Currently, over 300 million people worldwide have depression, and the socioeconomic burden of this debilitating disorder is anticipated to increase markedly over the coming decades against a background of increasing global turmoil. Despite this impending crisis, we are still waiting for improved therapeutic options for this disorder to emerge, which has led to increasing criticism of the role and value of preclinical models of depression. In this Review, we examine this landscape, focusing firstly on issues related to the terminology used in this context and the myriad of preclinical approaches to modelling and assaying aspects of depression in rodents. We discuss the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits. We then examine the technical strategies available to dissect these models and review emerging evidence for putative druggable disease mechanisms. Finally, we propose a brief framework for future research that makes optimal use of these models and will, we hope, accelerate the discovery of improved antidepressants.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
James, S. L. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018).
World Health Organization. Depression and other common mental disorders: global health estimates (WHO, 2017).
World Health Organization. Depression (WHO, 2018).
Insel, T. Post by former NIMH Director Thomas Insel: the global cost of mental illness. NIMH https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2011/the-global-cost-of-mental-illness.shtml (2011).
Bloom, D. E. et al. The global economic burden of non-communicable diseases (World Economic Forum, 2011).
World Health Organization. Preventing suicide: a global imperative (WHO, 2014).
Hillhouse, T. M. & Porter, J. H. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp. Clin. Psychopharmacol. 23, 1–21 (2015).
Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019).
Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic (FDA, 2019).
Bale, T. L. et al. The critical importance of basic animal research for neuropsychiatric disorders. Neuropsychopharmacology 44, 1349–1353 (2019).
Cipriani, A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391, 1357–1366 (2018). This comprehensive and large-scale meta-analysis revealed that clinically prescribed antidepressants are generally more effective than placebo, although the overall effect size (0.3) is modest.
Conway, C. R., George, M. S. & Sackeim, H. A. Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry 74, 9–10 (2017).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 5th edn (American Psychiatric Publishing, 2013).
Drysdale, A. T. et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat. Med. 23, 28–38 (2016). This functional MRI study was the first to subdivide major depression into four so-called biotypes based on patterns of resting-state functional connectivity in key brain networks.
Milaneschi, Y. et al. Polygenic dissection of major depression clinical heterogeneity. Mol. Psychiatry 21, 516–522 (2015).
Dinga, R. et al. Evaluating the evidence for biotypes of depression: methodological replication and extension of Drysdale et al. (2017). NeuroImage Clin. 22, 101796 (2019).
Kendler, K. S. The phenomenology of major depression and the representativeness and nature of DSM criteria. Am. J. Psychiatry 173, 771–780 (2016).
Galvão-Coelho, N. L., Galvão, A. C. M., da Silva, F. S. & de Sousa, M. B. C. Common marmosets: a potential translational animal model of juvenile depression. Front. Psychiatry 8, 175 (2017).
Kalueff, A. V., Stewart, A. M. & Gerlai, R. Zebrafish as an emerging model for studying complex brain disorders. Trends Pharmacol. Sci. 35, 63–75 (2014).
Guloksuz, S., van Os, J. & Rutten, B. P. F. The exposome paradigm and the complexities of environmental research in psychiatry. JAMA Psychiatry 75, 985–986 (2018).
Flint, J. & Kendler, K. S. The genetics of major depression. Neuron 81, 484–503 (2014).
Monteggia, L. M., Heimer, H. & Nestler, E. J. Meeting report: can we make animal models of human mental illness? Biol. Psychiatry 84, 542–545 (2018).
Naicker, K., Galambos, N. L., Zeng, Y., Senthilselvan, A. & Colman, I. Social, demographic, and health outcomes in the 10 years following adolescent depression. J. Adolesc. Health 52, 533–538 (2013).
Kok, R. M. & Reynolds, C. F. 3rd Management of depression in older adults: a review. JAMA 317, 2114–2122 (2017).
Bale, T. L. & Epperson, C. N. Sex as a biological variable: who, what, when, why, and how. Neuropsychopharmacology 42, 386–396 (2017).
McKinney, W. T. Jr & Bunney, W. E. Jr. Animal model of depression: I. Review of evidence: implications for research. JAMA Psychiatry 21, 240–248 (1969).
Willner, P. Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case. Prog. Neuropsychopharmacol. Biol. Psychiatry 10, 677–690 (1986).
Belzung, C. & Lemoine, M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol. Mood Anxiety Disord. 1, 9 (2011).
Tricklebank, M. D. & Garner, J. P. in Drug Discovery for Psychiatric Disorders (eds Rankovic, Z. Hargreaves, R. & Bingham, M.). Ch. 20, 534-557 (Royal Society of Chemistry, 2012).
Sjoberg, E. A. Logical fallacies in animal model research. Behav. Brain Funct. 13, 3 (2017). A recent perspective piece on some of the philosophical and practical challenges in using animal models for research with discussions on confirmation bias and validity criteria.
Geyer, M. & Markou, A. in Psychopharmacology: The Fourth Generation of Progress (eds Bloom, F. E. & Kupfer, D. J.) 787–798 (Raven, 1995).
Kaiser, T. & Feng, G. Modeling psychiatric disorders for developing effective treatments. Nat. Med. 21, 979–988 (2015).
van der Staay, J. F., Arndt, S. S. & Nordquist, R. E. The standardization–generalization dilemma: a way out. Genes Brain Behav. 9, 849–855 (2010).
Bogue, M. A. et al. Mouse Phenome Database: an integrative database and analysis suite for curated empirical phenotype data from laboratory mice. Nucleic Acids Res. 46, D843–D850 (2018). Run by the Jackson laboratory, this database is a comprehensive resource for researchers wanting to explore mouse genotype–phenotype relationships. Researchers can also submit their data.
Prendergast, B. J., Onishi, K. G. & Zucker, I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 40, 1–5 (2014).
Jacobson, L. H. & Cryan, J. F. Feeling strained? Influence of genetic background on depression-related behavior in mice: a review. Behav. Genet. 37, 171–213 (2007).
Festing, M. F. W. Evidence should trump intuition by preferring inbred strains to outbred stocks in preclinical research. ILAR J. 55, 399–404 (2014).
