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A Framework for Developing Translationally Relevant Animal Models of Stress-Induced Changes in Eating Behavior

Open AccessPublished:July 02, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.06.020

      Abstract

      Stress often affects eating behaviors, leading to increased eating in some individuals and decreased eating in others. Identifying physiological and psychological factors that determine the direction of eating responses to stress has been a major goal of epidemiological and clinical studies. However, challenges of standardizing the stress exposure in humans hinder efforts to uncover the underlying mechanisms. The issue of what determines the direction of stress-induced feeding responses has not been directly addressed in animal models, but assays that combine stress with a feeding-related task are commonly used as readouts of other behaviors, such as anxiety. Sex, estrous cyclicity, circadian cyclicity, caloric restriction, palatable diets, elevated body weight, and properties of the stressors similarly influence feeding behavior in humans and rodent models. Yet, most rodent studies do not use conditions that are most relevant for studying feeding behavior in humans. This review proposes a conceptual framework for incorporating these influences to develop reproducible and translationally relevant assays to study effects of stress on food intake. Such paradigms have the potential to uncover links between emotional eating and obesity as well as to the etiology of eating disorders.

      Keywords

      The goal of this review was to develop a conceptual framework to guide the development of reproducible and translationally relevant assays to study effects of stress on food intake. Stress represents a challenge to homeostasis. In the broadest terms, it occurs when a biological system detects a failure to control a variable that is critical for survival and/or reproductive success (
      • Del Guidice M.
      • Buck C.L.
      • Chaby L.E.
      • Gormally B.M.
      • Taff C.C.
      • Thawley C.J.
      • et al.
      What is stress? A systems perspective.
      ). To maintain energy balance, organisms have evolved robust mechanisms to integrate interoceptive signals of fuel availability with predictions about the caloric value of foods that are available (
      • Sternson S.M.
      • Nicholas Betley J.
      • Cao Z.F.
      Neural circuits and motivational processes for hunger.
      ). Food seeking and consummatory behaviors involve risks, such as getting sick from spoiled or poisonous food, exposure to extreme temperatures, and lurking predators. Strong evolutionary pressures fostered the development of systems that respond to challenges to energy homeostasis in a manner that maximizes benefits while minimizing risk (
      • Nonacs P.
      State dependent behavior and themarginal value theorem.
      ). When external stressors pose an imminent threat to survival, interoceptive signals of hunger that promote food seeking and consummatory behaviors are suppressed.
      The relationship between a severe stress and feeding behaviors is preserved in present-day society, where stresses such as job loss, divorce, or death of a loved one are usually accompanied by anhedonia and weight loss (
      • Stone A.A.
      • Brownell K.D.
      The stress-eating paradox: Multiple daily measurements in adult males and females.
      ,
      • Kandiah J.
      • Yake M.
      • Willett H.
      Effects of stress on eating practices among adults.
      ). On the other hand, in the context of a chronic threat, an organism will die if it is not motivated enough to take the risk to find food. Therefore, it is important that the drive to seek food overcomes fear in a state of negative energy balance and that nutrient intake occurs in the most efficient way possible through the consumption of calorically dense foods (
      • Nonacs P.
      State dependent behavior and themarginal value theorem.
      ,
      • Wells J.C.
      Ecological volatility and human evolution: A novel perspective on life history and reproductive strategy.
      ). The tendency to eat junk foods in response to stress is well documented in clinical and epidemiological studies (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Kandiah J.
      • Yake M.
      • Jones J.
      • Meyer M.
      Stress influences appetite and comfort food preferences in college women.
      ,
      • Zellner D.A.
      • Loaiza S.
      • Gonzalez Z.
      • Pita J.
      • Morales J.
      • Pecora D.
      • et al.
      Food selection changes under stress.
      ).
      The relative strength of signals relaying information about internal fuel availability, perceived threats in the environment, and the reward value of the food item determines whether food intake is increased or decreased in response to mild and moderate stressors (
      • Adam T.C.
      • Epel E.S.
      Stress, eating and the reward system.
      ). Yet, studies that examined the effect of stress on eating attitudes or intake reported mixed results (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Greeno C.G.
      • Wing R.R.
      Stress-induced eating.
      ,
      • Wallis D.J.
      • Hetherington M.M.
      Emotions and eating. Self-reported and experimentally induced changes in food intake under stress.
      ). This led to the hypothesis that individual differences in the perception of external stressors and reward value of food underlie this heterogeneity (
      • Greeno C.G.
      • Wing R.R.
      Stress-induced eating.
      ,
      • Tanofsky-Kraff M.
      • Wilfley D.E.
      • Spurrell E.
      Impact of interpersonal and ego-related stress on restrained eaters.
      ,
      • Laitinen J.
      • Ek E.
      • Sovio U.
      Stress-related eating and drinking behavior and body mass index and predictors of this behavior.
      ,
      • Klatzkin R.R.
      • Baldassaro A.
      • Rashid S.
      Physiological responses to acute stress and the drive to eat: The impact of perceived life stress.
      ). Identifying physiological and psychological factors that determine the direction of eating responses to stress has been a major goal of epidemiological and clinical studies. However, challenges of standardizing the stress exposure in humans hinder efforts to uncover the underlying mechanism.
      This relationship between stress and feeding in rodents is best studied in the context of pathophysiological eating behaviors. Rodent paradigms to model binge-eating behavior and activity-based anorexia produce a consistent and robust increase or suppression of food intake, respectively [reviewed in (
      • Corwin R.L.
      • Avena N.M.
      • Boggiano M.M.
      Feeding and reward: Perspectives from three rat models of binge eating.
      ,
      • Scharner S.
      • Stengel A.
      Animal models for anorexia nervosa—a systematic review.
      )]. Standardization of these assays has permitted comparisons of findings between laboratories and across species that are critical to establish relevance to humans. Several key elements of the neural signature of individuals with anorexia nervosa have been recapitulated in the activity-based anorexia model, such as disrupted reward signaling (
      • Frank G.K.
      • Bailer U.F.
      • Henry S.E.
      • Drevets W.
      • Meltzer C.C.
      • Price J.C.
      • et al.
      Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride.
      ,
      • Kaye W.H.
      • Wierenga C.E.
      • Bailer U.F.
      • Simmons A.N.
      • Bischoff-Grethe A.
      Nothing tastes as good as skinny feels: The neurobiology of anorexia nervosa.
      ,
      • Foldi C.J.
      • Milton L.K.
      • Oldfield B.J.
      The role of mesolimbic reward neurocircuitry in prevention and rescue of the activity-based anorexia (ABA) phenotype in rats.
      ) and reduced serotonin signing (
      • Frank G.K.
      • Kaye W.H.
      • Meltzer C.C.
      • Price J.C.
      • Greer P.
      • McConaha C.
      • et al.
      Reduced 5-HT2A receptor binding after recovery from anorexia nervosa.
      ,
      • Audenaert K.
      • Van Laere K.
      • Dumont F.
      • Vervaet M.
      • Goethals I.
      • Slegers G.
      • et al.
      Decreased 5-HT2a receptor binding in patients with anorexia nervosa.
      ,
      • Verhagen L.A.
      • Luijendijk M.C.
      • Korte-Bouws G.A.
      • Korte S.M.
      • Adan R.A.
      Dopamine and serotonin release in the nucleus accumbens during starvation-induced hyperactivity.
      ), supporting construct validity. The ability to perform neurogenetic manipulations of discrete circuits and pathways in these models is accelerating progress in the understanding of mechanisms driving pathological eating behaviors (
      • Foldi C.J.
      • Milton L.K.
      • Oldfield B.J.
      The role of mesolimbic reward neurocircuitry in prevention and rescue of the activity-based anorexia (ABA) phenotype in rats.
      ,
      • Beeler J.A.
      • Mourra D.
      • Zanca R.M.
      • Kalmbach A.
      • Gellman C.
      • Klein B.Y.
      • et al.
      Vulnerable and resilient phenotypes in a mouse model of anorexia nervosa.
      ,
      • Miletta M.C.
      • Iyilikci O.
      • Shanabrough M.
      • Sestan-Pesa M.
      • Cammisa A.
      • Zeiss C.J.
      • et al.
      AgRP neurons control compulsive exercise and survival in an activity-based anorexia model.
      ). However, because they are designed to induce a specific type of outcome (i.e., anorexia vs. binge eating), they cannot be used to identify determinants of stress-induced increases versus decreases in food intake.
      While the relationship between stress and feeding in a nonpathophysiological context has not been explored directly, paradigms commonly use stress-induced suppression of appetitive behaviors as a surrogate measure of anxiety- or depression-like behaviors in rodents [reviewed in (
      • Dulawa S.C.
      • Hen R.
      Recent advances in animal models of chronic antidepressant effects: The novelty-induced hypophagia test.
      ,
      • Kokras N.
      • Dalla C.
      Sex differences in animal models of psychiatric disorders.
      )]. We initially set out to mine the literature for studies that combine stress with measurements of food intake, with the goal of developing a predictive model of stress-induced changes in food intake; we identified 57 publications that fit these criteria. Unfortunately, the lack of standardization across key features of the paradigms precluded meaningful comparisons.
      The purpose of this review is to provide a framework for developing standardized assays to study determinants of stress-related eating behavior that are translationally relevant to humans. First, we consider major influences on feeding behavior—sex, estrous cyclicity, circadian cyclicity, caloric restriction, palatable diets, elevated body weight, and properties of the stressors—and discuss the degree to which they are conserved between humans and rodents. We summarize evidence that implicates each factor in feeding responses to stress from studies in humans and rodent models. Then we discuss the degree to which the selected rodent studies recapitulate conditions that are relevant for humans. Finally, we present recommendations for incorporating these influences into the design of paradigms to evaluate the effects of stress on food intake.

