Social organization of mice Rats and mice are the most common species used to model depression in the laboratory. However, there is very little indication within the current framework to suggest that these species’ natural social organizations required them to develop depression as an adaptation. In the wild, there are strong pressures for mice to disperse [23] and they are aggressively territorial, living in small groups usually comprised of one male and several females [13,28,29]. Reproduction is closely linked to food supply [75] and as mice rarely survive more than two winters it has been estimated that each female produces around 40 offspring in her lifetime [92] with males fathering around 120–160 offspring in theirs, which may on rare occasions involve matings with females from neighbouring territories [18]. Evidence of mouse territoriality can also be seen in laboratory situations [49] and simple housing manipulations can be used to reveal the two social forms of mice, dominants and subordinates [71]. Subordinate animals are typified by their poor physical condition, impaired reproductive status and low resistance to parasite infection/disease [16]. In view of the heavy predation pressure on mice [55], subordinates do not survive for more than short periods in the wild [13]. In the context of animals losing their social status, male mice are highly infanticidal, so much so that dominants have had to develop mechanisms to prevent them killing their own young [67]. Therefore, where a male loses dominance and his territory is taken over by another male, then all the pups remaining in the natal nest site are killed. Females remain within the territory as the principle reproductive resource and must bear the loss of their latest litter unless they can manage to protect these through their ‘maternal aggression’ [65]. They suffer no damage to their reproductive potential beyond that, as their earlier litters will have already dispersed and they retain access to dominant males. Losing males in dominance contests are, however, driven from their territory and as animals in unfamiliar environments are more vulnerable to predation [40, 51] where they may be expected to be quickly lost. Where they are not lost, the only further opportunity formerly dominant animals have to reproduce is to either compete for and win another males’ territory or form another breeding unit from scratch [63]. Therefore, it is most unlikely that mice have developed depression as an adaptation. Where males lose their territories, this is to animals coming in from the outside. Otherwise there is complete spatial separation of dominant and subordinate animals, except in the most unusual of circumstances [29]. Hence, there is no social hierarchy and no advantage to be gained by adopting social strategies designed to increase the chances of surviving the transitional phase to subordinate status.
Social organization of rats With regard to rats, Linnaeus once thought that these were huge mice (Mus decumanus) in view of their similar physical appearances [11, p. 3]. Their social structures are, however, completely different. Laboratory strains of rats are derived from Rattus norvegicus and in the wild these are a burrowing species that live in colonies and form social hierarchies composed of a and b males. Females do not appear to form hierarchies of their own. Alpha males are usually the largest and do not defer to other rats in the
colony. Beta males are subordinate to alpha males. A third subtype,
x, has also been described. However, these are not thought to exist outside confined colonies as these animals are repeatedly attacked by the alpha animals and rapidly develop poor condition, often dying very quickly of no obvious physical cause [9–11]. Rat colonies are territorial and intruders are vigorously attacked. ‘Intruder’ under these circumstances is determined by olfactory signals. Rats spend a lot of their time in close physical contact [11] and so develop a colonial scent. Animals that do not have this smell are attacked and driven away [22,85,87]. In view of this scent barrier, there is great pressure for colonies to be populated by animals that are descended from that colony and hence have a high probability of being related to each other. In keeping with this, rats, unlike mice, play fight as juveniles [11,66,84] and this influences status in later life. Consequently, there is little actual fighting amongst established colony members and status is, where necessary, maintained by threat rather than attack [86]. Although alpha males are more aggressive than beta animals, this characteristic does not necessarily translate into greater access to females. In free-living colonies, oestrous females may mate up to 300 times during a 6–10 h period with those males that are in sufficient condition to avoid the bites that the females direct at them as they dismount [81]. This promiscuous mating strategy produces uncertainty of parentage and so protects the females’ young from potential infanticide [91]. Hence, in free-living rat colonies all related males have access to females and only reproductively compete with each other at the level of the sperm. The crucial nature of this relatedness is demonstrated by studies using artificially created colonies composed of unrelated animals, where alpha males attempt to monopolize access to females and to drive other males away [14,81] Reproductive units dominated by related males are also seen in other species [19] and although these animals do not have equal reproductive success amongst themselves [64], in sociobiological terms this is of little consequence as individuals within these breeding units by definition share many of the same genes. Therefore, in established rat colonies alpha status offers only marginal reproductive advantage and so there is very little competition for this, particularly