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Review Article | Open Access

Animal models of stress and stress-related neurocircuits: A comprehensive review

Mengxin Ma1,2,§, Xin Chang1,§, Haitao Wu1,3,4()
Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China
Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
Chinese Institute for Brain Research, Beijing 102206, China
Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226019, China

§ Mengxin Ma and Xin Chang contributed equally to this work.

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Abstract

Stress is considered to be one of the common pathogenic factors leading to mental disorders. Acute severe stress events or chronic distress could lead to depression and psychiatric disorders. Therefore, the establishment of stress animal models in the laboratory to mimic the stress suffering in humans would be beneficial for better understanding the etiology and mechanisms underlying stress-induced mental disorders. In addition, the development of powerful tools such as optogenetics and chemogenetics has made more rapid progress to reveal the critical neural circuits in regulating the pathogenesis of stress-induced disorders. This review firstly summarized the well-established different types of stress animal models widely used in the laboratory including acute stress models, chronic stress models, models of surgical stress, drug-induced stress models, and genetic mutation-associated stress models. Moreover, we also summarized the latest progress in understanding the characteristics and mechanisms of stress-related neurocircuits that are critical for discovering novel therapeutic strategies for stress-induced mental disorders.

Keywords

stress modelsmental disordersneurocircuitsoptogenetics

References

[1]
Lisman, J., Buzsáki, G., Eichenbaum, H., Nadel, L., Ranganath, C., Redish, A. D. Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nature Neuroscience, 2017, 20(11): 1434-1447.
Crossref Google Scholar
[2]
Hammen, C. Stress and depression. Annual Review of Clinical Psychology, 2005, 1: 293-319.
Crossref Google Scholar
[3]
Greenberg, N., Carr, J. A., Summers, C. H. Causes and consequences of stress. Integrative and Comparative Biology, 2002, 42(3): 508-516.
Crossref Google Scholar
[4]
Fox, M. E., Lobo, M. K. The molecular and cellular mechanisms of depression: A focus on reward circuitry. Molecular Psychiatry, 2019, 24(12): 1798-1815.
Crossref Google Scholar
[5]
Henn, F. A., Vollmayr, B. Stress models of depression: Forming genetically vulnerable strains. Neuroscience & Biobehavioral Reviews, 2005, 29(4-5): 799-804.
Crossref Google Scholar
[6]
Malhi, G. S., Mann, J. J. Depression. The Lancet, 2018, 392(10161): 2299-2312.
Crossref Google Scholar
[7]
Kumar, V., Bhat, Z. A., Kumar, D. Animal models of anxiety: A comprehensive review. Journal of Pharmacological and Toxicological Methods, 2013, 68(2): 175-183.
Crossref Google Scholar
[8]
Grosenick, L., Shi, T. C., Gunning, F. M., Dubin, M. J., Downar, J., Liston, C. Functional and optogenetic approaches to discovering stable subtype-specific circuit mechanisms in depression. Biological Psychiatry Cognitive Neuroscience and Neuroimaging, 2019, 4(6): 554-566.
Crossref Google Scholar
[9]
Nestler, E. J., Hyman, S. E. Animal models of neuropsychiatric disorders. Nature Neuroscience, 2010, 13(10): 1161-1169.
Crossref Google Scholar
[10]
Belzung, C., Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: A review. Behavioural Brain Research, 2001, 125(1-2): 141-149.
Crossref Google Scholar
[11]
Hao, Y. Z., Ge, H. X., Sun, M. Y., Gao, Y. Selecting an appropriate animal model of depression. International Journal of Molecular Sciences, 2019, 20(19): 4827.
Crossref Google Scholar
[12]
Glavin, G. B., Paré, W. P., Sandbak, T., Bakke, H. K., Murison, R. Restraint stress in biomedical research: An update. Neuroscience & Biobehavioral Reviews, 1994, 18(2): 223-249.
