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From mice to men: What can animal models tell us about the relationship between mental health and physical activity?
Mental Health and Physical Activity 2 (2009) 10–15
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Mental Health and Physical Activity journal homepage: www.elsevier.com/locate/menpa
From mice to men: What can animal models tell us about the relationship between mental health and physical activity? Gary Remington a, b, * a b
Faculty of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Medication Assessment Program for Schizophrenia (MAPS), Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2009 Accepted 25 January 2009
Physical activity has been associated with numerous benefits that extend to mental health, although how these benefits are accrued is not clear. The notion that animal research can prove useful in this regard may initially seem irrelevant and even inapplicable. However, there is a growing body of evidence, focusing in particular on exercise, to suggest that the biochemical changes induced with exercise include many of the same systems involved in psychiatric illnesses such as depression and anxiety disorder. Moreover, these changes parallel what has been linked to the clinical benefits of pharmacotherapy. While animal studies cannot adequately tap into the psychological benefits of activity or exercise, they are better suited to address the biological component across a number of dimensions. The focus of this commentary is on how animal studies and/or models may be utilized to better understand the relationship between physical activity and mental health/illness. Animal work is not without its limitations and must stand the test of translational value. Against this standard, we are not pursuing comprehensive animal models that mirror the human condition as much as paradigms that elicit selected biological features of a mental disorder’s underlying pathophysiology. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Animal models Mental health Physical activity
Few topics generate the polarized debate observed around discussions of animal research. Its proponents relate the numerous discoveries that have been dependent on such research (e.g., vaccines, antibiotics, organ transplantation) (Belmatoug & Fantin, 1997; Gradmann, 2008; Seppen, Filali, & Elferink, 2009), while opponents are quick to point out the suffering, overuse, and lack of translational value (Baumans, 2004; Brune, 2002; McKinney, 2001; Perry, 2007; Qiu, 2007). For many working in the field of mental health promotion and treatment, animal research may be unfamiliar and appear irrelevant. Mental illness, unlike many physical diseases, is more easily framed as a human condition. Defined in part by behaviour, assessment of mental illness and, conversely, mental health is very much subjective and language-dependent (e.g., description of mood, anxiety, perceptual disturbances), calling into question what role animal research might serve (Insel, 2007). This said, animal research is now inextricably part of psychiatry, and the present commentary specifically addresses how it can shed light on the relationship between mental health and physical activity. Several comments regarding terminology are warranted at the outset. The terms physical activity and exercise will each be used,
* Tel.: þ1 416 535 8501x4750; fax: þ1 416 979 4292. E-mail address: [email protected] 1755-2966/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mhpa.2009.01.003
recognizing that they are not synonymous (Taylor & Faulkner, 2008), and whenever possible the distinction between acute and chronic exposure will be clarified. The animal studies routinely involve rodents (rats or mice), where open field locomotion (movement within a large box) is generally used as a measure of activity, while access to a running wheel or treadmill represents examples of exercise. Acute exposure generally refers to one or, at most, several bouts of exercise within a circumscribed time interval, while chronic exposure involves, for example, access to exercise over a 1-month interval. It should be acknowledged that there are no clearly established criteria that allow comparison of exercise in terms of type, intensity, or duration (Dishman et al., 2006). Reference will be made to both mental health and psychiatric illness; however, mental health is not defined as an absence of psychiatric illness. Just as activity subsumes exercise as one subset, mental health subsumes those with psychiatric illness as simply one subpopulation. It extends to all individuals though, an important distinction when examining the literature. This is not meant as an exhaustive review. Rather, it is more of a primer for those less familiar with this line of research, focusing on psychiatric illness and examples of what we have learned through animal studies. It is written from the perspective of a clinician-researcher in the field of schizophrenia who began in animal research, left to do human work after feeling the animal
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studies might be ‘lost in translation’, ultimately returning to a combined approach that arose out of opportunities to ask similar questions at both levels – making it easier to ensure translational value.
members to a greater extent than in the general population (Gottesman & Gould, 2003).
1. Animal models
The notion that psychological well-being may be influenced by physical activity and health is by no means a new idea; that it is receiving greater attention at present speaks to the confluence of a number of factors over recent years (Carless & Faulkner, 2003). There was of course the exercise ‘craze’ that took hold in the 1970s and linked fitness with mental well-being (Brennan, 1985). However, this was an image-conscious movement that had little to do with major psychiatric illness. During this same time, psychiatry itself remained steeped in biological models and psychopharmacology as the search continued for newer and more effective psychotropic agents. Indeed, there were growing concerns that the ‘psyche’ was being lost to an increasingly myopic and reductionistic focus on biological therapies (Borgeat, Gagnon, Hudon, Lalonde, & Reid, 1985). There were other avenues, though, that would tie exercise specifically to both general mental health, as well as psychiatric disorders. Various lines of animal investigation have demonstrated that exercise favourably influences a number of biochemical factors involved in neurogenesis, neural plasticity and neuroprotection which are key elements in overall brain health (Cotman, Berchtold, & Christie, 2007; Dishman et al., 2006; Duman, 2005). This represents a centrally mediated effect that can not only enhance neurocognitive activities such as learning and memory, but protect against the negative effects associated with stress and aging (Dishman et al., 2006). In addition, exercise can produce peripherally mediated biochemical benefits through its favourable effects on such risk factors as hypertension, glucose dysregulation, and dyslipidemia (Cotman et al., 2007). Previously, work had demonstrated that sustained exercise (e.g., running, swimming) could induce at least some of the neurochemical changes observed with pharmacological treatment of psychiatric conditions such as depression (Blomstrand, Perrett, Parry-Billings, & Newsholme, 1989; Chaouloff, 1994; Chaouloff, Laude, & Elghozi, 1989; Dey, 1994; Ransford, 1982). This was not seen as an endorsement that exercise could replace pharmacotherapy, nor has this turned out to be the case (Mead et al., 2008); however, it offered biological evidence that exercise could translate to improvement in domains such as depression and anxiety, as well as add to our understanding of underlying pathophysiology. This line of thinking took yet another step with neuroimaging evidence in humans that non-pharmacological interventions (e.g., Cognitive Behavioural Therapy [CBT]) in depression can induce changes at the level of the central nervous system (CNS), in line with what is observed following effective pharmacotherapy (Goldapple et al., 2004; Kennedy et al., 2007). Such work further strengthened the position that the types of biochemical changes thought to mediate psychological conditions such as depression could be favourably altered indirectly without the need for medications.