Tuttle, A. H., Philip, V. M., Chesler, E. J. & Mogil, J. S. Comparing phenotypic variation between inbred and outbred mice. Nat. Methods 15, 994–996 (2018). A recent meta-analysis of preclinical studies, which revealed that trait stability in inbred strains is no different to that of outbred strains.
Commons, K. G., Cholanians, A. B., Babb, J. A. & Ehlinger, D. G. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem. Neurosci. 8, 955–960 (2017).
Molendijk, M. L. & de Kloet, E. R. Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology 62, 389–391 (2015).
Reardon, S. Depression researchers rethink popular mouse swim tests. Nature 571, 456–457 (2019).
Howe, J. R. V. I. et al. The mouse as a model for neuropsychiatric drug development. Curr. Biol. 28, R909–R914 (2018).
Thase, M. E., Gommoll, C., Chen, C., Kramer, K. & Sambunaris, A. Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder. Int. Clin. Psychopharmacol. 31, 332–340 (2016).
McClintock, S. M. et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J. Clin. Psychopharmacol. 31, 180–186 (2011).
Guilloux, J.-P., Seney, M., Edgar, N. & Sibille, E. Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J. Neurosci. Methods 197, 21–31 (2011). This paper details how to calculate z-scores from complementary behavioural assays.
de Chaumont, F. et al. Live Mouse Tracker: real-time behavioral analysis of groups of mice. Preprint at bioRxiv https://doi.org/10.1101/345132 (2018).
Pennington, Z. T. et al. ezTrack: an open-source video analysis pipeline for the investigation of animal behavior. Preprint at bioRxiv https://doi.org/10.1101/592592 (2019).
Mathis, A. et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat. Neurosci. 21, 1281–1289 (2018).
Suri, D. & Vaidya, V. A. The adaptive and maladaptive continuum of stress responses — a hippocampal perspective. Rev. Neurosci. 26, 415–442 (2015).
Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). A classic paper that comprehensively phenotyped over 400 mice exposed to the chronic social defeat stress paradigm.
Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014).
Castro, J. E. et al. Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity. Psychoneuroendocrinology 37, 1209–1223 (2012).
Sandi, C. et al. Chronic stress-induced alterations in amygdala responsiveness and behavior — modulation by trait anxiety and corticotropin-releasing factor systems. Eur. J. Neurosci. 28, 1836–1848 (2008).
Nasca, C., Bigio, B., Zelli, D., Nicoletti, F. & McEwen, B. S. Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol. Psychiatry 20, 755–763 (2015).
Miller, G. A. & Rockstroh, B. Endophenotypes in psychopathology research: where do we stand? Annu. Rev. Clin. Psychol. 9, 177–213 (2013).
Cryan, J. F., Sánchez, C., Dinan, T. G. & Borsini, F. in Animal and Translational Models for CNS Drug Discovery Ch. 7 (eds McArthur, R. A. & Borsini, F.) 165–197 (Academic Press, 2008).
Hasler, G., Drevets, W. C., Gould, T. D., Gottesman, I. I. & Manji, H. K. Toward constructing an endophenotype strategy for bipolar disorders. Biol. Psychiatry 60, 93–105 (2006).
Goldstein, B. L. & Klein, D. N. A review of selected candidate endophenotypes for depression. Clin. Psychol. Rev. 34, 417–427 (2014).
Webb, C. A. et al. Neural correlates of three promising endophenotypes of depression: evidence from the EMBARC study. Neuropsychopharmacology 41, 454–463 (2016). This clinical electroencephalography current density study revealed that differential activity of the anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex correlated with neuroticism, impaired cognition and blunted reward learning.
Palagini, L., Baglioni, C., Ciapparelli, A., Gemignani, A. & Riemann, D. REM sleep dysregulation in depression: state of the art. Sleep Med. Rev. 17, 377–390 (2013).
Talbot, C. J. et al. High-resolution mapping of quantitative trait loci in outbred mice. Nat. Genet. 21, 305 (1999).
Malkesman, O. et al. The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol. Psychiatry 67, 864–871 (2010).
Zanos, P. et al. A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro 4, ENEURO.0285–16.2017 (2017).
Terrillion, C. E., Francis, T. C., Puche, A. C., Lobo, M. K. & Gould, T. D. Decreased nucleus accumbens expression of psychiatric disorder risk gene Cacna1c promotes susceptibility to social stress. Int. J. Neuropsychopharmacol. 20, 428–433 (2017).
Ineichen, C. et al. Establishing a probabilistic reversal learning test in mice: evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin. Neuropharmacology 63, 1012–1021 (2012).
Der-Avakian, A., D’Souza, M. S., Pizzagalli, D. A. & Markou, A. Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research. Transl Psychiatry 3, e297 (2013).
Stuart, S. A., Butler, P., Munafo, M. R., Nutt, D. J. & Robinson, E. S. J. A translational rodent assay of affective biases in depression and antidepressant therapy. Neuropsychopharmacology 38, 1625–1635 (2013).
Hinchcliffe, J. K., Stuart, S. A., Mendl, M. & Robinson, E. S. J. Further validation of the affective bias test for predicting antidepressant and pro-depressant risk: effects of pharmacological and social manipulations in male and female rats. Psychopharmacology 234, 3105–3116 (2017).
Stuart, S. A., Wood, C. M. & Robinson, E. S. J. Using the affective bias test to predict drug-induced negative affect: implications for drug safety. Br. J. Pharmacol. 174, 3200–3210 (2017).
Riga, D. et al. Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats. Sci. Transl Med. 9, eaai8753 (2017).
Garza, J. et al. Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction. Int. J. Neuropsychopharmacol. 14, 303–317 (2011).
Richter, S. H. et al. Where have I been? Where should I go? Spatial working memory on a radial arm maze in a rat model of depression. PLOS ONE 8, e62458 (2013).
Khan, D. et al. Long-term effects of maternal immune activation on depression-like behavior in the mouse. Transl Psychiatry 4, e363 (2014).