where animals have grown up together. Breeding status may be lost following territorial invasion however and alpha and beta males are driven away from the colony [81]. As with mice, female rats remain within the territory and attempt to defend their latest litter through maternal aggression [72] suffering no further damage to their reproductive potential. Displaced males, however, have very little chance of surviving as they face attack in each new territory they enter [21] and males that remain in their colonies are repeatedly attacked by the new dominant and quickly succumb [11]. Within this context, there are only two possibilities for depression to be useful as a mechanism by which to survive the transition to a lower social status in these animals. These are, firstly, where omega animals survive and rejoin the new colony structure and secondly, where beta males switch allegiance and become accepted by the invaders. As far as the authors are aware there are no data concerning these events in free-living colonies, but it is difficult to see the benefit to the invader in allowing these animals to remain. Absence of evidence is of course not evidence of absence. However, parallels may be drawn from other species whose breeding units are also dominated by coalitions of related males. Following territory loss in these species all mature and juvenile males are driven away and all their pups are killed [69]. Therefore, it is most unlikely that the social structure of rats produces selection pressures towards the development of depression as an adaptation. Indeed, the very high mortality rate of omega animals strongly indicates that this species are not adapted to cope with such circumstances.
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Implications for current models of depression
High
The current analysis indicates that neither rats nor mice are adapted to become depressed. However, these are the species most often used to model depression in the laboratory. Therefore, the question arises as to what this means for the wealth of data generated using these animals in this context. The answer is, very little. For example, Willner [93], calling on the terminology of questionnaire designers, classifies the wide variety of animal models of depression as those having predictive, face or construct validities. Those with predictive validity are bioscreens that have no relationship to clinical depression, other than that their end points are altered by currently known antidepressants. Models with face validity attempt to produce responses that are similar in one or more respects to features seen in clinical depression however their defining characteristic remains the sensitivity of their end points to the actions of known antidepressants. Models with construct validity do not as yet exist. Current models of depression are therefore defined by their sensitivity to known antidepressants and so their development has therefore been drug-led. In consequence, their relationships to the clinical features of depression are secondary to their sensitivity to actions of the known antidepressants and this alone is sufficient for a model to be classified as a model of depression. It is beyond the scope of this paper to address the features of individual models. However, it is clear that many of these models fail the ‘‘Man on the Clapham omnibus” test (i.e. the logic of their use is not readily apparent). More importantly, the current definitions of what constitutes a model of depression are glaringly tautological. A model of depression is a model of depression because it is sensitive to actions of the known antidepressants. Therefore, whilst models used in this context are referred to as ‘models of depression’ they are in fact screens for drugs that act on
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the monoamine systems. As such, the species used in these tests are immaterial as there is no requirement for these to be adapted to show depressive responses. The choice of species is, however, crucial for the development of new models designed to break out of this tautological loop (Fig. 1). Importance of species choice for new model development The heavy reliance of clinicians on self-report and psychometric analysis with a strong emphasis on mood [54] has presented preclinicians with difficult targets to aim at, given that these only have access to animals’ behaviour and not their mood. However, in very recent years advances have been made in developing an understanding of the effects of psychiatric illness on human behaviour using ethological methods [35,36,46,90]. Ethology has been used in animal laboratories for many years [43,44]; however, this new use of the ethological method in clinical situations gives clear guidelines for model designers to follow. The laboratory aim is to clearly reproduce the behavioural expressions of depression described in the clinic. For this to be done effectively, the species used in these models are critical and these must be selected on the basis of an analysis of their social organizations in the wild that indicates that they are likely to have developed depression as an adaptation. Such an analysis reveals that common laboratory species such as gerbils [1,2,48,50,79,80] and marmosets [7,34,56] may fulfill this criterion but as the current manuscript shows, rats or mice do not. This conclusion raises several important scientific and ethical questions about the continued use of rats and mice in this context. The antidepressant therapies we currently have are universally recognized as being inadequate, yet one of the greatest contributors to the intellectual inertia that is currently preventing the development of truly novel drug-based antidepressant therapies is the continued use of inappropriate species to try and model a disorder they are not psychologically equipped to develop.