Animal models are designed to mirror a human condition in a way that offers opportunities to better understand its origins, course, and/or treatment. It is often assumed, mistakenly, that such models must parallel the human condition on all dimensions and this is not the case. Two personal examples reflect this. During my postgraduate work, our lab employed a species of mouse that exhibited a transient period of hyperkinesis during development that drew comparisons to what is observed in attention deficit hyperactivity disorder (ADHD) (Anisman, Grimmer, Irwin, Remington, & Sklar, 1979; Remington & Anisman, 1976). The model was effective in better understanding the possible contribution of neurotransmitter development, specifically norepinephrine and acetylcholine, to hyperactivity. How these animals might parallel ADHD at other levels though, for example neurocognitive measures, was not the focus of this work. More recently, our research in schizophrenia led to the pursuit of an animal model for antipsychotic-related weight gain, a major problem associated with the newest generation of antipsychotics (Allison & Casey, 2001; Newcomer, 2005). Like others (Baptista et al., 2002; Lee & Clifton, 2002), we failed to establish a parallel in this regard; that is, the drugs do not induce the weight gain in animals to the same extent observed in humans. However, effects on glucose regulation and locomotor activity paralleling what is observed in humans supported the utility of the model vis-a`-vis these dimensions (Mann et al., 2007). Animal studies are not necessarily confined to animal models. As an example of the former, it is common as part of preclinical animal studies to evaluate the effect of putative psychotropic medications on locomotor activity. In contrast, lack of response following inescapable shock has been forwarded as an animal model of depression inasmuch as it fits with the ‘learned helplessness’ hypothesis (Greenwood & Fleshner, 2008; Haracz, Minor, Wilkins, & Zimmermann, 1988). The former simply reflects a screening tool, while the latter is conceptually driven by the notion that a specific change in behaviour mirrors a human condition. 2. Animal research and psychiatry Animal studies have been part of medicine for centuries, although it was the advent of modern psychopharmacology in the 1950s that firmly established their role in psychiatry. They proved a useful tool as science worked backward to unravel the clinical benefits of various psychotropic drugs whose effects were often discovered serendipitously (Healy, 2002). With the identification of relevant behavioural measures that served as a proxy for effects in humans, they became important preclinical tools that could be used to screen putative psychiatric agents in the rapidly growing field of drug development (Geyer & Ellenbroek, 2003). As technology and knowledge advanced, the role of this work also evolved. Questions transitioned from how these medications work to theories regarding pathophysiology of the underlying disorders, with various strategies (e.g., lesion, pharmacological, genetic) employed to model specific endophenotypes – heritable abnormalities that characterize specific features of a particular illness (Gottesman & Gould, 2003; Yadid, 2005). For example, in schizophrenia deficits in working memory represent a candidate endophenotype, observed in both affected and non-affected family
3. Mental health and exercise
4. Psychiatric illness and physical health More recently, at least in the field of schizophrenia, a focus on physical activity (versus exercise) has been driven by very real and practical health concerns. It has been known for many years that those with schizophrenia have an increased risk of morbidity/ mortality, with a shortened lifespan of as much as 20–25 years (Hennekens, Hennekens, Hollar, & Casey, 2005). Interestingly, this information alone did little to stimulate intervention strategies; changes began to occur only after introduction of the second-
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generation or ‘atypical’ antipsychotics and a realization that as a class these drugs carried a marked liability for weight gain and metabolic disturbance, including type 2 diabetes (Newcomer, 2005). The added risk that these medications brought to the table seems to have tipped the balance, forcing caregivers to incorporate non-pharmacological treatment strategies focused on physical well-being and programs that encourage physical activity (AlvarezJimenez, Hetrick, Gonzalez-Blanch, Gleeson, & McGorry, 2008). As an aside, a growing recognition of the clinical limitations of our medications (Jones et al., 2006; Lieberman et al., 2005), in the face of such concerns, may also be contributing to a model of care that is more holistic in its approach. Regardless of reasons, the playing field has changed. There is greater focus on measuring outcomes that extend beyond symptomatic improvement (e.g. quality of life), and an increased awareness that more global measures of outcome can be favourably influenced by numerous interventions beyond medications. More active lifestyles and improved physical well-being represent one such strategy; an approach that serves to break down traditional notions regarding mind-body dualism (Faulkner & Biddle, 2001). It also encourages a more systematic evaluation of the interface between psychiatry, mental health and physical activity, and in so doing raises the question of how animal studies may be used to advance our understanding in this regard.
5.2. Morphology Considerable efforts in psychiatry have been devoted to understanding mental disorders from the standpoint of central nervous system (CNS) morphology (i.e., form and structure of brain regions), work advanced historically through neuropathological strategies (e.g., post-mortem studies) and accelerated over recent years with various neuroimaging techniques (e.g., functional Magnetic Resonance Imaging – fMRI; Positron Emission Tomography – PET). The hippocampus, for example, has been linked to cognition and implicated in various psychiatric conditions including anxiety, depression, and schizophrenia. Animal studies have demonstrated that exercise (e.g., wheel-running in rodents) is involved in the regulation of hippocampal neurogenesis in the aging brain (Fabel & Kempermann, 2008). Physical exercise favourably influences neurogenesis, whereas other factors (e.g., inflammation, stress) can have an opposite effect (Ehninger & Kempermann, 2006; Wu et al., 2007). Further animal work has extended this line of investigation, addressing how the effect is mediated. Retinoids, chemically related to Vitamin A, have been tied to neurogenesis although effects of physical exercise on this process do not appear to involve retinoid receptor activation (Aberg, Perlmann, Olson, & Brene, 2008). In contrast, sustained exercise (1 week of voluntary running) has been shown in animals to increase brain-derived neurotrophic factor (BDNF) in the hippocampus (Russo-Neustadt et al., 2001).
5. Animal studies: bridging psychiatry and physical activity 5.3. Mechanisms of action Animal studies approach this topic from a number of directions and the evidence, with examples, will be categorized as follows: behaviour; morphology; mechanisms of action; and, models. 5.1. Behaviour As will be seen in examples to follow, the animal literature has focused more on the role of exercise although physical activity has been used as a proxy for certain conditions (e.g., depression), as well as medication effects, including both response and side effects. Decreased activity or immobility have been linked to learned helplessness paradigms and taken as evidence that this represents a viable animal model for depression in humans. Conversely, reversal of this effect has been used as a measure for putative antidepressants, as can be observed with the forced swimming test in rodents (Porsolt, Brossard, Hautbois, & Roux, 2001; Russo-Neustadt, Ha, Ramirez, & Kesslak, 2001). Our own work looking at antipsychotic-induced weight gain and metabolic disturbances has demonstrated the same drugs that cause the greatest weight gain in humans produce prominent reductions in locomotor activity when administered to animals (Mann et al., 2007). While the same degree of weight gain is not observed in animals (Baptista et al., 2002; Lee & Clifton, 2002), this may be explained by other factors (e.g., species differences in drug metabolism and/or growth curves). It remains though that decreased activity associated with these drugs, possibly related to sedation (Haddad & Sharma, 2007), may play a contributory role in these side effects over and above any direct biochemical effect(s). There are animal data to indicate that exercise is associated with decreased substance use and/or the rewarding effects, a finding that has been demonstrated for various substances including amphetamine, cocaine and ethanol (Chen et al., 2008; Cosgrove, Hunter, & Carroll, 2002; Kanarek, Marks-Kaufman, D’Anci, & Przypek, 1995; McMillan, McClure, & Hardwick, 1995). The fact that this effect is observed across drugs that produce a variety of biochemical effects would suggest that it is mediated through mechanisms common to reward, for example dopamine (Chen et al., 2008; Hattori, Naoi, & Nishino, 1994).