Phillips, B. U. et al. Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice. Psychopharmacology 235, 2101–2111 (2018).
Tran, T. P. et al. The touchscreen operant platform for assessing cognitive functions in a rat model of depression. Physiol. Behav. 161, 74–80 (2016).
Willner, P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol. Stress 6, 78–93 (2017).
Pryce, C. R. & Fuchs, E. Chronic psychosocial stressors in adulthood: studies in mice, rats and tree shrews. Neurobiol. Stress 6, 94–103 (2017).
Berger, A. L. et al. The lateral habenula directs coping styles under conditions of stress via recruitment of the endocannabinoid system. Biol. Psychiatry 84, 611–623 (2018).
Novick, A. M. et al. Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress. Neuropharmacology 97, 194–200 (2015).
Iñiguez, S. D. et al. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress 17, 247–255 (2014).
Harris, A. Z. et al. A novel method for chronic social defeat stress in female mice. Neuropsychopharmacology 43, 1276–1283 (2018).
Takahashi, A. et al. Establishment of a repeated social defeat stress model in female mice. Sci. Rep. 7, 12838 (2017). To our knowledge, this article and that of reference 80 are the only two studies to have designed chronic social defeat stress protocols for use in female mice.
Kabbaj, M. et al. Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior. Psychopharmacology 158, 382–387 (2001).
Donahue, R. J., Muschamp, J. W., Russo, S. J., Nestler, E. J. & Carlezon, W. A. Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol. Psychiatry 76, 550–558 (2014).
Yang, C. et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5, e632 (2015).
Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016).
Deng, Z. F. et al. miR-214-3p targets beta-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice. Cereb. Cortex 29, 1509–1519 (2019).
Page, G. G., Opp, M. R. & Kozachik, S. L. Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat. Neurobiol. Stress. 3, 105–113 (2016).
Gururajan, A. et al. Resilience to chronic stress is associated with specific neurobiological, neuroendocrine and immune responses. Brain Behav. Immun. 80, 583–594 (2019).
Peña, C. J. et al. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356, 1185–1188 (2017). In this mouse study, maternal separation within a specific time window (postnatal days 10–17 or 10–20) increased the susceptibility of offspring to social defeat stress in adulthood.
Hultman, R. et al. Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Cell 173, 166–180 (2018).
Bagot, R. C. et al. Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron 90, 969–983 (2016).
Berube, P., Laforest, S., Bhatnagar, S. & Drolet, G. Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress. Physiol. Behav. 122, 237–245 (2013).
Kanarik, M. et al. Brain responses to chronic social defeat stress: effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats. Eur. Neuropsychopharmacol. 21, 92–107 (2011).
Larrieu, T. & Sandi, C. Stress-induced depression: is social rank a predictive risk factor? BioEssays 40, e1800012 (2018). The authors of this study showed that the dominant mouse in a group of four co-housed mice was more susceptible to chronic social defeat stress than subordinate mice.
Muir, J. et al. In vivo fiber photometry reveals signature of future stress susceptibility in nucleus accumbens. Neuropsychopharmacology 43, 255–263 (2018). This paper demonstrated that increased baseline activity of D1 dopamine receptors on medium spiny neurons in the nucleus accumbens was predictive of resilience to chronic social defeat stress.
Meshalkina, D. A. & Kalueff, A. V. Commentary: ethological evaluation of the effects of social defeat stress in mice: beyond the social interaction ratio. Front. Behav. Neurosci. 10, 155–155 (2016).
Henriques-Alves, A. M. & Queiroz, C. M. Ethological evaluation of the effects of social defeat stress in mice: beyond the social interaction ratio. Front. Behav. Neurosci. 9, 364–364 (2016).
Schmidt, M. V. et al. Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology 32, 417–429 (2007).
Schmidt, M. V. et al. A novel chronic social stress paradigm in female mice. Horm. Behav. 57, 415–420 (2010).
Nowacka-Chmielewska, M. M., Kasprowska-Liskiewicz, D., Barski, J. J., Obuchowicz, E. & Malecki, A. The behavioral and molecular evaluation of effects of social instability stress as a model of stress-related disorders in adult female rats. Stress 20, 549–561 (2017).
Hodges, T. E. et al. Social instability stress in adolescent male rats reduces social interaction and social recognition performance and increases oxytocin receptor binding. Neuroscience 359, 172–182 (2017).
Pittet, F., Babb, J. A., Carini, L. & Nephew, B. C. Chronic social instability in adult female rats alters social behavior, maternal aggression and offspring development. Dev. Psychobiol. 59, 291–302 (2017). This paper showed that adult female rats exposed to the social instability paradigm were pro-social towards female intruders; interestingly, their offspring had impaired growth and were socially anxious.
Holmes, T. H. & Rahe, R. H. The social readjustment rating scale. J. Psychosom. Res. 11, 213–218 (1967).
Smith, B. L. et al. Behavioral and physiological consequences of enrichment loss in rats. Psychoneuroendocrinology 77, 37–46 (2017).
Morano, R., Hoskins, O., Smith, B. L. & Herman, J. P. Loss of environmental enrichment elicits behavioral and physiological dysregulation in female rats. Front. Behav. Neurosci. 12, 287–287 (2019).
Rogers, J., Renoir, T. & Hannan, A. J. Gene-environment interactions informing therapeutic approaches to cognitive and affective disorders. Neuropharmacology 45, 37–48 (2017).
Wojcicki, J. M. et al. Telomere length is associated with oppositional defiant behavior and maternal clinical depression in Latino preschool children. Transl Psychiatry 5, e581 (2015).
Lederbogen, F. et al. City living and urban upbringing affect neural social stress processing in humans. Nature 474, 498–501 (2011).
Sterley, T. L. et al. Social transmission and buffering of synaptic changes after stress. Nat. Neurosci. 21, 393–403 (2018). In addition to highlighting that the effects of stress are transmissible, this paper also demonstrated that naive female mice were able to buffer the effects of an acute stressor administered to a co-housed conspecific.
Warren, B. L. et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol. Psychiatry 73, 7–14 (2013).