      Methodology

      We performed an extensive search of the PubMed database for assays involving stress and feeding-related tasks. Studies using these assays usually focus on anxiety- and depressive-like behaviors, so ancillary effects on food intake are rarely described in the abstract. While we used keyword searches to identify relevant articles, we manually inspected the contents of each article and selected those that quantified caloric intake. Keywords included the following: “food intake,” “stress,” “chronic stress,” “early life stress,” “novelty-suppressed feeding,” “novelty-suppressed hypophagia,” “hyponeophagia,” “sucrose intake,” “sucrose preference,” “fast-refeeding,” “circadian cyclicity,” “sex,” “estrous,” “estrogen,” “age,” “palatable diet,” “chronic high fat diet,” “adiposity,” “caloric restriction,” “social isolation.” After excluding activity-based anorexia and binge-eating models that are designed to achieve a targeted outcome, we identified 57 studies that met our criteria (Table S1). Some used one or more assays that measure acute intake in response to acute, subchronic, or chronic stress: fast/refeeding (n = 7), hyponeophagia (n = 1), novelty-suppressed feeding (n = 12), novelty-induced hypophagia (n = 4), food choice (n = 1), and sucrose preference (n = 15). Some also reported intake patterns over hourly, daily, or weekly time scales (n = 29). We searched for patterns across these studies with the goal of identifying aspects of the paradigms that determine whether stress increases or decreases intake.

      Effects of Sex in Paradigms Involving Stress and Feeding

      In humans and rodents, males and females experience stress-induced changes in food intake, with sex differences in the impacts of distinct types of stress (
      • Stone A.A.
      • Brownell K.D.
      The stress-eating paradox: Multiple daily measurements in adult males and females.
      ,
      • Tanofsky-Kraff M.
      • Wilfley D.E.
      • Spurrell E.
      Impact of interpersonal and ego-related stress on restrained eaters.
      ,
      • Johnston A.L.
      • File S.E.
      Sex differences in animal tests of anxiety.
      ,
      • McCormick C.M.
      • Robarts D.
      • Kopeikina K.
      • Kelsey J.E.
      Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats.
      ,
      • Shi H.
      • Strader A.D.
      • Woods S.C.
      • Seeley R.J.
      Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy.
      ). For example, in both mice and humans, females preferentially decrease energy expenditure during caloric restriction, and males consume more when access to food is restored after caloric restriction (
      • Shi H.
      • Strader A.D.
      • Woods S.C.
      • Seeley R.J.
      Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy.
      ,
      • Zandian M.
      • Ioakimidis I.
      • Bergh C.
      • Leon M.
      • Sodersten P.
      A sex difference in the response to fasting.
      ).
      In humans, anxiety, depressive symptoms (
      • Altemus M.
      • Sarvaiya N.
      • Neill Epperson C.
      Sex differences in anxiety and depression clinical perspectives.
      ), eating disorders, and subclinical disordered eating behaviors (
      • Jacobi C.
      • Hayward C.
      • de Zwaan M.
      • Kraemer H.C.
      • Agras W.S.
      Coming to terms with risk factors for eating disorders: Application of risk terminology and suggestions for a general taxonomy.
      ,
      • Hudson J.I.
      • Hiripi E.
      • Pope Jr., H.G.
      • Kessler R.C.
      The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication.
      ) are more prevalent in females. The earliest studies of stress-induced eating behavior reported stronger effects in women (
      • Greeno C.G.
      • Wing R.R.
      Stress-induced eating.
      ). These observations fostered an overall bias toward stress-induced increases in intake in females that is reflected in subjects chosen for clinical and epidemiological research, as well as the lay press. As the number and size of studies examining stress-induced feeding behaviors increased, findings of sex differences were inconsistent (
      • Torres S.J.
      • Nowson C.A.
      Relationship between stress, eating behavior, and obesity.
      ). Sex differences in responses to different types of stress could contribute to the variability in the findings (
      • Stone A.A.
      • Brownell K.D.
      The stress-eating paradox: Multiple daily measurements in adult males and females.
      ,
      • Tanofsky-Kraff M.
      • Wilfley D.E.
      • Spurrell E.
      Impact of interpersonal and ego-related stress on restrained eaters.
      ,
      • Nguyen-Rodriguez S.T.
      • Unger J.B.
      • Spruijt-Metz D.
      Psychological determinants of emotional eating in adolescence.
      ,
      • Clauss N.
      • Byrd-Craven J.
      Exposure to a sex-specific stressor mitigates sex differences in stress-induced eating.
      ). For example, women are generally more sensitive to interpersonal and emotional stress, while men are more sensitive to ego-threatening stressors (
      • Tanofsky-Kraff M.
      • Wilfley D.E.
      • Spurrell E.
      Impact of interpersonal and ego-related stress on restrained eaters.
      ,
      • Laitinen J.
      • Ek E.
      • Sovio U.
      Stress-related eating and drinking behavior and body mass index and predictors of this behavior.
      ).
      In rodent models, reports of sex biases in studies of stress-related feeding behaviors are similarly heterogeneous. While some studies showed no significant sex differences in the effects of stress (
      • Barfield E.T.
      • Moser V.A.
      • Hand A.
      • Grisel J.E.
      Beta-endorphin modulates the effect of stress on novelty-suppressed feeding.
      ,
      • Kiselycznyk C.
      • Zhang X.
      • Huganir R.L.
      • Holmes A.
      • Svenningsson P.
      Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice.
      ,
      • Savarese A.
      • Lasek A.W.
      Regulation of anxiety-like behavior and Crhr1 expression in the basolateral amygdala by LMO3.
      ,
      • Wang C.
      • Zhang Y.
      • Shao S.
      • Cui S.
      • Wan Y.
      • Yi M.
      Ventral hippocampus modulates anxiety-like behavior in male but not female C57BL/6J mice.
      ,
      • Ranaei E.
      • Torshizi S.
      • Amini A.
      • Heidari M.H.
      • Namvarpour Z.
      • Fathabady F.F.
      • et al.
      Peripubertal stress following maternal immune activation sex-dependently alters depression-like behaviors in offspring.
      ), others reported reduced intake in females during the stress paradigms (
      • Rouzer S.K.
      • Cole J.M.
      • Johnson J.M.
      • Varlinskaya E.I.
      • Diaz M.R.
      Moderate maternal alcohol exposure on gestational day 12 impacts anxiety-like behavior in offspring.
      ,
      • Miragaia A.S.
      • de Oliveira Wertheimer G.S.
      • Consoli A.C.
      • Cabbia R.
      • Longo B.M.
      • Girardi C.E.N.
      • et al.
      Maternal deprivation increases anxiety- and depressive-like behaviors in an age-dependent fashion and reduces neuropeptide Y expression in the amygdala and hippocampus of male and female young adult rats.
      ,
      • Cabbia R.
      • Consoli A.
      • Suchecki D.
      Association of 24 h maternal deprivation with a saline injection in the neonatal period alters adult stress response and brain monoamines in a sex-dependent fashion.
      ,
      • Greiner E.M.
      • Petrovich G.D.
      The effects of novelty on food consumption in male and female rats.
      ). As seen in humans, sex differences in responses to the type of stress incorporated in the study could confound interpretation of the results. For example, experimental paradigms that involve substantial movement, such as open field tests, elicit higher locomotor activity in female rodents (
      • Johnston A.L.
      • File S.E.
      Sex differences in animal tests of anxiety.
      ,
      • McCormick C.M.
      • Robarts D.
      • Kopeikina K.
      • Kelsey J.E.
      Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats.
      ,
      • Ramos A.
      • Berton O.
      • Mormede P.
      • Chaouloff F.
      A multiple-test study of anxiety-related behaviours in six inbred rat strains.
      ,
      • Bernatova I.
      • Puzserova A.
      • Dubovicky M.
      Sex differences in social stress-induced pressor and behavioral responses in normotensive and prehypertensive rats.
      ). On the other hand, males spend more time engaged in social interaction when paired with conspecifics (
      • Johnston A.L.
      • File S.E.
      Sex differences in animal tests of anxiety.
      ).
      In the selected studies, almost half (47%) used males exclusively, while 16% used only females (Figure 1). The rest included both sexes in their design. This demonstrates the strong bias of animal studies toward studying males. The growing appreciation of the importance of characterizing sex differences (
      • Becker J.B.
      • Prendergast B.J.
      • Liang J.W.
      Female rats are not more variable than male rats: A meta-analysis of neuroscience studies.
      ,
      • Prendergast B.J.
      • Onishi K.G.
      • Zucker I.
      Female mice liberated for inclusion in neuroscience and biomedical research.
      ) and the National Institutes of Health mandate to include sex as a biological variable (
      • Clayton J.A.
      • Collins F.S.
      Policy: NIH to balance sex in cell and animal studies.
      ) have spurred a recent increase in the number of studies in our analysis that incorporate both sexes (38% of studies in the 2010s vs. 0% in the 1990s).
      Figure thumbnail gr1
      Figure 1Sex. Numbers of publications that used males exclusively, used females exclusively, or incorporated both sexes by decade.