It was pointed out earlier that much of our understanding regarding the mechanisms of action of psychotropics (the biochemical mechanisms by which they effect a clinical response) has occurred in a backward fashion. The serendipitous discovery of drugs with antidepressant and antipsychotic properties, for example, required that subsequent work ‘deconstruct’ their pharmacology and biochemical responses, which then formed the basis of pathophysiological models for future investigation (e.g., hyperdopaminergic model of schizophrenia) (Seeman, 1987; Van Rossum, 1967). That physical activity in the form of exercise can have value in disorders such as depression has been clearly established (Mead et al., 2008), and animal work along these lines has been able to elucidate mechanisms by which this may occur. Indeed, it has indicated that exercise may mirror, at least in part, biochemical changes that occur as a function of drug treatment. For example, exercise increases neurotrophic factors such as BDNF in the hippocampus (Chen & Russo-Neustadt, 2007; Russo-Neustadt et al., 2001), as well as dynorphin in the striatum/accumbens (Bjornebekk, Mathe, & Brene, 2005; Russo-Neustadt et al., 2001) in animals. Effective treatments for depression, such as antidepressants and electroconvulsive therapy (ECT), have also been associated with such increases in humans. Neuropeptide Y (NPY), as measured by mRNA levels in the hippocampus, is also increased with exercise and correlated with increased cell proliferation (Bjornebekk, Mathe, & Brene, 2006), while exercise and antidepressant treatment increase galanin (GAL) gene expression, also a neuropeptide, in the locus coeruleus (Holmes, Yoo, & Dishman, 2006). Altered neurotransmitter activity has been central to proposed explanations of numerous psychiatric disorders and the positive effects of psychotropic agents. The benefits of exercise in conditions such as anxiety and depression suggest that it too may induce improvement through similar mechanisms, and raises the possibility that it can shed further light on the precise nature of these effects. For example, an important role for serotonin has been implicated in anxiety and depression, as well as the beneficial
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effects of anxiolytics and antidepressants; however, the serotonergic system is complex, with at least 15 receptor subpopulations. Animal studies are well-positioned to address such questions – central to this type of work though are viable behavioural models and receptor-selective compounds. To demonstrate, short-term exercise (five daily treadmill sessions 1 h) has not been shown to alter serotonin 5-HT1A receptors or anxiety-related behaviours (e.g., decreased activity in open spaces, as measured using an elevatedplus maze) in rodents (Chaouloff, 1994). In contrast, the anxiogenic properties of the 5-HT agonist metachlorophenylpiperazine (mCPP) are attenuated with longer-term (2 weeks access to a running wheel) exercise (Fox, Hammack, & Falls, 2008). In another report, longer-term exercise was associated with enhanced sensitivity of 5-HT2 receptors, in combination with subsensitivity of 5-HT1A autoreceptors (Dey, 1994). This type of work serves to elucidate how exercise may exert positive effects on mental states such as anxiety, and at the same time has implications for understanding the underlying pathophysiology and developing effective treatment interventions. For example, the noted effects of exercise on 5-HT1A receptors (Chaouloff, 1994; Dey, 1994), in combination with work involving the selective 5-HT1A antagonist WAY 100,635 (Muraki, Inoue, & Koyama, 2008), offers diverse but converging support for 5-HT1A receptors in anxiety, which in turn can be incorporated into anxiolytic drug development. By the same token, the finding that exercise upregulates a neurotrophic factor signalling cascade also implicated in depression and antidepressant activity suggests several things: (a) it gives further credence to this system in the pathophysiology of depression, (b) it offers additional support for exercise as a potential treatment intervention, and (c) it adds to the evidence that such neurotrophic factors represent viable therapeutic targets in antidepressant drug development (Hunsberger et al., 2007). This is not to say that the focus must be confined to drug development. That exercise and cognitive strategies such as CBT can induce biological changes paralleling what is observed pharmacologically (Hattori et al., 1994; Kennedy et al., 2007; Ransford, 1982; Russo-Neustadt et al., 2001) encourages a search for non-pharmacological interventions that, at the very least, may complement pharmacotherapy. Animal studies have, in fact, demonstrated that environmental manipulations (e.g., stress reduction, exercise, dietary restriction), share common biochemical changes that are thought to mediate antidepressant-related clinical benefits (Adam & Epel, 2007; Duman, 2005; Duman, Schlesinger, Russell, & Duman, 2008). 5.4. Models Animal studies are also suited to the evaluation of models themselves although, in truth (and as evident with the previous discussion), boundaries between morphology, mechanisms of actions and models are not always clear. Stress and changes in the hypothalamic-pituitary-adrenal (HPA) system, however, represents an example of a well-established model that can be used to examine questions related to physical activity and mental health. Stress has long been identified as a potentially negative factor in mental well-being, contributing to conditions like anxiety/ depression. Moreover, it has been linked to numerous changes at the level of the HPA system. The animal analogue of ‘learned helplessness’ represents an experimental paradigm for evaluating physiological changes in the face of uncontrollable stress (invoked in the form of inescapable shock) (Greenwood & Fleshner, 2008). Inescapable and unpredictable stress increases circulating corticosterone and decreases both hippocampal BDNF and glucocorticoid receptor mRNA, while behaviourally it reduces intake of a sucrose
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solution as well as open field activity and impairs spatial performance (Zheng et al., 2006). Access to exercise, however, is associated with benefits in attenuating these adverse effects. Along similar lines, exercise has been able to reverse chemically-induced hypoactivity of the HPA axis (Kim et al., 2008). Animal studies have also been used to demonstrate differences in response to stress as a function of type of activity (Dishman, 1997), and hormesis (i.e., the benefits of low levels of stress) (Mattson, 2008). Finally, it warrants comment that animal models can provide information relevant to exercise physiology and disease pathology. Although these findings may not be specific to mental health, the integral relationship between these two facets of well-being make it impossible to look at either independently. As an example, dietinduced insulin resistance has been linked to reduced hippocampal synaptic plasticity and impaired cognitive function, possibly through effects on BDNF (Stranahan et al., 2008). Exercise has been associated with increased insulin sensitivity, suggesting that it may be able to play a protective role (Guo et al., 2008). Just as with stress, where the effects of exercise vary according to its presence or absence, the physiological effects of exercise can vary according to the presence or absence of physical disease. For example, a single bout of exercise has positive effects on proangiogenic factors (involved in the formation of new blood vessels e.g., vascular endothelial growth factor-A or VEGF-A) in healthy skeletal muscle although this is not observed in diabetic mice (Kivela et al., 2008). 