Low
Reproductive Potential
References
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Middle
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Social Status Fig. 1. The adaptive significance of depression: The above figure represents a hypothetical grouping in which selection pressures towards the development of depression as an adaptation are likely to exist. Individuals are represented by the black circles. High ranking animals have greater reproductive potential than lower ranking animals. Loss of social status (represented by the dotted white lines) therefore produces damage to reproductive potential. Animals may continue to reproduce only by remaining in the group. Depression confers benefit to animals losing social status by increasing their chances of surviving the transition period to a lower rank and so gives reproductive advantage over those animals that die or are driven away. Therefore, there is a selection pressure towards the development of depression as an adaptation, especially in species where changes in social rankings are relatively common.
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Depression as an evolutionary adaptation: Implications for the development of preclinical models C.A. Hendrie a,*, A.R. Pickles b a b
Institute of Psychological Sciences, University of Leeds, Leeds LS2 9JT, UK School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
a r t i c l e
i n f o
Article history: Received 16 September 2008 Accepted 25 September 2008
s u m m a r y Several authors have suggested that rather than being a disease state, depression is an evolutionary adaptation to human social organization. Adaptations are produced in response to selection pressures and similar adaptations may easily have evolved in a range of other species. The current paper seeks to identify the social pressures that may lead to a species developing depression as an adaptation and the potential benefits that this may confer. It also examines whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression as an adaptation are likely to exist. It is proposed that depression is a useful adaptation in group-living animals, where there is competition for a social rank that gives reproductive advantage over others. The cluster of symptoms associated with depression include altered activity patterns, reduced sociability and appetite, and increased submissiveness. This combination strongly suggests that the function of depression is to reduce the likelihood of an individual being subject to further attack once they have lost social status and so increase their chances of survival in the period immediately following this. Successful transition from high to low status may provide further opportunities to reproduce. Hence, animals that become depressed during this critical period gain a reproductive advantage over those that do not, as these are either killed or expelled from the group. Wild mice do not have social hierarchies and are highly territorial. Wild rats do have social hierarchies however these only compete for reproductive advantage at the level of the sperm, and social status does not translate into significantly greater access to mates. Therefore, there are no selection pressures in these species towards the development of depression and so it is most unlikely that rats and mice have this adaptation. It is concluded that current models of depression based on rats and mice are in reality models of monoamine activity and that progression beyond this tautology requires future models to be developed using species selected on the basis of their social organizations in the wild. Hendrie and Pickles, Medical Hypotheses. Ó 2008 Elsevier Ltd. All rights reserved.
Introduction Depression has a clear genetic component [59] and in recent years serious consideration has been given to the view that this is because it is not a disease state but an evolutionary adaptation to situations that arise as a result of human social organization [60,68,70,89]. In evolutionary terms, there are selection pressures towards the development of adaptations and as adaptations are not endpoints in themselves, these must confer benefit to individuals that show these responses. The same evolutionary pressures may produce similar adaptations in a range of species. Therefore, whilst there is no A priori reason to suppose that depression is a response uniquely seen in humans, there are strong reasons to suppose that this will not be seen in all species. This latter point has important consequences for the modeling of depression in the lab-
* Corresponding author. Tel.: +44 1133435736; fax: +44 1133435749. E-mail address: [email protected] (C.A. Hendrie). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.09.053
oratory as, in the same way that flight cannot be studied in animals that do not fly, depression cannot be modeled in species that are not adapted to show this response. The current paper proposes that depression is not a response uniquely seen in humans and seeks (i) to identify the social pressures that may lead to a species developing this adaptation and the advantages it may confer and (ii) to examine whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression are likely to exist.