      Recommendation

      The fact that sex differences were observed in some contexts across species (
      • Greeno C.G.
      • Wing R.R.
      Stress-induced eating.
      ,
      • Rouzer S.K.
      • Cole J.M.
      • Johnson J.M.
      • Varlinskaya E.I.
      • Diaz M.R.
      Moderate maternal alcohol exposure on gestational day 12 impacts anxiety-like behavior in offspring.
      ,
      • Miragaia A.S.
      • de Oliveira Wertheimer G.S.
      • Consoli A.C.
      • Cabbia R.
      • Longo B.M.
      • Girardi C.E.N.
      • et al.
      Maternal deprivation increases anxiety- and depressive-like behaviors in an age-dependent fashion and reduces neuropeptide Y expression in the amygdala and hippocampus of male and female young adult rats.
      ,
      • Cabbia R.
      • Consoli A.
      • Suchecki D.
      Association of 24 h maternal deprivation with a saline injection in the neonatal period alters adult stress response and brain monoamines in a sex-dependent fashion.
      ,
      • Greiner E.M.
      • Petrovich G.D.
      The effects of novelty on food consumption in male and female rats.
      ) suggests that studies should be powered to detect sex-specific differences in sensitivity to the type of stress that is incorporated into the paradigm. If true, it may be necessary to develop sex-specific variations of a paradigm.

      Effects of Estrous Cyclicity in Paradigms Involving Stress and Feeding

      In both human and rodent females, food intake is influenced by hormones that fluctuate across the ovarian cycle (
      • Buffenstein R.
      • Poppitt S.D.
      • McDevitt R.M.
      • Prentice A.M.
      Food intake and the menstrual cycle: A retrospective analysis, with implications for appetite research.
      ,
      • Tarttelin M.F.
      • Gorski R.A.
      Variations in food and water intake in the normal and acyclic female rat.
      ,
      • ter Haar M.B.
      Circadian and estrual rhythms in food intake in the rat.
      ).
      In humans, individual behaviors are highly predictable (
      • Stone A.A.
      • Brownell K.D.
      The stress-eating paradox: Multiple daily measurements in adult males and females.
      ,
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ), suggesting that these responses are primarily driven by invariant factors. However, there are significant associations between levels of ovarian hormones and likelihood of engaging in emotional eating, and these are exacerbated in conditions of stress [reviewed in (
      • Fowler N.
      • Vo P.T.
      • Sisk C.L.
      • Klump K.L.
      Stress as a potential moderator of ovarian hormone influences on binge eating in women.
      )].
      In rodent models, ovariectomy leads to increased food intake that is reversed by estradiol replacement, consistent with an anorexigenic action of estrogen (
      • Geary N.
      • Asarian L.
      Cyclic estradiol treatment normalizes body weight and test meal size in ovariectomized rats.
      ). Potential effects of gonadal hormones on food intake have been used to justify the exclusion of females (
      • Ellacott K.L.
      • Morton G.J.
      • Woods S.C.
      • Tso P.
      • Schwartz M.W.
      Assessment of feeding behavior in laboratory mice.
      ). Yet, studies that explicitly examined stress-induced feeding behaviors in female rodents across the estrous cycle do not support the idea that these fluctuations are a major source of variability (
      • Wang C.
      • Zhang Y.
      • Shao S.
      • Cui S.
      • Wan Y.
      • Yi M.
      Ventral hippocampus modulates anxiety-like behavior in male but not female C57BL/6J mice.
      ,
      • Calvez J.
      • Timofeeva E.
      Behavioral and hormonal responses to stress in binge-like eating prone female rats.
      ,
      • Anversa R.G.
      • Campbell E.J.
      • Ch’ng S.S.
      • Gogos A.
      • Lawrence A.J.
      • Brown R.M.
      A model of emotional stress-induced binge eating in female mice with no history of food restriction.
      ,
      • Alonso-Caraballo Y.
      • Fetterly T.L.
      • Jorgensen E.T.
      • Nieto A.M.
      • Brown T.E.
      • Ferrario C.R.
      Sex specific effects of “junk-food” diet on calcium permeable AMPA receptors and silent synapses in the nucleus accumbens core.
      ). However, there are some contexts when differences in the levels of gonadal hormones exert a strong effect on food intake, such as a severe fast (
      • Shakya M.
      • Briski K.P.
      Rebound feeding in the wake of short-term suspension of food intake differs in the presence of estrous cycle peak versus nadir levels of estradiol.
      ) or adolescent stress (
      • Lamontagne S.J.
      • Wilkin M.M.
      • Menard J.L.
      • Olmstead M.C.
      Mid-adolescent stress differentially affects binge-like intake of sucrose across estrous cycles in female rats.
      ).
      Of the selected studies that included females, 33% reported estrous phase.