Finnell, J. E. et al. Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences. PLOS ONE 12, e0172868 (2017).
Hostinar, C. E., Sullivan, R. M. & Gunnar, M. R. Psychobiological mechanisms underlying the social buffering of the HPA axis: a review of animal models and human studies across development. Psychol. Bull. 140, 256–282 (2014).
Finnell, J. E. et al. Essential role of ovarian hormones in susceptibility to the consequences of witnessing social defeat in female rats. Biol. Psychiatry 84, 372–382 (2018).
Kentner, A. C., Cryan, J. F. & Brummelte, S. Resilience priming: translational models for understanding resiliency and adaptation to early life adversity. Dev. Psychobiol. 61, 350–375 (2018).
Berger, J., Heinrichs, M., von Dawans, B., Way, B. M. & Chen, F. S. Cortisol modulates men’s affiliative responses to acute social stress. Psychoneuroendocrinology 63, 1–9 (2016).
Rogers-Carter, M. M. et al. Insular cortex mediates approach and avoidance responses to social affective stimuli. Nat. Neurosci. 21, 404–414 (2018).
Infurna, M. R. et al. Associations between depression and specific childhood experiences of abuse and neglect: a meta-analysis. J. Affect. Disord. 190, 47–55 (2016).
Choi, N. G., DiNitto, D. M., Marti, C. N. & Segal, S. P. Adverse childhood experiences and suicide attempts among those with mental and substance use disorders. Child Abuse Negl. 69, 252–262 (2017).
Teicher, M. H., Samson, J. A., Anderson, C. M. & Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat. Rev. Neurosci. 17, 652–666 (2016).
Schmidt, M. V., Wang, X.-D. & Meijer, O. C. Early life stress paradigms in rodents: potential animal models of depression? Psychopharmacology 214, 131–140 (2011).
Tractenberg, S. G. et al. An overview of maternal separation effects on behavioural outcomes in mice: evidence from a four-stage methodological systematic review. Neurosci. Biobehav. Rev. 68, 489–503 (2016). A comprehensive review and critique of 94 preclinical studies that have used the maternal separation paradigm in mice, with a focus on variations in methodology.
Heim, C. & Binder, E. B. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene–environment interactions, and epigenetics. Exp. Neurol. 233, 102–111 (2012).
Molet, J., Maras, P. M., Avishai-Eliner, S. & Baram, T. Z. Naturalistic rodent models of chronic early-life stress. Dev. Psychobiol. 56, 1675–1688 (2014).
Goodwill, H. L. et al. Early life stress leads to sex differences in development of depressive-like outcomes in a mouse model. Neuropsychopharmacology 44, 711–720 (2019).
Rice, C. J., Sandman, C. A., Lenjavi, M. R. & Baram, T. Z. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology 149, 4892–4900 (2008). The first description of a chronic early life stress paradigm involving fragmented nursing, which has been utilized to assess intergenerational effects.
Heun-Johnson, H. & Levitt, P. Early-life stress paradigm transiently alters maternal behavior, dam–pup interactions, and offspring vocalizations in mice. Front. Behav. Neurosci. 10, 142 (2016).
Santarelli, S. et al. An adverse early life environment can enhance stress resilience in adulthood. Psychoneuroendocrinology 78, 213–221 (2017).
Schmidt, M. V. Animal models for depression and the mismatch hypothesis of disease. Psychoneuroendocrinology 36, 330–338 (2011). This review discusses the proposal that early life adversity itself might not necessarily be a risk factor for depression and suggests instead that depression could result from a mismatch between early life and adulthood experiences, against a background of other predisposing factors. Experimental data in support of this hypothesis are reported in reference 127.
Murthy, S. & Gould, E. Early life stress in rodents: animal models of illness or resilience? Front. Behav. Neurosci. 12, 157 (2018).
O’Keane, V., Frodl, T. & Dinan, T. G. A review of atypical depression in relation to the course of depression and changes in HPA axis organization. Psychoneuroendocrinology 37, 1589–1599 (2012).
Baumeister, D., Lightman, S. L. & Pariante, C. M. The interface of stress and the HPA axis in behavioural phenotypes of mental illness. Curr. Top. Behav. Neurosci. 18, 13–24 (2014).
Anacker, C., Zunszain, P. A., Carvalho, L. A. & Pariante, C. M. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36, 415–425 (2011).
Demuyser, T. et al. In-depth behavioral characterization of the corticosterone mouse model and the critical involvement of housing conditions. Physiol. Behav. 156, 199–207 (2016).
Sturm, M., Becker, A., Schroeder, A., Bilkei-Gorzo, A. & Zimmer, A. Effect of chronic corticosterone application on depression-like behavior in C57BL/6N and C57BL/6J mice. Genes Brain Behav. 14, 292–300 (2015).
Herrmann, M. et al. The challenge of continuous exogenous glucocorticoid administration in mice. Steroids 74, 245–249 (2009).
Short, A. K. et al. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Transl Psychiatry 6, e837 (2016). This study demonstrated the intergenerational effects of paternal corticosterone treatment: F1 males were hyper-anxious and F2 males had a depressive-like phenotype.
Brotto, L. A., Gorzalka, B. B. & Barr, A. M. Paradoxical effects of chronic corticosterone on forced swim behaviours in aged male and female rats. Eur. J. Pharmacol. 424, 203–209 (2001).
Mekiri, M., Gardier, A. M., David, D. J. & Guilloux, J.-P. Chronic corticosterone administration effects on behavioral emotionality in female C57BL/6 mice. Exp. Clin. Psychopharmacol. 25, 94–104 (2017).
Kalynchuk, L. E., Gregus, A., Boudreau, D. & Perrot-Sinal, T. S. Corticosterone increases depression-like behavior, with some effects on predator odor-induced defensive behavior, in male and female rats. Behav. Neurosci. 118, 1365–1377 (2004).
Rosa, P. B. et al. Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice. Pharmacol. Biochem. Behav. 127, 1–6 (2014).
Vreeburg, S. A. et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch. Gen. Psychiatry 66, 617–626 (2009).