Animal modeling and general mammalian features Laboratory rats and mice have been used since very early in the modern scientific epoch [52,58] and findings from these have formed the basis of many significant advances in our understanding and treatment of human organic diseases over the last hundred years and more. The main reason for the extensive use of these
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species is because of their general characteristics as mammals and their high fecundity, relatively small size and comparative docility [76] rather than any special features that they share with humans. As a class, mammals are remarkably similar and although there are over 4000 species (of which nearly half are rodents) in 20 orders, over 130 families and around 1000 genera, with birth weights ranging from 3 g to 6500 kg and adult lengths varying from 4 cm to more than 30 m, these are all clearly derived from a common ancestral stock [45]. Therefore, the morphology and physiology of all mammals are recognizably similar, and so rats and mice may usefully be used as models for human organic diseases. However, mammals are also to some extent social animals for at least some part of their lives. This arises in consequence of their need to suckle their young. These social organizations may be very simple, involving only a very few animals in transient groupings or they may be very complex, involving animals living permanently in very large groups made up of several generations and both sexes. The social organizations of mammals include all variations between these possibilities and individuals are adapted to meet the demands of their own particular social environment. Therefore, whilst mammalian morphology and physiology are recognizably similar across these species, their social adaptations are specialized and to a large extent species-specific. At the beginning of the 21st Century, drug treatments for depression remain only marginally different from those discovered by serendipity more than 50 years ago (c.f. imipramine and fluoxetine). If the reasons for this relatively slow progress lie within the animals that are used to model depression, then this is most likely to be due to their social rather than physiological characteristics.
Sociobiological considerations The basic tenet of sociobiology is that individuals are carriers of genes and that the survival and ultimate reproduction of these genes is their primary goal [94]. There are various routes to reproductive success, however the two most important aspects of these are access to mates and survival rates of the offspring. In most mammalian species there is a male-biased operational sex ratio [39] that is the result of far fewer eggs being available than sperm [25,88]. Therefore, males compete amongst themselves for access to females. At its simplest this competition may be at the level of the sperm [8]. However, social hierarchies may also develop that give dominant animal’s preferential sexual access. For example, in chimpanzees, alpha males sire more than half of a colony’s offspring during their reign [47]. Consequently, securing a high rank in these hierarchies has a profound influence on a males’ ability to reproduce. As a general rule subordinate animals mate less often, less successfully and/or have access to lower quality gametes than their dominant counterparts [27,38,53,62,78,82], although this is not always the case [12]. Therefore, there is often intense competition for dominance [31,32,61,73]. Social rank is also important for females [5]. Males have a lower threshold to mate than females [24] and so females are almost always assured of opportunities to copulate. However, not all mates are equally desirable, as the social rank of an offspring is heavily influenced by the social status of its parents [20, p. 98]. Further, the major cost of reproduction almost always falls on females in terms of gestation, lactation and other aspects of postnatal care [3, p. 397]. Therefore, females may form their own dominance hierarchies [2,4] or adopt other strategies [17], in order to secure matings with high-ranking males and so ensure that their investment is made in offspring with the highest possible reproductive potential. In species that make a significant parental investment there is a trade-off between levels of parental care needed to increase
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survival rates and the number of offspring that are not produced because of the need to provide this care [3, p. 482]. Therefore, these species produce only a relatively few offspring over a lifetime and each of these is of enormous value as a mechanism by which the parents’ genes may continue to be reproduced. In sociobiological terms, loss of any one of these offspring is disastrous, as is the loss of access to mates in species where significant investment is made to procure these. Therefore, animals that make significant parental investment and make significant investment in procuring their mates are extremely vulnerable to damage to their reproductive potential. This damage may be caused by the loss of a previous investment (and an indirect future investment), such as the death of a child or it may be caused by damage to future investment, such as the loss of a high social rank that gives preferential access to mates.