6. Model animals and translational value Summarizing, animal models hold an important role in helping us understand the complex interrelationship between mental health and physical activity. Providing opportunities for more selective and invasive intervention/assessment (e.g., lesion studies, post-mortem examination), they are particularly well-positioned to address questions not easily amenable to investigation at the human level. Established models can accelerate hypothesis testing, and access to unique techniques for sampling (e.g., knockout strains, transgenic animals) offer opportunities for genetic manipulation and behavioural observation that are without parallel in humans. As an example, a targeted mutation of the 5-HT2C receptor in mice has advanced our understanding of this particular receptor in hyperphagia and obesity (Nonogaki, Strack, Dallman, & Tecott, 1998). This, in turn, has implications for the newer antipsychotics and their liability for weight gain, as the pharmacological profile of these compounds includes serotonergic antagonism (Meltzer, 1993, 2007; Richelson, 1999). Animal studies are not without their limitations. As representations of specific mental disorders, they routinely constitute only a component of what is observed in the human condition. We are forced to make conceptual leaps regarding behaviour across species (e.g., learned helplessness and depression), and there is a recognized lack of homology (shared similarities) between physiological and behavioural characteristics of different species (Yadid, 2005). Certain symptoms, such as the perceptual disturbances of psychosis, simply cannot be modeled. Exercise intensity is often considered a critical variable in studies examining exercise and mental health (e.g., Chu, Buckworth, Kirby, & Emery, in press; Everson, Daley, & Ussher, 2008) yet it is difficult to manipulate in the context of research using animals. Additionally, with an intervention like exercise, animal studies offer empiric biological measures that can be quantified, but fall short from the standpoint of tapping into the accompanying psychological and social benefits. In this era of fiscal restraint and limited research dollars, can animal research compete? It has been astutely argued that over the next years we need more ‘model animals’ rather than animal models, shifting focus from creating animal behaviours that
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phenotypically resemble aspects of mental disorders to developing animals that share the molecular and cellular abnormalities identified in mental disorders (Insel, 2007; Ma, 2004). There is as well evidence that we need to be more stringent methodologically in order to replicate the human condition as closely as possible (Perel et al., 2007). Further, the emphasis on translational research that now prevails demands that science and clinical medicine partner in developing animal work that is both generalizable and relevant (Qiu, 2007). Ultimately, human investigations take precedent – animal models remain inherently limited in drawing inferences regarding the human experience. This said, animal studies (if not models) address obvious constraints in human research and will continue to play an essential and supportive role. What is likely to change is the nature of their contribution. Advances in neuroimaging, for example, allow us opportunities at the human level in understanding central mechanisms mediating behaviour that were unavailable even a decade ago. Rightfully, this type of work overrides earlier inferential approaches based on animal studies. At the same time though, recent gains in the field of genetics have us seeking molecular targets and strategies for manipulation that must rely heavily on animal research at this point to make gains in our understanding. References Aberg, E., Perlmann, T., Olson, L., & Brene, S. (2008). Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus. Hippocampus, 18, 785–792. Adam, T. C., & Epel, E. S. (2007). Stress, eating and the reward system. Physiology & Behavior, 91, 449–458. Allison, D. B., & Casey, D. E. (2001). Antipsychotic-induced weight gain: a review of the literature. Journal of Clinical Psychiatry, 62(Suppl. 7), 22–31. Alvarez-Jimenez, M., Hetrick, S. E., Gonzalez-Blanch, C., Gleeson, J. F., & McGorry, P. D. (2008). Non-pharmacological management of antipsychoticinduced weight gain: systematic review and meta-analysis of randomised controlled trials. British Journal of Psychiatry, 193, 101–107. Anisman, H., Grimmer, L., Irwin, J., Remington, G., & Sklar, L. S. (1979). Escape performance after inescapable shock in selectively bred lines of mice: response maintenance and catecholamine activity. Journal of Comparative and Physiological Psychology, 93, 229–241. Baptista, T., Araujo de Baptista, E., Ying Kin, N. M., Beaulieu, S., Walker, D., Joober, R., et al. (2002). Comparative effects of the antipsychotics sulpiride or risperidone in rats. I: bodyweight, food intake, body composition, hormones and glucose tolerance. Brain Research, 957(1), 144–151. Baumans, V. (2004). Use of animals in experimental research: an ethical dilemma? Gene Therapy, 11(Suppl. 1), S64–66. Belmatoug, N., & Fantin, B. (1997). Contribution of animal models of infection for the evaluation of the activity of antimicrobial agents. International Journal of Antimicrobial Agents, 9, 73–82. Bjornebekk, A., Mathe, A. A., & Brene, S. (2005). The antidepressant effect of running is associated with increased hippocampal cell proliferation. International Journal of Neuropsychopharmacology, 8, 357–368. Bjornebekk, A., Mathe, A. A., & Brene, S. (2006). Running has differential effects on NPY, opiates, and cell proliferation in an animal model of depression and controls. Neuropsychopharmacology, 31, 256–264. Blomstrand, E., Perrett, D., Parry-Billings, M., & Newsholme, E. A. (1989). Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiologica Scandinavica, 136, 473–481. Borgeat, F., Gagnon, J., Hudon, M., Lalonde, P., & Reid, W. (1985). Teaching therapeutic skills of a psychological nature to future physicians. Canadian Journal of Psychiatry, 30, 445–449. Brennan, A. J. (1985). Health and fitness boom moves into corporate America. Occupational Health & Safety, 54. 38–40, 42–35. Brune, K. (2002). Animal experimentation in sciences: sadistic nonsense or indispensable necessity? Alternativen zu Tierexperimenten, 19, 130–136. Carless, D., & Faulkner, G. (2003). Physical activity and mental health. In J. McKenna, & C. Riddoch (Eds.), Perspectives on health and exercise (pp. 61–82). UK: Palgrave Macmillan. Chaouloff, F. (1994). Influence of physical exercise on 5-HT1A receptor- and anxietyrelated behaviours. Neuroscience Letters, 176, 226–230. Chaouloff, F., Laude, D., & Elghozi, J. L. (1989). Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals. Journal of Neural Transmission, 78, 121–130.