      Recommendation

      Considering that levels of gonadal hormones can affect the outcome of the assay in some contexts (
      • Shakya M.
      • Briski K.P.
      Rebound feeding in the wake of short-term suspension of food intake differs in the presence of estrous cycle peak versus nadir levels of estradiol.
      ,
      • Lamontagne S.J.
      • Wilkin M.M.
      • Menard J.L.
      • Olmstead M.C.
      Mid-adolescent stress differentially affects binge-like intake of sucrose across estrous cycles in female rats.
      ), differences across the estrous cycle should first be assessed. As collecting vaginal smears and frequent handling of the mice can affect stress levels, developing assays that do not vary across the estrous cycle is preferable.

      Effects of Circadian Cyclicity in Paradigms Involving Stress and Feeding

      In both humans and rodents, systems regulating feeding behaviors fluctuate across the circadian cycle, with orexinergic pathways gradually increasing the homeostatic drive for feeding and arousal across the inactive phase, peaking at the onset of the active phase [reviewed in (
      • Challet E.
      The circadian regulation of food intake.
      )].
      Humans are active and usually eat during the light cycle. Studies in shift workers show that working at night is associated with increased intake of junk food or foods with a high carbohydrate content (
      • Reinberg A.
      • Migraine C.
      • Apfelbaum M.
      • Brigant L.
      • Ghata J.
      • Vieux N.
      • et al.
      Circadian and ultradian rhythms in the feeding behaviour and nutrient intakes of oil refinery operators with shift-work every 3-4 days.
      ,
      • de Assis M.A.
      • Kupek E.
      • Nahas M.V.
      • Bellisle F.
      Food intake and circadian rhythms in shift workers with a high workload.
      ) and with dysregulated eating behaviors (
      • Almajwal A.M.
      Stress, shift duty, and eating behavior among nurses in Central Saudi Arabia.
      ,
      • Wong H.
      • Wong M.C.
      • Wong S.Y.
      • Lee A.
      The association between shift duty and abnormal eating behavior among nurses working in a major hospital: A cross-sectional study.
      ).
      Rodents ingest the majority of their daily food intake during their active phase, similar to humans, but their active phase is at night (
      • Stephan F.K.
      • Zucker I.
      Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions.
      ,
      • Rivera-Estrada D.
      • Aguilar-Roblero R.
      • Alva-Sanchez C.
      • Villanueva I.
      The homeostatic feeding response to fasting is under chronostatic control.
      ). Yet, most studies using rodent behavioral assays are performed during the day. Direct comparisons of the active and inactive phases demonstrate that appetitive behaviors and motivation to eat are significantly higher at the onset of the dark period (
      • Rivera-Estrada D.
      • Aguilar-Roblero R.
      • Alva-Sanchez C.
      • Villanueva I.
      The homeostatic feeding response to fasting is under chronostatic control.
      ,
      • Kant G.J.
      • Bauman R.A.
      Effects of chronic stress and time of day on preference for sucrose.
      ,
      • Osnaya-Ramirez R.I.
      • Palma-Gomez M.
      • Escobar C.
      Binge eating for sucrose is time of day dependent and independent of food restriction: Effects on mesolimbic structures.
      ), regardless of the length of the fast (
      • Stephan F.K.
      • Zucker I.
      Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions.
      ,
      • Rivera-Estrada D.
      • Aguilar-Roblero R.
      • Alva-Sanchez C.
      • Villanueva I.
      The homeostatic feeding response to fasting is under chronostatic control.
      ).
      Of the assays analyzed here that evaluated acute feeding behaviors (n = 41) (as opposed to daily intake), 82% were in the inactive phase, 13% were in the active phase, and only 5% assessed both the active and the inactive phases (Figure 2).
      Figure thumbnail gr2
      Figure 2Circadian cyclicity. Percentage of assays that evaluated food intake in the active phase (13%), the inactive phase (82%), or both (5%).

      Recommendation

      While the outcome of assays modeling other aspects of behaviors such as anxiety or social behaviors may not be affected (
      • Yang M.
      • Weber M.D.
      • Crawley J.N.
      Light phase testing of social behaviors: Not a problem.
      ), feeding is tightly regulated by influences of circadian cyclicity in both humans and rodents. Evaluating dark phase behavior is necessary to translate food intake–related findings to humans.

      Effects of Caloric Restriction in Paradigms Involving Stress and Feeding

      In both humans and rodents, the state of negative energy balance created by caloric restriction influences the drive to eat (
      • Harris R.B.
      • Kasser T.R.
      • Martin R.J.
      Dynamics of recovery of body composition after overfeeding, food restriction or starvation of mature female rats.
      ,
      • Leibel R.L.
      • Rosenbaum M.
      • Hirsch J.
      Changes in energy expenditure resulting from altered body weight.
      ,
      • Polidori D.
      • Sanghvi A.
      • Seeley R.J.
      • Hall K.D.
      How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake.
      ).
      In humans, reducing caloric intake to lose weight has been shown to modulate the effects of stress on eating in both laboratory-based and questionnaire-based studies. People who are dieting are more likely to report stress-induced hyperphagia, while nonrestrained eaters are more likely to report stress-induced hypophagia, regardless of sex (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Oliver G.
      • Wardle J.
      • Gibson E.L.
      Stress and food choice: A laboratory study.
      ,
      • Roberts C.
      • Troop N.
      • Connan F.
      • Treasure J.
      • Campbell I.C.
      The effects of stress on body weight: Biological and psychological predictors of change in BMI.
      ). Although fasting also promotes subsequent eating in humans, most studies are based on self-reported measurement, without explicit consideration of acute prandial state, and generally focus on eating in the absence of hunger (
      • Fisher J.O.
      • Birch L.L.
      Restricting access to foods and children’s eating.
      ).
      In rodents, caloric restriction is used as a way to achieve binge eating–like behaviors in rodents when associated with chronic stress and access to palatable diets (
      • Pankevich D.E.
      • Teegarden S.L.
      • Hedin A.D.
      • Jensen C.L.
      • Bale T.L.
      Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating.
      ,
      • Hagan M.M.
      • Chandler P.C.
      • Wauford P.K.
      • Rybak R.J.
      • Oswald K.D.
      The role of palatable food and hunger as trigger factors in an animal model of stress induced binge eating.
      ,
      • Boggiano M.M.
      • Chandler P.C.
      Binge eating in rats produced by combining dieting with stress.
      ,
      • Micioni Di Bonaventura M.V.
      • Lutz T.A.
      • Romano A.
      • Pucci M.
      • Geary N.
      • Asarian L.
      • et al.
      Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats.
      ), but the effects of caloric restriction on nonpathological feeding behaviors were not thoroughly studied. A prolonged (24–48 hours) fast is more commonly used to trigger food intake in various assays (i.e., fast/refeed, novelty-suppressed feeding, sucrose preference test). This approach implicates a metabolic and psychological stress in rodents (
      • Woodward C.J.
      • Hervey G.R.
      • Oakey R.E.
      • Whitaker E.M.
      The effects of fasting on plasma corticosterone kinetics in rats.
      ,
      • Jensen T.L.
      • Kiersgaard M.K.
      • Sorensen D.B.
      • Mikkelsen L.F.
      Fasting of mice: A review.
      ) and can change behaviors in rodents (
      • Pierre P.J.
      • Skjoldager P.
      • Bennett A.J.
      • Renner M.J.
      A behavioral characterization of the effects of food deprivation on food and nonfood object interaction: An investigation of the information-gathering functions of exploratory behavior.
      ).
      Of studies analyzed here that evaluated acute feeding behaviors, 58% were performed after a fast (overnight or longer), 5% were performed after a short food deprivation (several hours), and the remainder were performed in the random fed state (Figure 3). Only one of the studies we analyzed examined the effects of stress in the context of weight loss (
      • Pankevich D.E.
      • Teegarden S.L.
      • Hedin A.D.
      • Jensen C.L.
      • Bale T.L.
      Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating.
      ).
      Figure thumbnail gr3
      Figure 3Prandial state. Percentage of assays evaluating the effects of stress on food intake after a fast (58%), after food deprivation (5%), or in the fed state (37%).