Crossref Google Scholar
[13]
Buynitsky, T., Mostofsky, D. I. Restraint stress in biobehavioral research: Recent developments. Neuroscience & Biobehavioral Reviews, 2009, 33(7): 1089-1098.
Crossref Google Scholar
[14]
McLaughlin, K. J., Gomez, Baran, S. E., Conra, C. D. The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms. Brain Research, 2007, 1161: 56-64.
Crossref Google Scholar
[15]
Xu, P., Wang, K. Z., Lu, C., Dong, L. M., Chen, Y. X., Wang, Q., Shi, Z., Yang, Y. Y., Chen, S. G., Liu, X. M. Effects of the chronic restraint stress induced depression on reward-related learning in rats. Behavioural Brain Research, 2017, 321: 185-192.
Crossref Google Scholar
[16]
Willner, P., Towell, A., Sampson, D., Sopholeous, S., Muscat, R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology, 1987, 93: 358-364.
Crossref Google Scholar
[17]
Willner, P. Chronic mild stress (CMS) revisited: Consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology, 2005, 52(2): 90-110.
Crossref Google Scholar
[18]
Svitlana, A., Bijata, M., Ponimaskin, E., Wlodarczyk, J. Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neuroscience and biobehavioral reviews, 2018, 99: 101-116.
Crossref Google Scholar
[19]
Burstein, O., Doron, R. The unpredictable chronic mild stress protocol for inducing anhedonia in mice. Journal of Visualized Experiments, 2018. .
Crossref Google Scholar
[20]
Sapolsky, R. M. The influence of social hierarchy on primate health. Science, 2005, 308(5722): 648-652.
Crossref Google Scholar
[21]
Kudryavtseva, N. N., Bakshtanovskaya, I. V., Koryakina, L. A. Social model of depression in mice of C57BL/6J strain. Pharmacology Biochemistry and Behavior, 1991, 38(2): 315-320.
Crossref Google Scholar
[22]
Berton, O. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science, 2006, 311(5762): 864-868.
Crossref Google Scholar
[23]
Golden, S. A., Covington, H. E., Berton, O., Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nature Protocols, 2011, 6(8): 1183-1191.
Crossref Google Scholar
[24]
Czéh, B., Fuchs, E., Wiborg, O., Simon, M. Animal models of major depression and their clinical implications. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 64: 293-310.
Crossref Google Scholar
[25]
Seligman, M. P. Learned helplessness. Annual Review of Medicine, 1972, 23(1): 407-412.
Crossref Google Scholar
[26]
Gururajan, A., Reif, A., Cryan, J. F., Slattery, D. A. The future of rodent models in depression research. Nature Reviews Neuroscience, 2019, 20(11): 686-701.
Crossref Google Scholar
[27]
Willner, P. Validation criteria for animal models of human mental disorders: Learned helplessness as a paradigm case. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 1986, 10(6): 677-690.
Crossref Google Scholar
[28]
Porsolt, R. D., Anton, G., Blavet, N., Jalfre, M. Behavioural despair in rats: A new model sensitive to antidepressant treatments. European Journal of Pharmacology, 1978, 47(4): 379-391.
Crossref Google Scholar
[29]
Yu, H. Y., Yin, Z. J., Yang, S. J., Ma, S. P., Qu, R. Baicalin reverses depressive-like behaviours and regulates apoptotic signalling induced by olfactory bulbectomy. Phytotherapy Research, 2016, 30(3): 469-475.
Crossref Google Scholar
[30]
Farzin, D., Mansouri, N. Antidepressant-like effect of harmane and other beta-carbolines in the mouse forced swim test. European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology, 2006, 16(5): 324-328.
Crossref Google Scholar
[31]
McArthur, R., Borsini, F. Animal models of depression in drug discovery: A historical perspective. Pharmacology Biochemistry and Behavior, 2006, 84(3): 436-452.
Crossref Google Scholar
[32]
Flint, J., Kendler, K. S. The genetics of major depression. Neuron, 2014, 81(5): 1214.
Crossref Google Scholar
[33]