Depression as an adaptation In species where there is competition for a rank that gives reproductive advantage over others, it is inevitable that this social status will at some point be lost, in view of increasing age, injury or simply facing bigger or more aggressive rivals. This may occur in both sexes. At its most punitive, all the previously high-ranking animals’ offspring may be killed or driven away by the newly dominant animal [15]. This infanticide may be perpetrated by both sexes on both sexes [33] and is a reproductive catastrophe for the victims. It is proposed that depression is an adaptation to situations such as these. That is, where there has been a loss of social status in species, where rank gives a reproductive advantage over others and where no or only very few offspring survive their parents loss of rank. Surviving a downward movement through a social hierarchy may give rise to opportunities to improve upon what is otherwise a very poor genetic legacy, and depression is the mechanism by which the chances of survival are increased during the transition to a lower social rank. For depression to be effective under these circumstances and hence to have adaptive significance, its core symptoms must serve to protect affected individuals from further attack and the increased vulnerability to disease that is associated with this period [26,57], which indeed appears to be the case. Sleep disturbances ensure that depressed individuals are active mainly at times when other animals are not [42]. Reduced appetite [77] and libido [83] means that the need for affected animals to compete for these resources is minimized [77]. Reduced sociability [37,46] places affected animals at the edge of social groupings and hence largely away from points of conflict. As a by-product this also reduces the risk of contagion from other animals. Where contact with other animals is unavoidable, submissive gestures such as a hunched posture, downward gaze and avoidance of eye contact [36,68] serve to reduce the probability of further attack and hence the likelihood of physical harm, as does the suppression of social signals through ‘arrested flight’ that is also seen in depression [35]. These core symptoms of human depression give strong indication that the behavioural consequences of the low mood that is associated with depression [6,74] and with losing in competitive situations [41] is the mechanism by which individuals survive a downward change in their status, rather than its product. Those with little or no chance of reproducing, such as the old or poorly fecund, are also those most likely to consider suicide [30]. Those that do not possess this adaptation leave or are driven from the group or die and so also forgo the opportunity to reproduce once they have lost social status. Therefore, although depression is associated with a negative mood state, there is clear indication that there is a positive selection pressure towards its development. The key social features required for its development as an adapta-
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tion are (i) that within a social hierarchy there is competition for high rank that gives reproductive advantage over others; (ii) that no, or only very few offspring survive the parents’ loss of rank and (iii) that previously high ranking animals’ only further opportunities for reproductive success come from remaining within these groups. Social organization of mice Rats and mice are the most common species used to model depression in the laboratory. However, there is very little indication within the current framework to suggest that these species’ natural social organizations required them to develop depression as an adaptation. In the wild, there are strong pressures for mice to disperse [23] and they are aggressively territorial, living in small groups usually comprised of one male and several females [13,28,29]. Reproduction is closely linked to food supply [75] and as mice rarely survive more than two winters it has been estimated that each female produces around 40 offspring in her lifetime [92] with males fathering around 120–160 offspring in theirs, which may on rare occasions involve matings with females from neighbouring territories [18]. Evidence of mouse territoriality can also be seen in laboratory situations [49] and simple housing manipulations can be used to reveal the two social forms of mice, dominants and subordinates [71]. Subordinate animals are typified by their poor physical condition, impaired reproductive status and low resistance to parasite infection/disease [16]. In view of the heavy predation pressure on mice [55], subordinates do not survive for more than short periods in the wild [13]. In the context of animals losing their social status, male mice are highly infanticidal, so much so that dominants have had to develop mechanisms to prevent them killing their own young [67]. Therefore, where a male loses dominance and his territory is taken over by another male, then all the pups remaining in the natal nest site are killed. Females remain within the territory as the principle reproductive resource and must bear the loss of their latest litter unless they can manage to protect these through their ‘maternal aggression’ [65]. They suffer no damage to their reproductive potential beyond that, as their earlier litters will have already dispersed and they retain access to dominant males. Losing males in dominance contests are, however, driven from their territory and as animals in unfamiliar environments are more vulnerable to predation [40, 51] where they may be expected to be quickly lost. Where they are not lost, the only further opportunity formerly dominant animals have to reproduce is to either compete for and win another males’ territory or form another breeding unit from scratch [63]. Therefore, it is most unlikely that mice have developed depression as an adaptation. Where males lose their territories, this is to animals coming in from the outside. Otherwise there is complete spatial separation of dominant and subordinate animals, except in the most unusual of circumstances [29]. Hence, there is no social hierarchy and no advantage to be gained by adopting social strategies designed to increase the chances of surviving the transitional phase to subordinate status.