      Recommendation

      Shifting studies to the active phase (as decribed above) eliminates the need for a fast, which is stressful (
      • Woodward C.J.
      • Hervey G.R.
      • Oakey R.E.
      • Whitaker E.M.
      The effects of fasting on plasma corticosterone kinetics in rats.
      ,
      • Jensen T.L.
      • Kiersgaard M.K.
      • Sorensen D.B.
      • Mikkelsen L.F.
      Fasting of mice: A review.
      ) and not relevant to humans. Conversely, the effect of chronic caloric restriction on stress-induced changes in feeding behaviors needs to be evaluated more thoroughly in rodents, as it is commonly observed in humans (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Roberts C.
      • Troop N.
      • Connan F.
      • Treasure J.
      • Campbell I.C.
      The effects of stress on body weight: Biological and psychological predictors of change in BMI.
      ,
      • Wardle J.
      • Steptoe A.
      • Oliver G.
      • Lipsey Z.
      Stress, dietary restraint and food intake.
      ).

      Effects of Palatable Diets in Paradigms Involving Stress and Feeding

      In humans and rodents, palatable diets activate reward circuits in the brain that regulate motivated behaviors (
      • Salamone J.D.
      • Correa M.
      • Mingote S.
      • Weber S.M.
      Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: Implications for studies of natural motivation, psychiatry, and drug abuse.
      ,
      • Berridge K.C.
      • Robinson T.E.
      • Aldridge J.W.
      Dissecting components of reward: ‘liking’, ‘wanting’, and learning.
      ,
      • Val-Laillet D.
      • Aarts E.
      • Weber B.
      • Ferrari M.
      • Quaresima V.
      • Stoeckel L.E.
      • et al.
      Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity.
      ).
      In humans, both chronic self-reported stress and acute laboratory stress increase consumption of high fat, palatable snack foods in males and females, with no impact on overall caloric intake (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Oliver G.
      • Wardle J.
      • Gibson E.L.
      Stress and food choice: A laboratory study.
      ).
      In rodent models, although stress is often linked to the consumption of “comfort foods” (
      • Dallman M.F.
      • Pecoraro N.
      • Akana S.F.
      • La Fleur S.E.
      • Gomez F.
      • Houshyar H.
      • et al.
      Chronic stress and obesity: A new view of “comfort food.
      ,
      • Schroeder M.
      • Jakovcevski M.
      • Polacheck T.
      • Drori Y.
      • Ben-Dor S.
      • Roh S.
      • et al.
      Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.
      ), this is not the case for all stressors. For example, in males, social isolation (
      • Izadi M.S.
      • Radahmadi M.
      • Ghasemi M.
      • Rayatpour A.
      Effects of isolation and social subchronic stresses on food intake and levels of leptin, ghrelin, and glucose in male rats.
      ,
      • Oliver D.K.
      • Intson K.
      • Sargin D.
      • Power S.K.
      • McNabb J.
      • Ramsey A.J.
      • et al.
      Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.
      ) and chronic mild stress (
      • Willner P.
      • Muscat R.
      • Papp M.
      Chronic mild stress-induced anhedonia: A realistic animal model of depression.
      ,
      • Aslani S.
      • Harb M.R.
      • Costa P.S.
      • Almeida O.F.
      • Sousa N.
      • Palha J.A.
      Day and night: Diurnal phase influences the response to chronic mild stress.
      ,
      • Remus J.L.
      • Stewart L.T.
      • Camp R.M.
      • Novak C.M.
      • Johnson J.D.
      Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference.
      ,
      • Fang G.
      • Wang Y.
      Effects of rTMS on hippocampal endocannabinoids and depressive-like behaviors in adolescent rats.
      ,
      • Qu N.
      • Wang X.M.
      • Zhang T.
      • Zhang S.F.
      • Li Y.
      • Cao F.Y.
      • et al.
      Estrogen receptor alpha agonist is beneficial for young female rats against chronic unpredicted mild stress-induced depressive behavior and cognitive deficits.
      ) can decrease intake of sucrose.
      Of the selected studies, only 27% involved palatable diets, and 37% used sucrose solutions. The composition of the palatable diets varied widely; 17 out of 26 assays involved distinct combinations of palatable foods.

      Recommendations

      Palatable diets are usually an option for humans and seem to play a critical role in the feeding response to stress (
      • Oliver G.
      • Wardle J.
      Perceived effects of stress on food choice.
      ,
      • Oliver G.
      • Wardle J.
      • Gibson E.L.
      Stress and food choice: A laboratory study.
      ). Therefore, they should be incorporated into rodent paradigms. However, the degree to which differences in macronutrient composition (i.e., high fat vs. high sugar) and whether the diet is presented in liquid or solid form should be considered, and diets should be standardized to permit comparisons between studies.