Guffanti, G., Gameroff, M. J., Warner, V., Talati, A., Glatt, C. E., Wickramaratne, P., Weissman, M. M. Heritability of major depressive and comorbid anxiety disorders in multi-generational families at high risk for depression. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2016, 171(8): 1072-1079.
Crossref Google Scholar
[34]
Corfield, E. C., Yang, Y., Martin, N. G., Nyholt, D. R. A continuum of genetic liability for minor and major depression. Translational Psychiatry, 2017, 7(5): e1131.
Crossref Google Scholar
[35]
Boyle, E. A., Li, Y. I., Pritchard, J. K. An expanded view of complex traits: From polygenic to omnigenic. Cell, 2017, 169(7): 1177-1186.
Crossref Google Scholar
[36]
Nishi, K., Kanemaru, K., Diksic, M. A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats. Neurochemistry International, 2009, 54(5-6): 299-307.
Crossref Google Scholar
[37]
Solberg, L. C., Olson, S. L., Turek, F. W., Redei, E. Altered hormone levels and circadian rhythm of activity in the WKY rat, a putative animal model of depression. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001, 281(3): R786-R794.
Crossref Google Scholar
[38]
Rezvani, A. H., Parsian, A., Overstreet, D. H. The Fawn-Hooded (FH/Wjd) rat: A genetic animal model of comorbid depression and alcoholism. Psychiatric Genetics, 2002, 12(1): 1-16.
Crossref Google Scholar
[39]
Sorge, R. E., Martin, L. J., Isbester, K. A., Sotocinal, S. G., Rosen, S., Tuttle, A. H., Wieskopf, J. S., Acland, E. L., Dokova, A., Kadoura, B. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature Methods, 2014, 11(6): 629-632.
Crossref Google Scholar
[40]
Covington, H. E., Lobo, M. K., Maze, I., Vialou, V., Hyman, J. M., Zaman, S., LaPlant, Q., Mouzon, E., Ghose, S., Tamminga, C. A. et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. Journal of Neuroscience, 2010, 30(48): 16082-16090.
Crossref Google Scholar
[41]
Bagot, R. C., Parise, E. M., Peña, C. J., Zhang, H. X., Maze, I., Chaudhury, D., Persaud, B., Cachope, R., Bolaños-Guzmán, C. A., Cheer, J. F. et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nature Communications, 2015, 6(1): 1-9.
Crossref Google Scholar
[42]
Vialou, V., Bagot, R. C., Cahill, M. E., Ferguson, D., Robison, A. J., Dietz, D. M., Fallon, B., Mazei-Robison, M., Ku, S. M., Harrigan, E. et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: Role of FosB. Journal of Neuroscience, 2014, 34(11): 3878-3887.
Crossref Google Scholar
[43]
Rahman, M. M., Shukla, A. Chattarji, S. Extinction recall of fear memories formed before stress is not affected despite higher theta activity in the amygdala. eLife, 2018, 7: e35450.
Crossref Google Scholar
[44]
Cho, J. H., Deisseroth, K., Bolshakov, V. Y. Synaptic encoding of fear extinction in mPFC-amygdala circuits. Neuron, 2013, 80(6): 1491-1507.
Crossref Google Scholar
[45]
Park, K., Chung, C. Differential alterations in cortico-amygdala circuitry in mice with impaired fear extinction. Molecular Neurobiology, 2020, 57(2): 710-721.
Crossref Google Scholar
[46]
Park, K., Chung, C. Differential alterations in cortico-amygdala circuitry in mice with impaired fear extinction. Molecular Neurobiology, 2020, 57(2): 710-721.
Crossref Google Scholar
[47]
Liu, W. Z., Zhang, W. H., Zheng, Z. H., Zou, J. X., Liu, X. X., Huang, S. H., You, W. J., He, Y., Zhang, J. Y., Wang, X. D. et al. Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety. Nature Communications, 2020, 11(1): 1-15.
Crossref Google Scholar
[48]
Hiser, J., Koenigs, M. The multifaceted role of the ventromedial prefrontal cortex in emotion, decision making, social cognition, and psychopathology. Biological Psychiatry, 2018, 83(8): 638-647.
Crossref Google Scholar
[49]
Jovanovic, T., Norrholm, S. D. Neural mechanisms of impaired fear inhibition in posttraumatic stress disorder. Frontiers in Behavioral Neuroscience, 2011, 5: 44. .
Crossref Google Scholar
[50]