Social organization of rats With regard to rats, Linnaeus once thought that these were huge mice (Mus decumanus) in view of their similar physical appearances [11, p. 3]. Their social structures are, however, completely different. Laboratory strains of rats are derived from Rattus norvegicus and in the wild these are a burrowing species that live in colonies and form social hierarchies composed of a and b males. Females do not appear to form hierarchies of their own. Alpha males are usually the largest and do not defer to other rats in the
colony. Beta males are subordinate to alpha males. A third subtype,
x, has also been described. However, these are not thought to exist outside confined colonies as these animals are repeatedly attacked by the alpha animals and rapidly develop poor condition, often dying very quickly of no obvious physical cause [9–11]. Rat colonies are territorial and intruders are vigorously attacked. ‘Intruder’ under these circumstances is determined by olfactory signals. Rats spend a lot of their time in close physical contact [11] and so develop a colonial scent. Animals that do not have this smell are attacked and driven away [22,85,87]. In view of this scent barrier, there is great pressure for colonies to be populated by animals that are descended from that colony and hence have a high probability of being related to each other. In keeping with this, rats, unlike mice, play fight as juveniles [11,66,84] and this influences status in later life. Consequently, there is little actual fighting amongst established colony members and status is, where necessary, maintained by threat rather than attack [86]. Although alpha males are more aggressive than beta animals, this characteristic does not necessarily translate into greater access to females. In free-living colonies, oestrous females may mate up to 300 times during a 6–10 h period with those males that are in sufficient condition to avoid the bites that the females direct at them as they dismount [81]. This promiscuous mating strategy produces uncertainty of parentage and so protects the females’ young from potential infanticide [91]. Hence, in free-living rat colonies all related males have access to females and only reproductively compete with each other at the level of the sperm. The crucial nature of this relatedness is demonstrated by studies using artificially created colonies composed of unrelated animals, where alpha males attempt to monopolize access to females and to drive other males away [14,81] Reproductive units dominated by related males are also seen in other species [19] and although these animals do not have equal reproductive success amongst themselves [64], in sociobiological terms this is of little consequence as individuals within these breeding units by definition share many of the same genes. Therefore, in established rat colonies alpha status offers only marginal reproductive advantage and so there is very little competition for this, particularly where animals have grown up together. Breeding status may be lost following territorial invasion however and alpha and beta males are driven away from the colony [81]. As with mice, female rats remain within the territory and attempt to defend their latest litter through maternal aggression [72] suffering no further damage to their reproductive potential. Displaced males, however, have very little chance of surviving as they face attack in each new territory they enter [21] and males that remain in their colonies are repeatedly attacked by the new dominant and quickly succumb [11]. Within this context, there are only two possibilities for depression to be useful as a mechanism by which to survive the transition to a lower social status in these animals. These are, firstly, where omega animals survive and rejoin the new colony structure and secondly, where beta males switch allegiance and become accepted by the invaders. As far as the authors are aware there are no data concerning these events in free-living colonies, but it is difficult to see the benefit to the invader in allowing these animals to remain. Absence of evidence is of course not evidence of absence. However, parallels may be drawn from other species whose breeding units are also dominated by coalitions of related males. Following territory loss in these species all mature and juvenile males are driven away and all their pups are killed [69]. Therefore, it is most unlikely that the social structure of rats produces selection pressures towards the development of depression as an adaptation. Indeed, the very high mortality rate of omega animals strongly indicates that this species are not adapted to cope with such circumstances.