Niraula, A., Wang, Y., Godbout, J. P. & Sheridan, J. F. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J. Neurosci. 38, 2328–2340 (2018).
Maier, S. F. & Seligman, M. E. Learned helplessness at fifty: insights from neuroscience. Psychol. Rev. 123, 349–367 (2016).
Chourbaji, S. et al. The suitability of 129SvEv mice for studying depressive-like behaviour: both males and females develop learned helplessness. Behav. Brain Res. 211, 105–110 (2010).
Baratta, M. V. et al. Behavioural and neural sequelae of stressor exposure are not modulated by controllability in females. Eur. J. Neurosci. 47, 959–967 (2018).
Azzinnari, D. et al. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology 85, 328–341 (2014).
Roy, B., Wang, Q. & Dwivedi, Y. Long noncoding RNA-associated transcriptomic changes in resiliency or susceptibility to depression and response to antidepressant treatment. Int. J. Neuropsychopharmacol. 21, 461–472 (2018).
Holanda, V. A. D. et al. NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine. Psychopharmacology 235, 3093–3102 (2018). This paper and that of reference 147 respectively demonstrate the utility of the learned helplessness paradigm to evaluate compounds with both fast-acting and slow-acting antidepressant potential.
Barr, A. M. & Markou, A. Psychostimulant withdrawal as an inducing condition in animal models of depression. Neurosci. Biobehav. Rev. 29, 675–706 (2005).
Renoir, T., Pang, T. Y. & Lanfumey, L. Drug withdrawal-induced depression: serotonergic and plasticity changes in animal models. Neurosci. Biobehav. Rev. 36, 696–726 (2012).
Barr, J. L., Renner, K. J. & Forster, G. L. Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus. Neuropharmacology 59, 395–405 (2010).
Ishikawa, M. et al. Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens. J. Physiol. 591, 4827–4841 (2013).
Koob, G. F. & Volkow, N. D. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3, 760–773 (2016).
Lutz, P. E., Reiss, D., Ouagazzal, A. M. & Kieffer, B. L. A history of chronic morphine exposure during adolescence increases despair-like behaviour and strain-dependently promotes sociability in abstinent adult mice. Behav. Brain Res. 243, 44–52 (2013). The authors of this study showed that, during adolescence, 6 days of morphine treatment followed by 4 weeks of withdrawal increased social and despair behaviour in adult male mice.
Che, Y. et al. Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. Psychopharmacology 227, 605–614 (2013).
Amiri, S. et al. NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice. Neuroscience 329, 122–133 (2016).
Cryan, J. F., Hoyer, D. & Markou, A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol. Psychiatry 54, 49–58 (2003).
Fish, E. W. et al. Intracranial self-stimulation in FAST and SLOW mice: effects of alcohol and cocaine. Psychopharmacolgy 220, 719–730 (2012).
Kenny, P. J., Hoyer, D. & Koob, G. F. Animal models of addiction and neuropsychiatric disorders and their role in drug discovery: honoring the legacy of Athina Markou. Biol. Psychiatry 83, 940–946 (2018).
Maes, M. et al. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology 24, 115–120 (1990).
Maes, M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 664–675 (2011).
Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016).
Meyer, U. Prenatal poly(I:C) exposure and other developmental immune activation models in rodent systems. Biol. Psychiatry 75, 307–315 (2014).
Kentner, A. C. et al. Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model. Neuropsychopharmacology 44, 245–258 (2019).
Sekio, M. & Seki, K. Lipopolysaccharide-induced depressive-like behavior is associated with α1-adrenoceptor dependent downregulation of the membrane GluR1 subunit in the mouse medial prefrontal cortex and ventral tegmental area. Int. J. Neuropsychopharmacol. 18, pyu005 (2014).
Zheng, L.-S. et al. Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. Stem Cell Rep. 3, 73–84 (2014).
Finnell, J. E. & Wood, S. K. Neuroinflammation at the interface of depression and cardiovascular disease: evidence from rodent models of social stress. Neurobiol. Stress 4, 1–14 (2016).
Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017). This study demonstrated that susceptibility to chronic social defeat stress in mice was associated with decreased integrity of the blood–brain barrier.
Otte, C. et al. Major depressive disorder. Nat. Rev. Dis. Prim. 2, 16065 (2016). A concise primer describing major depressive disorder, its subtypes, neurobiology and epidemology.
Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572 (2011).
Kokras, N. & Dalla, C. Sex differences in animal models of psychiatric disorders. Br. J. Pharmacol. 171, 4595–4619 (2014).
Zucker, I. & Beery, A. K. Males still dominate animal studies. Nature 465, 690 (2010).
Shansky, R. M. Are hormones a “female problem” for animal research? Science 364, 825 (2019). A recent perspective piece on the importance of addressing sex bias in research, which also outlines when and when not to consider tracking the oestrus cycle of experimental female rodents.
Becker, J. B., Prendergast, B. J. & Liang, J. W. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol. Sex Differ. 7, 34 (2016).
Hillerer, K. M., Neumann, I. D., Couillard-Despres, S., Aigner, L. & Slattery, D. A. Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats. Hippocampus 23, 476–487 (2013).
Hodes, G. E. et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J. Neurosci. 35, 16362–16376 (2015).
Sood, A., Chaudhari, K. & Vaidya, V. A. Acute stress evokes sexually dimorphic, stressor-specific patterns of neural activation across multiple limbic brain regions in adult rats. Stress 21, 136–150 (2018).
Stroud, L. R., Salovey, P. & Epel, E. S. Sex differences in stress responses: social rejection versus achievement stress. Biol. Psychiatry 52, 318–327 (2002).
Wang, J. et al. Gender difference in neural response to psychological stress. Soc. Cogn. Affect. Neurosci. 2, 227–239 (2007).
LeGates, T. A., Kvarta, M. D. & Thompson, S. M. Sex differences in antidepressant efficacy. Neuropsychopharmacology 44, 140–154 (2019).
Labonté, B. et al. Sex-specific transcriptional signatures in human depression. Nat. Med. 23, 1102–1111 (2017). This translational study highlighted the potential role for DUSP6 as a mediator of the stress response in females.