      Effects of Elevated Body Weight in Paradigms Involving Stress and Feeding

      In humans and rodents, diet-induced obesity is associated with changes in systems regulating reward and motivation to eat (
      • Wang G.J.
      • Volkow N.D.
      • Fowler J.S.
      The role of dopamine in motivation for food in humans: Implications for obesity.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ,
      • Johnson P.M.
      • Kenny P.J.
      Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.
      ,
      • Dutheil S.
      • Ota K.T.
      • Wohleb E.S.
      • Rasmussen K.
      • Duman R.S.
      High-fat diet induced anxiety and anhedonia: Impact on brain homeostasis and inflammation.
      ,
      • Arcego D.M.
      • Krolow R.
      • Lampert C.
      • Toniazzo A.P.
      • Garcia E.D.S.
      • Lazzaretti C.
      • et al.
      Chronic high-fat diet affects food-motivated behavior and hedonic systems in the nucleus accumbens of male rats.
      ).
      In humans, elevated body mass index is consistently associated with eating in the absence of hunger in both children (
      • Miller A.L.
      • Riley H.
      • Domoff S.E.
      • Gearhardt A.N.
      • Sturza J.
      • Kaciroti N.
      • et al.
      Weight status moderates stress-eating in the absence of hunger associations in children.
      ) and adults (
      • Laitinen J.
      • Ek E.
      • Sovio U.
      Stress-related eating and drinking behavior and body mass index and predictors of this behavior.
      ,
      • Lemmens S.G.
      • Rutters F.
      • Born J.M.
      • Westerterp-Plantenga M.S.
      Stress augments food ‘wanting’ and energy intake in visceral overweight subjects in the absence of hunger.
      ). High body mass index and chronic stress are also strongly associated with unhealthy eating habits in shift workers (
      • Akerstedt T.
      • Knutsson A.
      • Westerholm P.
      • Theorell T.
      • Alfredsson L.
      • Kecklund G.
      Sleep disturbances, work stress and work hours: A cross-sectional study.
      ,
      • Liu Q.
      • Shi J.
      • Duan P.
      • Liu B.
      • Li T.
      • Wang C.
      • et al.
      Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis.
      ). Increased cravings for highly palatable foods in satiated individuals with obesity (
      • Lemmens S.G.
      • Rutters F.
      • Born J.M.
      • Westerterp-Plantenga M.S.
      Stress augments food ‘wanting’ and energy intake in visceral overweight subjects in the absence of hunger.
      ,
      • Geliebter A.
      • Aversa A.
      Emotional eating in overweight, normal weight, and underweight individuals.
      ) in the presence of dampened dopaminergic reward circuits (
      • Wang G.J.
      • Volkow N.D.
      • Fowler J.S.
      The role of dopamine in motivation for food in humans: Implications for obesity.
      ,
      • Stice E.
      • Spoor S.
      • Bohon C.
      • Veldhuizen M.G.
      • Small D.M.
      Relation of reward from food intake and anticipated food intake to obesity: A functional magnetic resonance imaging study.
      ) are proposed to drive excessive caloric intake.
      In rodents, the most common model of obesity is chronic exposure to a high fat diet (HFD) or high fat/high sugar diet. As observed in humans with obesity, prolonged HFD exposure weakens signaling in dopamine reward circuits in male rats (
      • Johnson P.M.
      • Kenny P.J.
      Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.
      ,
      • Dutheil S.
      • Ota K.T.
      • Wohleb E.S.
      • Rasmussen K.
      • Duman R.S.
      High-fat diet induced anxiety and anhedonia: Impact on brain homeostasis and inflammation.
      ,
      • Arcego D.M.
      • Krolow R.
      • Lampert C.
      • Toniazzo A.P.
      • Garcia E.D.S.
      • Lazzaretti C.
      • et al.
      Chronic high-fat diet affects food-motivated behavior and hedonic systems in the nucleus accumbens of male rats.
      ). Mice consume more calories overall, and chronic exposure devalues subsequent intake of standard chow after a fast in both sexes independent of body weight gain (
      • Mazzone C.M.
      • Liang-Guallpa J.
      • Li C.
      • Wolcott N.S.
      • Boone M.H.
      • Southern M.
      • et al.
      High-fat food biases hypothalamic and mesolimbic expression of consummatory drives.
      ). The relationship between chronic HFD exposure and stress-induced feeding behavior in rodents is complicated. It seems to magnify existing tendencies for stress-induced hyperphagic (
      • Bartolomucci A.
      • Cabassi A.
      • Govoni P.
      • Ceresini G.
      • Cero C.
      • Berra D.
      • et al.
      Metabolic consequences and vulnerability to diet-induced obesity in male mice under chronic social stress.
      ,
      • Razzoli M.
      • Sanghez V.
      • Bartolomucci A.
      Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder.
      ) or hypophagic responses (
      • Harris R.B.
      • Zhou J.
      • Youngblood B.D.
      • Rybkin I.I.
      • Smagin G.N.
      • Ryan D.H.
      Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets.
      ,
      • Finger B.C.
      • Dinan T.G.
      • Cryan J.F.
      High-fat diet selectively protects against the effects of chronic social stress in the mouse.
      ,
      • Aslani S.
      • Vieira N.
      • Marques F.
      • Costa P.S.
      • Sousa N.
      • Palha J.A.
      The effect of high-fat diet on rat’s mood, feeding behavior and response to stress.
      ). However, because each study here involved a different length of HFD exposure and type and duration of stress, it is hard to draw conclusions that are more definitive.
      Of the selected assays, only 23% incorporated elevated body weight into the paradigm, mostly through diet-induced obesity.

      Recommendations

      Considering the importance of the relationship between elevated body weight and stress eating in humans (
      • Laitinen J.
      • Ek E.
      • Sovio U.
      Stress-related eating and drinking behavior and body mass index and predictors of this behavior.
      ,
      • Liu Q.
      • Shi J.
      • Duan P.
      • Liu B.
      • Li T.
      • Wang C.
      • et al.
      Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis.
      ,
      • Geliebter A.
      • Aversa A.
      Emotional eating in overweight, normal weight, and underweight individuals.
      ), incorporating diet-induced obesity in rodent models would increase translatability and could help to parse effects of chronic versus acute exposure to palatable diets.

      Consideration of Stressors That Are Incorporated Into Paradigms Involving Stress and Feeding

      In both humans and rodents, variability in the type of stress incorporated into the study design hampers efforts to uncover determinants of stress-related feeding behaviors. The most consistent findings are that people are more likely to eat less as the severity of the stress increases (
      • Stone A.A.
      • Brownell K.D.
      The stress-eating paradox: Multiple daily measurements in adult males and females.
      ,
      • Kandiah J.
      • Yake M.
      • Willett H.
      Effects of stress on eating practices among adults.
      ), and when they engage in emotional eating, it usually involves consumption of palatable foods (
      • Kandiah J.
      • Yake M.
      • Jones J.
      • Meyer M.
      Stress influences appetite and comfort food preferences in college women.
      ,
      • Zellner D.A.
      • Loaiza S.
      • Gonzalez Z.
      • Pita J.
      • Morales J.
      • Pecora D.
      • et al.
      Food selection changes under stress.
      ,
      • Oliver G.
      • Wardle J.
      • Gibson E.L.
      Stress and food choice: A laboratory study.
      ,
      • Rutters F.
      • Nieuwenhuizen A.G.
      • Lemmens S.G.
      • Born J.M.
      • Westerterp-Plantenga M.S.
      Acute stress-related changes in eating in the absence of hunger.
      ). This general pattern is conserved in rodents (
      • Harris R.B.
      • Zhou J.
      • Youngblood B.D.
      • Rybkin I.I.
      • Smagin G.N.
      • Ryan D.H.
      Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets.
      ,
      • Rowland N.E.
      • Antelman S.M.
      Stress-induced hyperphagia and obesity in rats: A possible model for understanding human obesity.
      ,
      • Antelman S.M.
      • Rowland N.E.
      • Fisher A.E.
      Stress related recovery from lateral hypothalamic aphagia.
      ,
      • Bertiere M.C.
      • Sy T.M.
      • Baigts F.
      • Mandenoff A.
      • Apfelbaum M.
      Stress and sucrose hyperphagia: Role of endogenous opiates.
      ,
      • Levine A.S.
      • Morley J.E.
      Stress-induced eating in rats.
      ,
      • Marti O.
      • Marti J.
      • Armario A.
      Effects of chronic stress on food intake in rats: Influence of stressor intensity and duration of daily exposure.
      ,
      • Valles A.
      • Marti O.
      • Garcia A.
      • Armario A.
      Single exposure to stressors causes long-lasting, stress-dependent reduction of food intake in rats.
      ).
      We classified the selected studies according to the type of stressor (physical, psychological, social), the length of the stress (acute, subchronic, chronic) and the timing (early life, adolescence, adulthood). In addition to the intended stressors, we noted two additional stressors that are unintentionally imposed in many experiments in rodents: fasting and single housing. As discussed above, fasting is often used to motivate consumption of a chow diet during the day. It also increases the level of circulating stress hormones (
      • Woodward C.J.
      • Hervey G.R.
      • Oakey R.E.
      • Whitaker E.M.
      The effects of fasting on plasma corticosterone kinetics in rats.
      ,
      • Jensen T.L.
      • Kiersgaard M.K.
      • Sorensen D.B.
      • Mikkelsen L.F.
      Fasting of mice: A review.
      ) and food-seeking behavior (
      • Pierre P.J.
      • Skjoldager P.
      • Bennett A.J.
      • Renner M.J.
      A behavioral characterization of the effects of food deprivation on food and nonfood object interaction: An investigation of the information-gathering functions of exploratory behavior.
      ). Measurement of individual food intake in rodents usually necessitates single housing, which has sex-specific effects on the function of the hypothalamic-pituitary-adrenal axis (
      • Nichols D.J.
      • Chevins P.F.
      Effects of housing on corticosterone rhythm and stress responses in female mice.
      ,
      • Serra M.
      • Pisu M.G.
      • Floris I.
      • Biggio G.
      Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat.
      ,
      • Arndt S.S.
      • Laarakker M.C.
      • van Lith H.A.
      • van der Staay F.J.
      • Gieling E.
      • Salomons A.R.
      • et al.
      Individual housing of mice—impact on behaviour and stress responses.
      ) and feeding behaviors (
      • Oliver D.K.
      • Intson K.
      • Sargin D.
      • Power S.K.
      • McNabb J.
      • Ramsey A.J.
      • et al.
      Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.
      ). In the studies analyzed here, 63% housed the animals individually, and only 7% compared single housing with group housing (Figure 4). There were no consistent patterns in the combination of stressors used. Of the 48 assays that involved an intentional stress, we identified 35 different combinations of experimental conditions when sorted by the acute assay, type of stressor, prandial state, and housing status. Although the variability in the study designs did not permit us to identify general determinants of the direction of feeding responses to stress, we highlight aspects of stressors that should be considered when designing assays.
      Figure thumbnail gr4
      Figure 4Social isolation. Percentage of assays evaluating the effects of stress on food intake in single-housed animals (63%), group-housed animals (30%), or both (7%).