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Nonogaki, K., Strack, A. M., Dallman, M. F., & Tecott, L. H. (1998). Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nature Medicine, 4, 1152–1156. Perel, P., Roberts, I., Sena, E., Wheble, P., Briscoe, C., Sandercock, P., et al. (2007). Comparison of treatment effects between animal experiments and clinical trials: systematic review. British Medical Journal, 334, 197. Perry, P. (2007). The ethics of animal research: a UK perspective. ILAR Journal, 48(1), 42–46. Porsolt, R. D., Brossard, G., Hautbois, C., & Roux, S. (2001). Rodent models of depression: forced swimming and tail suspension behavioral despair tests in rats and mice. Current Protocols in Neuroscience. Chapter 8:Unit 8.10A. Qiu, J. (2007). Debates on translational research: a balancing act. Lancet Neurology, 6(3), 208–209. Ransford, C. P. (1982). A role for amines in the antidepressant effect of exercise: a review. Medicine & Science in Sports & Exercise, 14, 1–10. Remington, G., & Anisman, H. (1976). Genetic and ontogenetic variations in locomotor activity following treatment with scopolamine or d-amphetamine. Developmental Psychobiology, 9, 579–585. Richelson, E. (1999). Receptor pharmacology of neuroleptics: relation to clinical effects. Journal of Clinical Psychiatry, 60(Suppl. 10), 5–14. Russo-Neustadt, A., Ha, T., Ramirez, R., & Kesslak, J. P. (2001). Physical activityantidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behavioral Brain Research, 120, 87–95. Seeman, P. (1987). Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse, 1, 133–152. Seppen, J., Filali, E. E., & Elferink, R. O. (2009). Small animal models of hepatocyte transplantation. Methods in Molecular Biology, 481, 1–8. Stranahan, A. M., Norman, E. D., Lee, K., Cutler, R. G., Telljohann, R. S., Egan, J. M., et al. (2008). Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus, 18, 1085–1088. Taylor, A. H., & Faulkner, G. (2008). Inaugural editorial. Mental Health and Physical Activity, 1, 1–8. Van Rossum, J. (1967). The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In H. Brill, J. O. Cole, P. Deniker, H. Hippius, & P. Bradley (Eds.), Neuropsychopharmacology, Proceedings of the 5th Collegium Internationale Neuro-psychopharmacologicum (CINP) (pp. 321–329). Amsterdam: Excerptica Medica. Wu, C. W., Chen, Y. C., Yu, L., Chen, H. I., Jen, C. J., Huang, A. M., et al. (2007). Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory. Journal of Neurochemistry, 103, 2471–2481. Yadid, G. (2005). Understanding through animal models. CNS Spectrums, 10(181). Zheng, H., Liu, Y., Li, W., Yang, B., Chen, D., Wang, X., et al. (2006). Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behavioural Brain Research, 168, 47–55.
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Mental Health and Physical Activity journal homepage: www.elsevier.com/locate/menpa
From mice to men: What can animal models tell us about the relationship between mental health and physical activity? Gary Remington a, b, * a b
Faculty of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Medication Assessment Program for Schizophrenia (MAPS), Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2009 Accepted 25 January 2009
Physical activity has been associated with numerous benefits that extend to mental health, although how these benefits are accrued is not clear. The notion that animal research can prove useful in this regard may initially seem irrelevant and even inapplicable. However, there is a growing body of evidence, focusing in particular on exercise, to suggest that the biochemical changes induced with exercise include many of the same systems involved in psychiatric illnesses such as depression and anxiety disorder. Moreover, these changes parallel what has been linked to the clinical benefits of pharmacotherapy. While animal studies cannot adequately tap into the psychological benefits of activity or exercise, they are better suited to address the biological component across a number of dimensions. The focus of this commentary is on how animal studies and/or models may be utilized to better understand the relationship between physical activity and mental health/illness. Animal work is not without its limitations and must stand the test of translational value. Against this standard, we are not pursuing comprehensive animal models that mirror the human condition as much as paradigms that elicit selected biological features of a mental disorder’s underlying pathophysiology. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Animal models Mental health Physical activity
Few topics generate the polarized debate observed around discussions of animal research. Its proponents relate the numerous discoveries that have been dependent on such research (e.g., vaccines, antibiotics, organ transplantation) (Belmatoug & Fantin, 1997; Gradmann, 2008; Seppen, Filali, & Elferink, 2009), while opponents are quick to point out the suffering, overuse, and lack of translational value (Baumans, 2004; Brune, 2002; McKinney, 2001; Perry, 2007; Qiu, 2007). For many working in the field of mental health promotion and treatment, animal research may be unfamiliar and appear irrelevant. Mental illness, unlike many physical diseases, is more easily framed as a human condition. Defined in part by behaviour, assessment of mental illness and, conversely, mental health is very much subjective and language-dependent (e.g., description of mood, anxiety, perceptual disturbances), calling into question what role animal research might serve (Insel, 2007). This said, animal research is now inextricably part of psychiatry, and the present commentary specifically addresses how it can shed light on the relationship between mental health and physical activity. Several comments regarding terminology are warranted at the outset. The terms physical activity and exercise will each be used,
* Tel.: þ1 416 535 8501x4750; fax: þ1 416 979 4292. E-mail address: [email protected] 1755-2966/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mhpa.2009.01.003
recognizing that they are not synonymous (Taylor & Faulkner, 2008), and whenever possible the distinction between acute and chronic exposure will be clarified. The animal studies routinely involve rodents (rats or mice), where open field locomotion (movement within a large box) is generally used as a measure of activity, while access to a running wheel or treadmill represents examples of exercise. Acute exposure generally refers to one or, at most, several bouts of exercise within a circumscribed time interval, while chronic exposure involves, for example, access to exercise over a 1-month interval. It should be acknowledged that there are no clearly established criteria that allow comparison of exercise in terms of type, intensity, or duration (Dishman et al., 2006). Reference will be made to both mental health and psychiatric illness; however, mental health is not defined as an absence of psychiatric illness. Just as activity subsumes exercise as one subset, mental health subsumes those with psychiatric illness as simply one subpopulation. It extends to all individuals though, an important distinction when examining the literature. This is not meant as an exhaustive review. Rather, it is more of a primer for those less familiar with this line of research, focusing on psychiatric illness and examples of what we have learned through animal studies. It is written from the perspective of a clinician-researcher in the field of schizophrenia who began in animal research, left to do human work after feeling the animal
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studies might be ‘lost in translation’, ultimately returning to a combined approach that arose out of opportunities to ask similar questions at both levels – making it easier to ensure translational value.
members to a greater extent than in the general population (Gottesman & Gould, 2003).
1. Animal models
The notion that psychological well-being may be influenced by physical activity and health is by no means a new idea; that it is receiving greater attention at present speaks to the confluence of a number of factors over recent years (Carless & Faulkner, 2003). There was of course the exercise ‘craze’ that took hold in the 1970s and linked fitness with mental well-being (Brennan, 1985). However, this was an image-conscious movement that had little to do with major psychiatric illness. During this same time, psychiatry itself remained steeped in biological models and psychopharmacology as the search continued for newer and more effective psychotropic agents. Indeed, there were growing concerns that the ‘psyche’ was being lost to an increasingly myopic and reductionistic focus on biological therapies (Borgeat, Gagnon, Hudon, Lalonde, & Reid, 1985). There were other avenues, though, that would tie exercise specifically to both general mental health, as well as psychiatric disorders. Various lines of animal investigation have demonstrated that exercise favourably influences a number of biochemical factors involved in neurogenesis, neural plasticity and neuroprotection which are key elements in overall brain health (Cotman, Berchtold, & Christie, 2007; Dishman et al., 2006; Duman, 2005). This represents a centrally mediated effect that can not only enhance neurocognitive activities such as learning and memory, but protect against the negative effects associated with stress and aging (Dishman et al., 2006). In addition, exercise can produce peripherally mediated biochemical benefits through its favourable effects on such risk factors as hypertension, glucose dysregulation, and dyslipidemia (Cotman et al., 2007). Previously, work had demonstrated that sustained exercise (e.g., running, swimming) could induce at least some of the neurochemical changes observed with pharmacological treatment of psychiatric conditions such as depression (Blomstrand, Perrett, Parry-Billings, & Newsholme, 1989; Chaouloff, 1994; Chaouloff, Laude, & Elghozi, 1989; Dey, 1994; Ransford, 1982). This was not seen as an endorsement that exercise could replace pharmacotherapy, nor has this turned out to be the case (Mead et al., 2008); however, it offered biological evidence that exercise could translate to improvement in domains such as depression and anxiety, as well as add to our understanding of underlying pathophysiology. This line of thinking took yet another step with neuroimaging evidence in humans that non-pharmacological interventions (e.g., Cognitive Behavioural Therapy [CBT]) in depression can induce changes at the level of the central nervous system (CNS), in line with what is observed following effective pharmacotherapy (Goldapple et al., 2004; Kennedy et al., 2007). Such work further strengthened the position that the types of biochemical changes thought to mediate psychological conditions such as depression could be favourably altered indirectly without the need for medications.