Gemmel, M., Kokras, N., Dalla, C. & Pawluski, J. L. Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring. Neuropharmacology 128, 168–180 (2018).
Gemmel, M. et al. Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: interactions with pre-gestational maternal stress. Psychoneuroendocrinology 84, 159–171 (2017).
Glover, M. E. et al. Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus. Eur. J. Neurosci. 50, 1843–1870 (2019).
Bowers, M. E. & Yehuda, R. Intergenerational transmission of stress in humans. Neuropsychopharmacology 41, 232–244 (2016).
Pembrey, M., Saffery, R. & Bygren, L. O. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51, 563–572 (2014).
Horsthemke, B. A critical view on transgenerational epigenetic inheritance in humans. Nat. Commun. 9, 2973 (2018).
Klengel, T., Dias, B. G. & Ressler, K. J. Models of intergenerational and transgenerational transmission of risk for psychopathology in mice. Neuropsychopharmacology 41, 219–231 (2016).
Benito, E. et al. RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment. Cell Rep. 23, 546–554 (2018).
Dietz, D. M. et al. Paternal transmission of stress-induced pathologies. Biol. Psychiatry 70, 408–414 (2011).
Jašarević, E., Howard, C. D., Misic, A. M., Beiting, D. P. & Bale, T. L. Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner. Sci. Rep. 7, 44182 (2017). The study showed that early prenatal stress had long-lasting effects on the microbiome of the dam, which in turn led to a disruption of the neonatal microbiome.
Razoux, F. et al. Transgenerational disruption of functional 5-HT1AR-induced connectivity in the adult mouse brain by traumatic stress in early life. Mol. Psychiatry 22, 519–526 (2017).
Bohacek, J. & Mansuy, I. M. A guide to designing germline-dependent epigenetic inheritance experiments in mammals. Nat. Methods 14, 243–249 (2017).
Bale, T. L. Epigenetic and transgenerational reprogramming of brain development. Nat. Rev. Neurosci. 16, 332–344 (2015).
Gapp, K. et al. Early life stress in fathers improves behavioural flexibility in their offspring. Nat. Commun. 5, 5466 (2014).
Chan, J. C., Nugent, B. M. & Bale, T. L. Parental advisory: maternal and paternal stress can impact offspring neurodevelopment. Biol. Psychiatry 83, 886–894 (2018). This is a comprehensive review of studies that have examined the intergenerational and transgenerational transmission of stress effects with an additional focus on putative mechanisms via which transmission occurs.
Guffanti, G. et al. Heritability of major depressive and comorbid anxiety disorders in multi-generational families at high risk for depression. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171, 1072–1079 (2016).
Corfield, E. C., Yang, Y., Martin, N. G. & Nyholt, D. R. A continuum of genetic liability for minor and major depression. Transl Psychiatry 7, e1131 (2017).
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018).
Howard, D. M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 22, 343–352 (2019).
Ormel, J., Hartman, C. A. & Snieder, H. The genetics of depression: successful genome-wide association studies introduce new challenges. Transl Psychiatry 9, 114 (2019). References 199, 200 and 201 are the most successful GWAS of depression to date.
Cai, N., Kendler, K. S. & Flint, J. Minimal phenotyping yields GWAS hits of low specificity for major depression. Preprint at bioRxiv https://doi.org/10.1101/440735 (2018).
Boyle, E. A., Li, Y. I. & Pritchard, J. K. An expanded view of complex traits: from polygenic to omnigenic. Cell 169, 1177–1186 (2017).
Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. & Visscher, P. M. Common disease is more complex than implied by the core gene omnigenic model. Cell 173, 1573–1580 (2018).
Zhong, P. et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife 7, e32420 (2018).
El Yacoubi, M., Rappeneau, V., Champion, E., Malleret, G. & Vaugeois, J. M. The H/Rouen mouse model displays depression-like and anxiety-like behaviors. Behav. Brain Res. 256, 43–50 (2013).
Schmuckermair, C. et al. Behavioral and neurobiological effects of deep brain stimulation in a mouse model of high anxiety- and depression-like behavior. Neuropsychopharmacology 38, 1234–1244 (2013).
Liebsch, G., Montkowski, A., Holsboer, F. & Landgraf, R. Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour. Behav. Brain Res. 94, 301–310 (1998).
Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).
Gibbs, R. A. et al. Genome sequence of the brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004).
Lynch, V. J. Use with caution: developmental systems divergence and potential pitfalls of animal models. Yale J. Biol. Med. 82, 53–66 (2009). In addition to developmental system drift as a concept that undermines the strength of rodent–human translational genetic studies, this review also discusses other factors such as positive selection and pseudo-orthology.
True, J. R. & Haag, E. S. Developmental system drift and flexibility in evolutionary trajectories. Evol. Dev. 3, 109–119 (2001).
Rossi, A. et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524, 230–233 (2015).
Mitchell, K. J., Huang, Z. J., Moghaddam, B. & Sawa, A. Following the genes: a framework for animal modeling of psychiatric disorders. BMC Biol. 9, 76 (2011).
Muir, J., Lopez, J. & Bagot, R. C. Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression. Neuropsychopharmacology 44, 1013–1026 (2019).
Söderlund, J. & Lindskog, M. Relevance of rodent models of depression in clinical practice: can we overcome the obstacles in translational neuropsychiatry? Int. J. Neuropsychopharmacol. 21, 668–676 (2018).
NIH National Institute of Mental Health. RDoC matrix. NIMH https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/constructs/rdoc-matrix.shtml (2019).
Hauser, T. U. et al. The feedback-related negativity (FRN) revisited: new insights into the localization, meaning and network organization. NeuroImage 84, 159–168 (2014).
Serre, F., Fatseas, M., Swendsen, J. & Auriacombe, M. Ecological momentary assessment in the investigation of craving and substance use in daily life: a systematic review. Drug Alcohol Depend. 148, 1–20 (2015).
Gerlai, R. Reproducibility and replicability in zebrafish behavioral neuroscience research. Pharmacol. Biochem. Behav. 178, 30–38 (2019).