Warden, M. R., Selimbeyoglu, A., Mirzabekov, J. J., Lo, M., Thompson, K. R., Kim, S. Y., Adhikari, A., Tye, K. M., Frank, L. M., Deisseroth, K. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature, 2012, 492(7429): 428-432.
Crossref Google Scholar
[51]
Challis, C., Beck, S. G., Berton, O. Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat. Frontiers in Behavioral Neuroscience, 2014, 8: 43. .
Crossref Google Scholar
[52]
Challis, C., Boulden, J., Veerakumar, A., Espallergues, J., Vassoler, F. M., Pierce, R. C., Beck, S. G., Berton, O. Raphe GABAergic neurons mediate the acquisition of avoidance after social defeat. Journal of Neuroscience, 2013, 33(35): 13978-13988.
Crossref Google Scholar
[53]
Kim, J. J., Diamond, D. M. The stressed hippocampus, synaptic plasticity and lost memories. Nature Reviews Neuroscience, 2002, 3(6): 453-462.
Crossref Google Scholar
[54]
MacQueen, G. M., Campbell, S., McEwen, B. S., MacDonald, K., Amano, S., Joffe, R. T., Nahmias, C., Young, L. T. Course of illness, hippocampal function, and hippocampal volume in major depression. PNAS, 2003, 100(3): 1387-1392.
Crossref Google Scholar
[55]
Bagot, R. C., Parise, E. M., Peña, C. J., Zhang, H. X., Maze, I., Chaudhury, D., Persaud, B., Cachope, R., Bolaños-Guzmán, C. A., Cheer, J. F. et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nature Communications, 2015, 6(1): 1-9.
Crossref Google Scholar
[56]
Carreno, F. R., Donegan, J. J., Boley, A. M., Shah, A., DeGuzman, M., Frazer, A., Lodge, D. J. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Molecular Psychiatry, 2016, 21(9): 1298-1308.
Crossref Google Scholar
[57]
Liu, X., Ramirez, S., Pang, P. T., Puryear, C. B., Govindarajan, A., Deisseroth, K., Tonegawa, S. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 2012, 484(7394): 381-385.
Crossref Google Scholar
[58]
Ramirez, S., Liu, X., Lin, P. A., Suh, J., Pignatelli, M., Redondo, R. L., Ryan, T. J., Tonegawa, S. Creating a false memory in the hippocampus. Science, 2013, 341(6144): 387-391.
Crossref Google Scholar
[59]
Ramirez, S., Liu, X., MacDonald, C. J., Moffa, A., Zhou, J., Redondo, R. L., Tonegawa, S. Activating positive memory engrams suppresses depression-like behaviour. Nature, 2015, 522(7556): 335-339.
Crossref Google Scholar
[60]
Schultz, W., Dayan, P., Montague, P. R. A neural substrate of prediction and reward. Science, 1997, 275(5306): 1593-1599.
Crossref Google Scholar
[61]
Kaufling, J. Alterations and adaptation of ventral tegmental area dopaminergic neurons in animal models of depression. Cell and Tissue Research, 2019, 377(1): 59-71.
Crossref Google Scholar
[62]
Holly, E. N., Miczek, K. A. Ventral tegmental area dopamine revisited: Effects of acute and repeated stress. Psychopharmacology, 2016, 233(2): 163-186.
Crossref Google Scholar
[63]
Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell, 2007, 131(2): 391-404.
Crossref Google Scholar
[64]
Cao, J. L., Covington, H. E., Friedman, A. K., Wilkinson, M. B., Walsh, J. J., Cooper, D. C., Nestler, E. J., Han, M. H. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. Journal of Neuroscience, 2010, 30(49): 16453-16458.
Crossref Google Scholar
[65]
Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H. C., Pomeranz, L., Christoffel, D. J. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature, 2013, 493(7433): 532-536.
Crossref Google Scholar
[66]
Tye, K. M., Mirzabekov, J. J., Warden, M. R., Ferenczi, E. A., Tsai, H. C., Finkelstein, J., Kim, S. Y., Adhikari, A., Thompson, K. R., Andalman, A. S. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature, 2013, 493(7433): 537-541.
Crossref Google Scholar
[67]
Friedman, A. K., Walsh, J. J., Juarez, B., Ku, S. M., Chaudhury, D., Wang, J., Li, X., Dietz, D. M., Pan, N., Vialou, V. F. et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science, 2014, 344(6181): 313-319.
Crossref Google Scholar
[68]