Animal models are designed to mirror a human condition in a way that offers opportunities to better understand its origins, course, and/or treatment. It is often assumed, mistakenly, that such models must parallel the human condition on all dimensions and this is not the case. Two personal examples reflect this. During my postgraduate work, our lab employed a species of mouse that exhibited a transient period of hyperkinesis during development that drew comparisons to what is observed in attention deficit hyperactivity disorder (ADHD) (Anisman, Grimmer, Irwin, Remington, & Sklar, 1979; Remington & Anisman, 1976). The model was effective in better understanding the possible contribution of neurotransmitter development, specifically norepinephrine and acetylcholine, to hyperactivity. How these animals might parallel ADHD at other levels though, for example neurocognitive measures, was not the focus of this work. More recently, our research in schizophrenia led to the pursuit of an animal model for antipsychotic-related weight gain, a major problem associated with the newest generation of antipsychotics (Allison & Casey, 2001; Newcomer, 2005). Like others (Baptista et al., 2002; Lee & Clifton, 2002), we failed to establish a parallel in this regard; that is, the drugs do not induce the weight gain in animals to the same extent observed in humans. However, effects on glucose regulation and locomotor activity paralleling what is observed in humans supported the utility of the model vis-a`-vis these dimensions (Mann et al., 2007). Animal studies are not necessarily confined to animal models. As an example of the former, it is common as part of preclinical animal studies to evaluate the effect of putative psychotropic medications on locomotor activity. In contrast, lack of response following inescapable shock has been forwarded as an animal model of depression inasmuch as it fits with the ‘learned helplessness’ hypothesis (Greenwood & Fleshner, 2008; Haracz, Minor, Wilkins, & Zimmermann, 1988). The former simply reflects a screening tool, while the latter is conceptually driven by the notion that a specific change in behaviour mirrors a human condition. 2. Animal research and psychiatry Animal studies have been part of medicine for centuries, although it was the advent of modern psychopharmacology in the 1950s that firmly established their role in psychiatry. They proved a useful tool as science worked backward to unravel the clinical benefits of various psychotropic drugs whose effects were often discovered serendipitously (Healy, 2002). With the identification of relevant behavioural measures that served as a proxy for effects in humans, they became important preclinical tools that could be used to screen putative psychiatric agents in the rapidly growing field of drug development (Geyer & Ellenbroek, 2003). As technology and knowledge advanced, the role of this work also evolved. Questions transitioned from how these medications work to theories regarding pathophysiology of the underlying disorders, with various strategies (e.g., lesion, pharmacological, genetic) employed to model specific endophenotypes – heritable abnormalities that characterize specific features of a particular illness (Gottesman & Gould, 2003; Yadid, 2005). For example, in schizophrenia deficits in working memory represent a candidate endophenotype, observed in both affected and non-affected family
3. Mental health and exercise
4. Psychiatric illness and physical health More recently, at least in the field of schizophrenia, a focus on physical activity (versus exercise) has been driven by very real and practical health concerns. It has been known for many years that those with schizophrenia have an increased risk of morbidity/ mortality, with a shortened lifespan of as much as 20–25 years (Hennekens, Hennekens, Hollar, & Casey, 2005). Interestingly, this information alone did little to stimulate intervention strategies; changes began to occur only after introduction of the second-
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generation or ‘atypical’ antipsychotics and a realization that as a class these drugs carried a marked liability for weight gain and metabolic disturbance, including type 2 diabetes (Newcomer, 2005). The added risk that these medications brought to the table seems to have tipped the balance, forcing caregivers to incorporate non-pharmacological treatment strategies focused on physical well-being and programs that encourage physical activity (AlvarezJimenez, Hetrick, Gonzalez-Blanch, Gleeson, & McGorry, 2008). As an aside, a growing recognition of the clinical limitations of our medications (Jones et al., 2006; Lieberman et al., 2005), in the face of such concerns, may also be contributing to a model of care that is more holistic in its approach. Regardless of reasons, the playing field has changed. There is greater focus on measuring outcomes that extend beyond symptomatic improvement (e.g. quality of life), and an increased awareness that more global measures of outcome can be favourably influenced by numerous interventions beyond medications. More active lifestyles and improved physical well-being represent one such strategy; an approach that serves to break down traditional notions regarding mind-body dualism (Faulkner & Biddle, 2001). It also encourages a more systematic evaluation of the interface between psychiatry, mental health and physical activity, and in so doing raises the question of how animal studies may be used to advance our understanding in this regard.
5.2. Morphology Considerable efforts in psychiatry have been devoted to understanding mental disorders from the standpoint of central nervous system (CNS) morphology (i.e., form and structure of brain regions), work advanced historically through neuropathological strategies (e.g., post-mortem studies) and accelerated over recent years with various neuroimaging techniques (e.g., functional Magnetic Resonance Imaging – fMRI; Positron Emission Tomography – PET). The hippocampus, for example, has been linked to cognition and implicated in various psychiatric conditions including anxiety, depression, and schizophrenia. Animal studies have demonstrated that exercise (e.g., wheel-running in rodents) is involved in the regulation of hippocampal neurogenesis in the aging brain (Fabel & Kempermann, 2008). Physical exercise favourably influences neurogenesis, whereas other factors (e.g., inflammation, stress) can have an opposite effect (Ehninger & Kempermann, 2006; Wu et al., 2007). Further animal work has extended this line of investigation, addressing how the effect is mediated. Retinoids, chemically related to Vitamin A, have been tied to neurogenesis although effects of physical exercise on this process do not appear to involve retinoid receptor activation (Aberg, Perlmann, Olson, & Brene, 2008). In contrast, sustained exercise (1 week of voluntary running) has been shown in animals to increase brain-derived neurotrophic factor (BDNF) in the hippocampus (Russo-Neustadt et al., 2001).