Nature Publishing Group. Announcement: transparency upgrade for Nature journals. Nature 543, 288 (2017).
Richetto, J., Polesel, M. & Weber-Stadlbauer, U. Effects of light and dark phase testing on the investigation of behavioural paradigms in mice: relevance for behavioural neuroscience. Pharmacol. Biochem. Behav. 178, 19–29 (2019).
Pankevich, D. E., Altevogt, B. M., Dunlop, J., Gage, F. H. & Hyman, S. E. Improving and accelerating drug development for nervous system disorders. Neuron 84, 546–553 (2014).
Steckler, T. et al. The preclinical data forum network: a new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience. Eur. Neuropsychopharmacol. 25, 1803–1807 (2015). A novel initiative from the European College of Neuropsychopharmacology in an attempt to provide guidelines and structures to improve data quality and reliability.
Gerhard, D. M. & Duman, R. S. Rapid-acting antidepressants: mechanistic insights and future directions. Curr. Behav. Neurosci. Rep. 5, 36–47 (2018).
Carhart-Harris, R. L. et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3, 619–627 (2016).
Eichler, H. G. et al. From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients. Clin. Pharmacol. Ther. 97, 234–246 (2015). In this state-of-the-art paper, the authors discuss the concept of adaptive licensing in which the drug development timeline is fundamentally restructured to accelerate approval of compounds to the clinic for a targeted population. Postmarketing reviews of safety and efficacy are then regularly carried out, which lead to either expansion or restriction of the treatment population.
Partch, C. L., Green, C. B. & Takahashi, J. S. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 24, 90–99 (2014).
Bunney, B. G. et al. Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder. Mol. Psychiatry 20, 48–55 (2015).
Wells, A. M. et al. Effects of chronic social defeat stress on sleep and circadian rhythms are mitigated by kappa-opioid receptor antagonism. J. Neurosci. 37, 7656–7668 (2017). A comprehensive review on the circadian clock and its dysregulation in major depression based on evidence from clinical and preclinical studies.
Bartlang, M. S., Oster, H. & Helfrich-Förster, C. Repeated psychosocial stress at night affects the circadian activity rhythm of male mice. J. Biol. Rhythm. 30, 228–241 (2015).
Trautmann, N. et al. Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and post-treatment depressive symptom trajectory. Neuropsychopharmacology 43, 2572–2577 (2018).
Bunney, B. G. & Bunney, W. E. Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms. Biol. Psychiatry 73, 1164–1171 (2013).
Orozco-Solis, R. et al. A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex. Biol. Psychiatry 82, 351–360 (2017). The authors of this study showed that an acute dose of ketamine was just as effective in producing an antidepressant-like effect, as assessed by the forced swim test, as was 12 h of sleep deprivation in mice.
Eisenstein, M. Microbiome: bacterial broadband. Nature 533, S104–S106 (2016).
Dinan, T. G. & Cryan, J. F. Gut–brain axis in 2016: brain–gut–microbiota axis — mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 14, 69–70 (2017).
Dinan, T. G., Stanton, C. & Cryan, J. F. Psychobiotics: a novel class of psychotropic. Biol. Psychiatry 74, 720–726 (2013).
Burokas, A. et al. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol. Psychiatry 82, 472–487 (2017).
Wallace, C. J. K. & Milev, R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann. Gen. Psychiatry 16, 14 (2017).
Abildgaard, A., Elfving, B., Hokland, M., Wegener, G. & Lund, S. Probiotic treatment reduces depressive-like behaviour in rats independently of diet. Psychoneuroendocrinology 79, 40–48 (2017).
Desbonnet, L. et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188 (2010).
Bharwani, A. et al. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology 63, 217–227 (2016).
O’Mahony, S. M. et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol. Psychiatry 65, 263–267 (2009).
Kelly, J. R. et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 82, 109–118 (2016). This study demonstrated that a faecal transplant from patients with major depression to rats resulted in the transfer of depressive-like behaviours.
Sherwin, E., Rea, K., Dinan, T. G. & Cryan, J. F. A gut (microbiome) feeling about the brain. Curr. Opin. Gastroenterol. 32, 96–102 (2016).
Fulling, C., Dinan, T. G. & Cryan, J. F. Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998–1002 (2019).
Strandwitz, P. et al. GABA-modulating bacteria of the human gut microbiota. Nat. Microbiol. 4, 396–403 (2019).
Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).
Luo, L., Callaway, E. M. & Svoboda, K. Genetic dissection of neural circuits: a decade of progress. Neuron 98, 256–281 (2018).
Richardson, D. S. & Lichtman, J. W. Clarifying tissue clearing. Cell 162, 246–257 (2015).
Vigouroux, R. J., Belle, M. & Chédotal, A. Neuroscience in the third dimension: shedding new light on the brain with tissue clearing. Mol. Brain 10, 33 (2017).
Thompson, P. M., Ge, T., Glahn, D. C., Jahanshad, N. & Nichols, T. E. Genetics of the connectome. Neuroimage 80, 475–488 (2013).
Gong, Q. & He, Y. Depression, neuroimaging and connectomics: a selective overview. Biol. Psychiatry 77, 223–235 (2015).
Huys, Q. J., Maia, T. V. & Frank, M. J. Computational psychiatry as a bridge from neuroscience to clinical applications. Nat. Neurosci. 19, 404–413 (2016).
Friston, K. J., Redish, A. D. & Gordon, J. A. Computational nosology and precision psychiatry. Comput. Psychiatr. 1, 2–23 (2017).
Ferrante, M. et al. Computational psychiatry: a report from the 2017 NIMH workshop on opportunities and challenges. Mol. Psychiatry 24, 479–483 (2019).
Bassett, D. S. & Sporns, O. Network neuroscience. Nat. Neurosci. 20, 353 (2017).
Krakauer, J. W., Ghazanfar, A. A., Gomez-Marin, A., MacIver, M. A. & Poeppel, D. Neuroscience needs behavior: correcting a reductionist bias. Neuron 93, 480–490 (2017).