      Type of Stress

      It is not possible to make general claims about the effect of social stress or physical stress on food intake because stressors of the same class can have different effects on food intake in rodents. For example, in males, social isolation and overcrowding decrease feeding (
      • Izadi M.S.
      • Radahmadi M.
      • Ghasemi M.
      • Rayatpour A.
      Effects of isolation and social subchronic stresses on food intake and levels of leptin, ghrelin, and glucose in male rats.
      ,
      • Oliver D.K.
      • Intson K.
      • Sargin D.
      • Power S.K.
      • McNabb J.
      • Ramsey A.J.
      • et al.
      Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.
      ,
      • Lin E.J.
      • Sun M.
      • Choi E.Y.
      • Magee D.
      • Stets C.W.
      • During M.J.
      Social overcrowding as a chronic stress model that increases adiposity in mice.
      ), while chronic social defeat stress promotes hyperphagia (
      • Razzoli M.
      • Sanghez V.
      • Bartolomucci A.
      Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder.
      ,
      • Mori M.
      • Murata Y.
      • Tsuchihashi M.
      • Hanakita N.
      • Terasaki F.
      • Harada H.
      • et al.
      Continuous psychosocial stress stimulates BMP signaling in dorsal hippocampus concomitant with anxiety-like behavior associated with differential modulation of cell proliferation and neurogenesis.
      ). In females, depriving access to maternal care can have opposite effects, depending on the severity of the manipulation. Maternal separation (3 hours for 14 days) increases consumption of a palatable diet, while maternal deprivation (no access for two 24-hour periods) decreases it (
      • de Lima R.M.S.
      • Dos Santos Bento L.V.
      • di Marcello Valladao Lugon M.
      • Barauna V.G.
      • Bittencourt A.S.
      • Dalmaz C.
      • et al.
      Early life stress and the programming of eating behavior and anxiety: Sex-specific relationships with serotonergic activity and hypothalamic neuropeptides.
      ).

      Timing of Stress Across the Life Span

      Exposure to stress across the life span can impact the outcome of the stress response on food intake in a sex-, age-, and diet-dependent manner in both humans [reviewed in (
      • Bale T.L.
      • Epperson C.N.
      Sex differences and stress across the lifespan.
      )] and rodents (
      • Miragaia A.S.
      • de Oliveira Wertheimer G.S.
      • Consoli A.C.
      • Cabbia R.
      • Longo B.M.
      • Girardi C.E.N.
      • et al.
      Maternal deprivation increases anxiety- and depressive-like behaviors in an age-dependent fashion and reduces neuropeptide Y expression in the amygdala and hippocampus of male and female young adult rats.
      ,
      • Cabbia R.
      • Consoli A.
      • Suchecki D.
      Association of 24 h maternal deprivation with a saline injection in the neonatal period alters adult stress response and brain monoamines in a sex-dependent fashion.
      ,
      • Schroeder M.
      • Jakovcevski M.
      • Polacheck T.
      • Drori Y.
      • Ben-Dor S.
      • Roh S.
      • et al.
      Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.
      ,
      • de Lima R.M.S.
      • Dos Santos Bento L.V.
      • di Marcello Valladao Lugon M.
      • Barauna V.G.
      • Bittencourt A.S.
      • Dalmaz C.
      • et al.
      Early life stress and the programming of eating behavior and anxiety: Sex-specific relationships with serotonergic activity and hypothalamic neuropeptides.
      ,
      • Mueller B.R.
      • Bale T.L.
      Sex-specific programming of offspring emotionality after stress early in pregnancy.
      ,
      • Hancock S.D.
      • Grant V.L.
      Sexually dimorphic effects of postnatal treatment on the development of activity-based anorexia in adolescent and adult rats.
      ,
      • Schroeder M.
      • Jakovcevski M.
      • Polacheck T.
      • Lebow M.
      • Drori Y.
      • Engel M.
      • et al.
      A methyl-balanced diet prevents CRF-induced prenatal stress-triggered predisposition to binge eating-like phenotype.
      ,
      • Enayati M.
      • Mosaferi B.
      • Homberg J.R.
      • Diniz D.M.
      • Salari A.A.
      Prenatal maternal stress alters depression-related symptoms in a strain- and sex-dependent manner in rodent offspring.
      ). In rodents, stress exposure throughout gestation does not affect baseline food intake in males (
      • Schroeder M.
      • Jakovcevski M.
      • Polacheck T.
      • Drori Y.
      • Ben-Dor S.
      • Roh S.
      • et al.
      Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.
      ,
      • Mueller B.R.
      • Bale T.L.
      Sex-specific programming of offspring emotionality after stress early in pregnancy.
      ), but it decreases baseline intake in females (
      • Schroeder M.
      • Jakovcevski M.
      • Polacheck T.
      • Drori Y.
      • Ben-Dor S.
      • Roh S.
      • et al.
      Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.
      ) and reduces sucrose preference in both sexes (
      • Mueller B.R.
      • Bale T.L.
      Sex-specific programming of offspring emotionality after stress early in pregnancy.
      ,
      • Enayati M.
      • Mosaferi B.
      • Homberg J.R.
      • Diniz D.M.
      • Salari A.A.
      Prenatal maternal stress alters depression-related symptoms in a strain- and sex-dependent manner in rodent offspring.
      ). Combining stress exposures in two developmental periods can produce synergistic effects. For example, male mice exhibit anhedonia when exposed to stress in both gestation and adolescence, but not when the manipulation is limited to one time period (
      • Ranaei E.
      • Torshizi S.
      • Amini A.
      • Heidari M.H.
      • Namvarpour Z.
      • Fathabady F.F.
      • et al.
      Peripubertal stress following maternal immune activation sex-dependently alters depression-like behaviors in offspring.
      ). Of the experiments that imposed developmental stressors, 6 were gestational, 8 were early postnatal, and 4 were adolescent. Even when study designs are similar, comparisons are hindered by differences in the reported outcome measures.