5. Animal studies: bridging psychiatry and physical activity 5.3. Mechanisms of action Animal studies approach this topic from a number of directions and the evidence, with examples, will be categorized as follows: behaviour; morphology; mechanisms of action; and, models. 5.1. Behaviour As will be seen in examples to follow, the animal literature has focused more on the role of exercise although physical activity has been used as a proxy for certain conditions (e.g., depression), as well as medication effects, including both response and side effects. Decreased activity or immobility have been linked to learned helplessness paradigms and taken as evidence that this represents a viable animal model for depression in humans. Conversely, reversal of this effect has been used as a measure for putative antidepressants, as can be observed with the forced swimming test in rodents (Porsolt, Brossard, Hautbois, & Roux, 2001; Russo-Neustadt, Ha, Ramirez, & Kesslak, 2001). Our own work looking at antipsychotic-induced weight gain and metabolic disturbances has demonstrated the same drugs that cause the greatest weight gain in humans produce prominent reductions in locomotor activity when administered to animals (Mann et al., 2007). While the same degree of weight gain is not observed in animals (Baptista et al., 2002; Lee & Clifton, 2002), this may be explained by other factors (e.g., species differences in drug metabolism and/or growth curves). It remains though that decreased activity associated with these drugs, possibly related to sedation (Haddad & Sharma, 2007), may play a contributory role in these side effects over and above any direct biochemical effect(s). There are animal data to indicate that exercise is associated with decreased substance use and/or the rewarding effects, a finding that has been demonstrated for various substances including amphetamine, cocaine and ethanol (Chen et al., 2008; Cosgrove, Hunter, & Carroll, 2002; Kanarek, Marks-Kaufman, D’Anci, & Przypek, 1995; McMillan, McClure, & Hardwick, 1995). The fact that this effect is observed across drugs that produce a variety of biochemical effects would suggest that it is mediated through mechanisms common to reward, for example dopamine (Chen et al., 2008; Hattori, Naoi, & Nishino, 1994).
It was pointed out earlier that much of our understanding regarding the mechanisms of action of psychotropics (the biochemical mechanisms by which they effect a clinical response) has occurred in a backward fashion. The serendipitous discovery of drugs with antidepressant and antipsychotic properties, for example, required that subsequent work ‘deconstruct’ their pharmacology and biochemical responses, which then formed the basis of pathophysiological models for future investigation (e.g., hyperdopaminergic model of schizophrenia) (Seeman, 1987; Van Rossum, 1967). That physical activity in the form of exercise can have value in disorders such as depression has been clearly established (Mead et al., 2008), and animal work along these lines has been able to elucidate mechanisms by which this may occur. Indeed, it has indicated that exercise may mirror, at least in part, biochemical changes that occur as a function of drug treatment. For example, exercise increases neurotrophic factors such as BDNF in the hippocampus (Chen & Russo-Neustadt, 2007; Russo-Neustadt et al., 2001), as well as dynorphin in the striatum/accumbens (Bjornebekk, Mathe, & Brene, 2005; Russo-Neustadt et al., 2001) in animals. Effective treatments for depression, such as antidepressants and electroconvulsive therapy (ECT), have also been associated with such increases in humans. Neuropeptide Y (NPY), as measured by mRNA levels in the hippocampus, is also increased with exercise and correlated with increased cell proliferation (Bjornebekk, Mathe, & Brene, 2006), while exercise and antidepressant treatment increase galanin (GAL) gene expression, also a neuropeptide, in the locus coeruleus (Holmes, Yoo, & Dishman, 2006). Altered neurotransmitter activity has been central to proposed explanations of numerous psychiatric disorders and the positive effects of psychotropic agents. The benefits of exercise in conditions such as anxiety and depression suggest that it too may induce improvement through similar mechanisms, and raises the possibility that it can shed further light on the precise nature of these effects. For example, an important role for serotonin has been implicated in anxiety and depression, as well as the beneficial
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effects of anxiolytics and antidepressants; however, the serotonergic system is complex, with at least 15 receptor subpopulations. Animal studies are well-positioned to address such questions – central to this type of work though are viable behavioural models and receptor-selective compounds. To demonstrate, short-term exercise (five daily treadmill sessions 1 h) has not been shown to alter serotonin 5-HT1A receptors or anxiety-related behaviours (e.g., decreased activity in open spaces, as measured using an elevatedplus maze) in rodents (Chaouloff, 1994). In contrast, the anxiogenic properties of the 5-HT agonist metachlorophenylpiperazine (mCPP) are attenuated with longer-term (2 weeks access to a running wheel) exercise (Fox, Hammack, & Falls, 2008). In another report, longer-term exercise was associated with enhanced sensitivity of 5-HT2 receptors, in combination with subsensitivity of 5-HT1A autoreceptors (Dey, 1994). This type of work serves to elucidate how exercise may exert positive effects on mental states such as anxiety, and at the same time has implications for understanding the underlying pathophysiology and developing effective treatment interventions. For example, the noted effects of exercise on 5-HT1A receptors (Chaouloff, 1994; Dey, 1994), in combination with work involving the selective 5-HT1A antagonist WAY 100,635 (Muraki, Inoue, & Koyama, 2008), offers diverse but converging support for 5-HT1A receptors in anxiety, which in turn can be incorporated into anxiolytic drug development. By the same token, the finding that exercise upregulates a neurotrophic factor signalling cascade also implicated in depression and antidepressant activity suggests several things: (a) it gives further credence to this system in the pathophysiology of depression, (b) it offers additional support for exercise as a potential treatment intervention, and (c) it adds to the evidence that such neurotrophic factors represent viable therapeutic targets in antidepressant drug development (Hunsberger et al., 2007). This is not to say that the focus must be confined to drug development. That exercise and cognitive strategies such as CBT can induce biological changes paralleling what is observed pharmacologically (Hattori et al., 1994; Kennedy et al., 2007; Ransford, 1982; Russo-Neustadt et al., 2001) encourages a search for non-pharmacological interventions that, at the very least, may complement pharmacotherapy. Animal studies have, in fact, demonstrated that environmental manipulations (e.g., stress reduction, exercise, dietary restriction), share common biochemical changes that are thought to mediate antidepressant-related clinical benefits (Adam & Epel, 2007; Duman, 2005; Duman, Schlesinger, Russell, & Duman, 2008). 5.4. Models Animal studies are also suited to the evaluation of models themselves although, in truth (and as evident with the previous discussion), boundaries between morphology, mechanisms of actions and models are not always clear. Stress and changes in the hypothalamic-pituitary-adrenal (HPA) system, however, represents an example of a well-established model that can be used to examine questions related to physical activity and mental health. Stress has long been identified as a potentially negative factor in mental well-being, contributing to conditions like anxiety/ depression. Moreover, it has been linked to numerous changes at the level of the HPA system. The animal analogue of ‘learned helplessness’ represents an experimental paradigm for evaluating physiological changes in the face of uncontrollable stress (invoked in the form of inescapable shock) (Greenwood & Fleshner, 2008). Inescapable and unpredictable stress increases circulating corticosterone and decreases both hippocampal BDNF and glucocorticoid receptor mRNA, while behaviourally it reduces intake of a sucrose