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Implications for current models of depression
High
The current analysis indicates that neither rats nor mice are adapted to become depressed. However, these are the species most often used to model depression in the laboratory. Therefore, the question arises as to what this means for the wealth of data generated using these animals in this context. The answer is, very little. For example, Willner [93], calling on the terminology of questionnaire designers, classifies the wide variety of animal models of depression as those having predictive, face or construct validities. Those with predictive validity are bioscreens that have no relationship to clinical depression, other than that their end points are altered by currently known antidepressants. Models with face validity attempt to produce responses that are similar in one or more respects to features seen in clinical depression however their defining characteristic remains the sensitivity of their end points to the actions of known antidepressants. Models with construct validity do not as yet exist. Current models of depression are therefore defined by their sensitivity to known antidepressants and so their development has therefore been drug-led. In consequence, their relationships to the clinical features of depression are secondary to their sensitivity to actions of the known antidepressants and this alone is sufficient for a model to be classified as a model of depression. It is beyond the scope of this paper to address the features of individual models. However, it is clear that many of these models fail the ‘‘Man on the Clapham omnibus” test (i.e. the logic of their use is not readily apparent). More importantly, the current definitions of what constitutes a model of depression are glaringly tautological. A model of depression is a model of depression because it is sensitive to actions of the known antidepressants. Therefore, whilst models used in this context are referred to as ‘models of depression’ they are in fact screens for drugs that act on
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the monoamine systems. As such, the species used in these tests are immaterial as there is no requirement for these to be adapted to show depressive responses. The choice of species is, however, crucial for the development of new models designed to break out of this tautological loop (Fig. 1). Importance of species choice for new model development The heavy reliance of clinicians on self-report and psychometric analysis with a strong emphasis on mood [54] has presented preclinicians with difficult targets to aim at, given that these only have access to animals’ behaviour and not their mood. However, in very recent years advances have been made in developing an understanding of the effects of psychiatric illness on human behaviour using ethological methods [35,36,46,90]. Ethology has been used in animal laboratories for many years [43,44]; however, this new use of the ethological method in clinical situations gives clear guidelines for model designers to follow. The laboratory aim is to clearly reproduce the behavioural expressions of depression described in the clinic. For this to be done effectively, the species used in these models are critical and these must be selected on the basis of an analysis of their social organizations in the wild that indicates that they are likely to have developed depression as an adaptation. Such an analysis reveals that common laboratory species such as gerbils [1,2,48,50,79,80] and marmosets [7,34,56] may fulfill this criterion but as the current manuscript shows, rats or mice do not. This conclusion raises several important scientific and ethical questions about the continued use of rats and mice in this context. The antidepressant therapies we currently have are universally recognized as being inadequate, yet one of the greatest contributors to the intellectual inertia that is currently preventing the development of truly novel drug-based antidepressant therapies is the continued use of inappropriate species to try and model a disorder they are not psychologically equipped to develop.
Low
Reproductive Potential
References
Low
Middle
High
Social Status Fig. 1. The adaptive significance of depression: The above figure represents a hypothetical grouping in which selection pressures towards the development of depression as an adaptation are likely to exist. Individuals are represented by the black circles. High ranking animals have greater reproductive potential than lower ranking animals. Loss of social status (represented by the dotted white lines) therefore produces damage to reproductive potential. Animals may continue to reproduce only by remaining in the group. Depression confers benefit to animals losing social status by increasing their chances of surviving the transition period to a lower rank and so gives reproductive advantage over those animals that die or are driven away. Therefore, there is a selection pressure towards the development of depression as an adaptation, especially in species where changes in social rankings are relatively common.
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