The authors gratefully acknowledge F. Freudenberg and A. O’Leary for their critical comments. D.A.S. is funded by European Community (EC) CORDIS (Community Research and Development Information Service) Framework Programme 7 (FP7) grant 602805; J.F.C. is employed by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI) through the Irish Government’s National Development Plan (grant no. 12/RC/2273). A.R. is funded by EC CORDIS FP7 grant 602805, Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) grant SFB1193 and EC Horizon 2020 Research and Innovation Framework Programme (H2020) grant 667302. A.G. is supported by a University of Sydney Research Fellowship and funded by H2020 grant MSCA-IF-2015 (DE-STRESS, Project ID: 704995). J.F.C. acknowledges research funding received from 4D Pharma, Alkermes, Cremo, Dupont Nutrition Biosciences, Mead Johnson Nutrition, Nutricia Danone and Suntory Wellness unrelated to the subject matter of this Review.
The authors declare no competing interests.
Peer review information
Nature Reviews Neuroscience thanks E. Nestler, E. Robinson and C. Sandi for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
EU Innovative Medicines Initiative framework: https://www.imi.europa.eu/
- Homological validity
The relevance of the selected model, species and strain to the phenotype or condition under investigation.
- Pathogenic validity
The degree of alignment between species (including mouse versus human) in the process leading to the disease condition. Pathogenic validity can be further subdivided into ontopathogenic validity (which examines the influence of early environmental factors on vulnerability) and triggering validity (which refers to the similarity of factors that lead to pathology such as stress experienced in adulthood).
- Mechanistic validity
How closely the disease process or mechanism observed in the model aligns with the presumed clinical pathology.
- Convergent validity
An overall assessment of face, construct or predictive validities in terms of similarity to the condition under investigation.
- Discriminant validity
The specificity of face, construct or predictive validities to the condition under investigation; for example, decreased sucrose preference is observed in mouse models of depression but is not seen in mouse models of anxiety or schizophrenia.
- Internal validity
Consistency between the phenotype or model being studied, theories of the underlying disease process, biological and other related aspects of the disease; for example, decreased sucrose preference is consistent with decreased preference in the female urine sniffing test. Internal validity also refers to the robustness of the experimental design; for example, in terms of minimizing bias and blinding.
- External validity
Refers to applicability of the model or phenotype being studied to the disease and the disease population; it can also refer to the extent to which the effects of a specific inducing manipulation are reproducible across different laboratories.
- Model versus test
A model that comprises both an independent variable, known as the inducing manipulation, and a dependent variable that acts as a behavioural or neurochemical readout; a test simply comprises the latter variable.
- Forced swim test
This test involves placing rodents in a cylinder filled with water, which forces them to swim. Protocols differ between rats and mice, particularly in terms of test duration (over 2 days in rats, only 1 day in mice). Behaviours typically scored include immobility and climbing time.
- Tail suspension test
This test involves suspending mice above the ground by the tail for 6 min with immobility time scored for the full session or for the final 4 min. In contrast to the forced swim test, this assay avoids the potential confounding effects of hypothermia and does not depend on the rodent’s ability to swim.
- Learned helplessness
Protocols for this assay differ greatly between mice and rats but they both examine the latency to escape an uncontrollable aversive shock stimulus.
A state in which an individual is unable to appropriately manage stress, overreacts to negative stimuli and has poor self-control.
- Elevated plus maze
For this test, rodents are placed on an elevated, plus-shaped apparatus that has two arms without walls and two with walls that intersect in a centre area. A mouse is placed in the centre area and given free access to all four arms. The time spent and entries into each arm are used as indicators of anxiety-like behaviour. Another extractable measure from this test includes head-dipping from the open arms, which is considered a risk-assessment behaviour.
- Novelty-suppressed feeding test
For this test, rodents are food restricted for a period of time prior to being placed in an open field under a bright light. In the middle of the field is a small piece of chow. Latency to approach and eat the piece of chow is a measure of anxiety-like behaviour. This assay also tests the ability of rodents to deal with the conflict of an anxiogenic environment and the drive to seek a food reward.
In female mice, the oestrus cycle is 4–5 days and comprises four stages: proestrus, oestrus, metoestrus and dioestrus.
Olfactory chemical signals released by rodents that can influence conspecific behaviour.
- Ultrasonic vocalization
Ultrasonic vocalizations in mice are proxy readouts for vocal communication in humans; they are observed in a range of different contexts, including mother–infant relationships, juvenile interactions and sexual encounters between conspecifics.
The birth of new neurons, which primarily occurs in distinct sub-regions of the hippocampus and is consistently observed in rodents; debate continues in the human literature.
- Intracranial self-stimulation
This assay uses an operant chamber, in which rodents self-administer electrical stimulation via electrodes implanted into brain reward structures such as the ventral tegmental area, nucleus accumbens and the medial forebrain bundle. A rightward shift in stimulation threshold is usually indicative of a stimulus-induced decrease in reward function (that is, anhedonia), whereas a leftward shift reflects an increase in reward function.
- Operant chamber
Also known as a Skinner box, this is an apparatus in which an animal must depress a lever or activate a similar sensor to obtain a reward.
- Maternal immune activation
In this paradigm, pregnant dams are injected with a single dose of polyinosinic:polycytidylic acid or lipopolysaccharide.
A term used to describe the connectivity between two components of the CNS.
About this article
Cite this article
Gururajan, A., Reif, A., Cryan, J.F. et al. The future of rodent models in depression research. Nat Rev Neurosci 20, 686–701 (2019). https://doi.org/10.1038/s41583-019-0221-6
Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause
Translational Psychiatry (2021)
Genetically encoded sensors enable micro- and nano-scopic decoding of transmission in healthy and diseased brains
Molecular Psychiatry (2021)
Creation of a gene expression portrait of depression and its application for identifying potential treatments
Scientific Reports (2021)
Nature Reviews Neuroscience (2021)
2-Phenyl-3-(phenylselanyl)benzofuran elicits acute antidepressant-like action in male Swiss mice mediated by modulation of the dopaminergic system and reveals therapeutic efficacy in both sexes