      Age of Acute Test

      The age of the animals at the time of the assay can influence its outcome. In rodents, chronic social defeat stress tends to increase sucrose preference in adult males (
      • Mori M.
      • Murata Y.
      • Tsuchihashi M.
      • Hanakita N.
      • Terasaki F.
      • Harada H.
      • et al.
      Continuous psychosocial stress stimulates BMP signaling in dorsal hippocampus concomitant with anxiety-like behavior associated with differential modulation of cell proliferation and neurogenesis.
      ), while it decreases it in adolescent males (
      • Alves-Dos-Santos L.
      • Resende L.S.
      • Chiavegatto S.
      Susceptibility and resilience to chronic social defeat stress in adolescent male mice: No correlation between social avoidance and sucrose preference.
      ). Even when studies are performed in “adult” animals, the differences in ages used in the studies we analyzed (range 21–630 days, median 70 days) can affect stress-induced feeding behaviors. Performing the test in older adult male rodents (>1 year) is more likely to result in decreased consumption of chow compared with younger adult animals (6–10 weeks) (
      • Yamada C.
      • Saegusa Y.
      • Nahata M.
      • Sadakane C.
      • Hattori T.
      • Takeda H.
      Influence of aging and gender differences on feeding behavior and ghrelin-related factors during social isolation in mice.
      ).

      Recommendations

      Ideally, the development of a consensus on several standardized assays that could be used as a battery to evaluate stress-related feeding would permit comparisons between groups, enhancing the rigor and reproducibility of the research, as shown for models of anorexia-like and binge-eating behaviors [reviewed in (
      • Corwin R.L.
      • Avena N.M.
      • Boggiano M.M.
      Feeding and reward: Perspectives from three rat models of binge eating.
      ,
      • Scharner S.
      • Stengel A.
      Animal models for anorexia nervosa—a systematic review.
      )]. Until that happens, there are several ways to increase the impact of studies by individual groups. First, the impact of varying the length and/or the severity of the stressor could be assessed. In addition, analyses at the individual level, instead of providing group averages, could permit comparisons between susceptible and resistant individuals that could uncover important determinants of feeding behavior. This strategy has been used successfully to study factors that promote susceptibility to binge eating in rats (
      • Boggiano M.M.
      • Artiga A.I.
      • Pritchett C.E.
      • Chandler-Laney P.C.
      • Smith M.L.
      • Eldridge A.J.
      High intake of palatable food predicts binge-eating independent of susceptibility to obesity: An animal model of lean vs obese binge-eating and obesity with and without binge-eating.
      ,
      • Klump K.L.
      • Suisman J.L.
      • Culbert K.M.
      • Kashy D.A.
      • Sisk C.L.
      Binge eating proneness emerges during puberty in female rats: A longitudinal study.
      ) and anorexia-like behaviors in mice (
      • Beeler J.A.
      • Mourra D.
      • Zanca R.M.
      • Kalmbach A.
      • Gellman C.
      • Klein B.Y.
      • et al.
      Vulnerable and resilient phenotypes in a mouse model of anorexia nervosa.
      ,
      • Madra M.
      • Zeltser L.M.
      BDNF-Val66Met variant and adolescent stress interact to promote susceptibility to anorexic behavior in mice.
      ).

      Technical Considerations in Measuring Feeding Behaviors

      Because some of the assays were designed to study anxiety-like behavior, the standard reported measures of food intake are not adequate to draw meaningful conclusions about appetite drive (
      • Ellacott K.L.
      • Morton G.J.
      • Woods S.C.
      • Tso P.
      • Schwartz M.W.
      Assessment of feeding behavior in laboratory mice.
      ). In assays involving intake of palatable food/drink, rodents are typically acclimated to the novel substance for a few days, without confirming that they reached a stable baseline (
      • Schalla M.A.
      • Kuhne S.G.
      • Friedrich T.
      • Hanel V.
      • Kobelt P.
      • Goebel-Stengel M.
      • et al.
      Sucrose preference and novelty-induced hypophagia tests in rats using an automated food intake monitoring system.
      ). If the test involves consumption of the diet in a manner to which the rodent is not accustomed (i.e., in a weight boat or pipette), they should be trained for 5 to 7 days beforehand. It is critical to ensure that baseline food intake is stable, particularly when introducing novel foods as part of the assay. Individuals that do not train to eat or drink in the test conditions should be excluded. Intake at baseline and in the stress condition should be reported. Paradigms in which the main outcome measure is latency to eat often report intake for 5 to 10 minutes after the start of the test. Measurements of food intake should begin after the first bite/lick and not at the start of the test. Finally, food intake should be recorded for at least 30 minutes (
      • Ellacott K.L.
      • Morton G.J.
      • Woods S.C.
      • Tso P.
      • Schwartz M.W.
      Assessment of feeding behavior in laboratory mice.
      ,
      • Schalla M.A.
      • Kuhne S.G.
      • Friedrich T.
      • Hanel V.
      • Kobelt P.
      • Goebel-Stengel M.
      • et al.
      Sucrose preference and novelty-induced hypophagia tests in rats using an automated food intake monitoring system.
      ).

      Summary and Recommendations

      Influences of sex, estrous cyclicity, circadian cyclicity, caloric restriction, palatable diets, elevated body weight, and properties of the stressors are conserved across species, supporting the use of rodent models to study stress-induced changes in food intake. The sheer number of factors that shape stress-related eating behaviors complicates efforts to uncover key pathways and therapeutic targets. We present some recommendations to foster efforts to develop reproducible and translationally relevant assays to study stress-induced feeding behaviors (Figure 5):
      • The research community would benefit from establishing a battery of assays to examine stress-induced feeding behavior with standardized protocols (including housing conditions and antecedent chronic stressors) and feeding-related outcomes measures.
      • Studies should be powered to detect sex differences. If the same stressor produces opposite effects on food intake, developing sex-specific paradigms may be needed. Similarly, potential effects of estrous cyclicity should also be considered, and adaptations to the protocol can be made to eliminate these effects if needed.
      • Assays should be performed in the active phase; this enhances translational relevance and avoids stresses from caloric restriction.
      • Palatable diets should be used in the acute test.
      • Studies of stress-induced overeating should include models of chronic exposure to obesogenic diets and/or caloric restriction to recapitulate observations in humans.
      • It is important to appreciate that measurement of food intake almost always involves single-housing of animals, which exerts opposite effects on feeding behaviors in males and females. Inclusion of group-housed control animals should be considered, as people are usually not socially isolated.
      Figure thumbnail gr5
      Figure 5Recommendations to increase translatability of rodent studies of stress-related eating behaviors.

      Future Directions

      Recent technical advances make it possible to perform unbiased analyses to identify brain regions and molecular pathways during a specific behavioral task. The development of translationally relevant assays of stress-related eating behaviors is needed to fully exploit these cutting-edge tools. Applying these new approaches to study the effects of stress on food intake has the potential to uncover links between emotional eating and obesity as well as links to the etiology of eating disorders.

      Acknowledgments and Disclosures

      This work was supported by the National Institutes of Health (Grant No. 1R01 MH113353 [to LMZ]), Klarman Family Foundation for Eating Disorders Research (to LMZ), and Russell Berrie Foundation (to LMZ).
      The authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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