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solution as well as open field activity and impairs spatial performance (Zheng et al., 2006). Access to exercise, however, is associated with benefits in attenuating these adverse effects. Along similar lines, exercise has been able to reverse chemically-induced hypoactivity of the HPA axis (Kim et al., 2008). Animal studies have also been used to demonstrate differences in response to stress as a function of type of activity (Dishman, 1997), and hormesis (i.e., the benefits of low levels of stress) (Mattson, 2008). Finally, it warrants comment that animal models can provide information relevant to exercise physiology and disease pathology. Although these findings may not be specific to mental health, the integral relationship between these two facets of well-being make it impossible to look at either independently. As an example, dietinduced insulin resistance has been linked to reduced hippocampal synaptic plasticity and impaired cognitive function, possibly through effects on BDNF (Stranahan et al., 2008). Exercise has been associated with increased insulin sensitivity, suggesting that it may be able to play a protective role (Guo et al., 2008). Just as with stress, where the effects of exercise vary according to its presence or absence, the physiological effects of exercise can vary according to the presence or absence of physical disease. For example, a single bout of exercise has positive effects on proangiogenic factors (involved in the formation of new blood vessels e.g., vascular endothelial growth factor-A or VEGF-A) in healthy skeletal muscle although this is not observed in diabetic mice (Kivela et al., 2008). 6. Model animals and translational value Summarizing, animal models hold an important role in helping us understand the complex interrelationship between mental health and physical activity. Providing opportunities for more selective and invasive intervention/assessment (e.g., lesion studies, post-mortem examination), they are particularly well-positioned to address questions not easily amenable to investigation at the human level. Established models can accelerate hypothesis testing, and access to unique techniques for sampling (e.g., knockout strains, transgenic animals) offer opportunities for genetic manipulation and behavioural observation that are without parallel in humans. As an example, a targeted mutation of the 5-HT2C receptor in mice has advanced our understanding of this particular receptor in hyperphagia and obesity (Nonogaki, Strack, Dallman, & Tecott, 1998). This, in turn, has implications for the newer antipsychotics and their liability for weight gain, as the pharmacological profile of these compounds includes serotonergic antagonism (Meltzer, 1993, 2007; Richelson, 1999). Animal studies are not without their limitations. As representations of specific mental disorders, they routinely constitute only a component of what is observed in the human condition. We are forced to make conceptual leaps regarding behaviour across species (e.g., learned helplessness and depression), and there is a recognized lack of homology (shared similarities) between physiological and behavioural characteristics of different species (Yadid, 2005). Certain symptoms, such as the perceptual disturbances of psychosis, simply cannot be modeled. Exercise intensity is often considered a critical variable in studies examining exercise and mental health (e.g., Chu, Buckworth, Kirby, & Emery, in press; Everson, Daley, & Ussher, 2008) yet it is difficult to manipulate in the context of research using animals. Additionally, with an intervention like exercise, animal studies offer empiric biological measures that can be quantified, but fall short from the standpoint of tapping into the accompanying psychological and social benefits. In this era of fiscal restraint and limited research dollars, can animal research compete? It has been astutely argued that over the next years we need more ‘model animals’ rather than animal models, shifting focus from creating animal behaviours that
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phenotypically resemble aspects of mental disorders to developing animals that share the molecular and cellular abnormalities identified in mental disorders (Insel, 2007; Ma, 2004). There is as well evidence that we need to be more stringent methodologically in order to replicate the human condition as closely as possible (Perel et al., 2007). Further, the emphasis on translational research that now prevails demands that science and clinical medicine partner in developing animal work that is both generalizable and relevant (Qiu, 2007). Ultimately, human investigations take precedent – animal models remain inherently limited in drawing inferences regarding the human experience. This said, animal studies (if not models) address obvious constraints in human research and will continue to play an essential and supportive role. What is likely to change is the nature of their contribution. Advances in neuroimaging, for example, allow us opportunities at the human level in understanding central mechanisms mediating behaviour that were unavailable even a decade ago. Rightfully, this type of work overrides earlier inferential approaches based on animal studies. At the same time though, recent gains in the field of genetics have us seeking molecular targets and strategies for manipulation that must rely heavily on animal research at this point to make gains in our understanding. References Aberg, E., Perlmann, T., Olson, L., & Brene, S. (2008). Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus. Hippocampus, 18, 785–792. Adam, T. C., & Epel, E. S. (2007). Stress, eating and the reward system. Physiology & Behavior, 91, 449–458. Allison, D. B., & Casey, D. E. (2001). Antipsychotic-induced weight gain: a review of the literature. Journal of Clinical Psychiatry, 62(Suppl. 7), 22–31. Alvarez-Jimenez, M., Hetrick, S. E., Gonzalez-Blanch, C., Gleeson, J. F., & McGorry, P. D. (2008). Non-pharmacological management of antipsychoticinduced weight gain: systematic review and meta-analysis of randomised controlled trials. British Journal of Psychiatry, 193, 101–107. Anisman, H., Grimmer, L., Irwin, J., Remington, G., & Sklar, L. S. (1979). Escape performance after inescapable shock in selectively bred lines of mice: response maintenance and catecholamine activity. Journal of Comparative and Physiological Psychology, 93, 229–241. Baptista, T., Araujo de Baptista, E., Ying Kin, N. M., Beaulieu, S., Walker, D., Joober, R., et al. (2002). Comparative effects of the antipsychotics sulpiride or risperidone in rats. I: bodyweight, food intake, body composition, hormones and glucose tolerance. Brain Research, 957(1), 144–151. Baumans, V. (2004). Use of animals in experimental research: an ethical dilemma? Gene Therapy, 11(Suppl. 1), S64–66. Belmatoug, N., & Fantin, B. (1997). Contribution of animal models of infection for the evaluation of the activity of antimicrobial agents. International Journal of Antimicrobial Agents, 9, 73–82. Bjornebekk, A., Mathe, A. A., & Brene, S. (2005). The antidepressant effect of running is associated with increased hippocampal cell proliferation. International Journal of Neuropsychopharmacology, 8, 357–368. Bjornebekk, A., Mathe, A. A., & Brene, S. (2006). Running has differential effects on NPY, opiates, and cell proliferation in an animal model of depression and controls. Neuropsychopharmacology, 31, 256–264. Blomstrand, E., Perrett, D., Parry-Billings, M., & Newsholme, E. A. (1989). Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiologica Scandinavica, 136, 473–481. Borgeat, F., Gagnon, J., Hudon, M., Lalonde, P., & Reid, W. (1985). Teaching therapeutic skills of a psychological nature to future physicians. Canadian Journal of Psychiatry, 30, 445–449. Brennan, A. J. (1985). Health and fitness boom moves into corporate America. Occupational Health & Safety, 54. 38–40, 42–35. Brune, K. (2002). Animal experimentation in sciences: sadistic nonsense or indispensable necessity? Alternativen zu Tierexperimenten, 19, 130–136. Carless, D., & Faulkner, G. (2003). Physical activity and mental health. In J. McKenna, & C. Riddoch (Eds.), Perspectives on health and exercise (pp. 61–82). UK: Palgrave Macmillan. Chaouloff, F. (1994). Influence of physical exercise on 5-HT1A receptor- and anxietyrelated behaviours. Neuroscience Letters, 176, 226–230. Chaouloff, F., Laude, D., & Elghozi, J. L. (1989). Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals. Journal of Neural Transmission, 78, 121–130.
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