Friedman, A. K., Walsh, J. J., Juarez, B., Ku, S. M., Chaudhury, D., Wang, J., Li, X., Dietz, D. M., Pan, N., Vialou, V. F. et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science, 2014, 344(6181): 313-319.
Crossref Google Scholar
[69]
Walsh, J. J., Friedman, A. K., Sun, H. S., Heller, E. A., Ku, S. M., Juarez, B., Burnham, V. L., Mazei-Robison, M. S., Ferguson, D., Golden, S. A. et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nature Neuroscience, 2014, 17(1): 27-29.
Crossref Google Scholar
[70]
Walsh, J. J., Friedman, A. K., Sun, H. S., Heller, E. A., Ku, S. M., Juarez, B., Burnham, V. L., Mazei-Robison, M. S., Ferguson, D., Golden, S. A. et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nature Neuroscience, 2014, 17(1): 27-29.
Crossref Google Scholar
[71]
Wook Koo, J., Labonté, B., Engmann, O., Calipari, E. S., Juarez, B., Lorsch, Z., Walsh, J. J., Friedman, A. K., Yorgason, J. T., Han, M. H. et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biological Psychiatry, 2016, 80(6): 469-478.
Crossref Google Scholar
[72]
Holtmaat, A., Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nature Reviews Neuroscience, 2009, 10(9): 647-658.
Crossref Google Scholar
[73]
Sousa, N., Almeida, O. F. X. Disconnection and reconnection: The morphological basis of (mal)adaptation to stress. Trends in Neurosciences, 2012, 35(12): 742-751.
Crossref Google Scholar
[74]
Mitra, R., Adamec, R., Sapolsky, R. Resilience against predator stress and dendritic morphology of amygdala neurons. Behavioural Brain Research, 2009, 205(2): 535-543.
Crossref Google Scholar
[75]
Zhang, J. Y., Liu, T. H., He, Y., Pan, H. Q., Zhang, W. H., Yin, X. P., Tian, X. L., Li, B. M., Wang, X. D., Holmes, A. et al. Chronic stress remodels synapses in an amygdala circuit-specific manner. Biological Psychiatry, 2019, 85(3): 189-201.
Crossref Google Scholar
[76]
Gourley, S. L., Swanson, A. M., Koleske, A. J. Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience. Journal of Neuroscience, 2013, 33(7): 3107-3112.
Crossref Google Scholar
[77]
Johnson, S. A., Wang, J. F., Sun, X., McEwen, B. S., Chattarji, S., Young, L. T. Lithium treatment prevents stress-induced dendritic remodeling in the rodent amygdala. Neuroscience, 2009, 163(1): 34-39.
Crossref Google Scholar
[78]
Phillips, A. G., Ahn, S., Howland, J. G. Amygdalar control of the mesocorticolimbic dopamine system: Parallel pathways to motivated behavior. Neuroscience & Biobehavioral Reviews, 2003, 27(6): 543-554.
Crossref Google Scholar
[79]
Phelps, E. A., Delgado, M. R., Nearing, K. I., LeDoux, J. E. Extinction learning in humans: Role of the amygdala and vmPFC. Neuron, 2004, 43(6): 897-905.
Crossref Google Scholar
[80]
McEwen, B. S., de Kloet, E. R., Rostene, W. Adrenal steroid receptors and actions in the nervous system. Physiological Reviews, 1986, 66(4): 1121-1188.
Crossref Google Scholar
[81]
Yizhar, O., Klavir, O. Reciprocal amygdala-prefrontal interactions in learning. Current Opinion in Neurobiology, 2018, 52: 149-155.
Crossref Google Scholar
[82]
Wellman, C. L., Izquierdo, A., Garrett, J. E., Martin, K. P., Carroll, J., Millstein, R., Lesch, K. P., Murphy, D. L., Holmes, A. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. Journal of Neuroscience, 2007, 27(3): 684-691.
Crossref Google Scholar
[83]
Andolina, D., Maran, D., Valzania, A., Conversi, D., Puglisi-Allegra, S. Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection. Neuropsychopharmacology, 2013, 38(10): 2057-2067.
Crossref Google Scholar
[84]
Andolina, D., Maran, D., Viscomi, M. T., Puglisi-Allegra, S. Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system. International Journal of Neuropsychopharmacology, 2015, 18(3): pyu074.
Crossref Google Scholar
[85]
Sutherland, R. J. The dorsal diencephalic conduction system: A review of the anatomy and functions of the habenular complex. Neuroscience & Biobehavioral Reviews, 1982, 6(1): 1-13.
Crossref Google Scholar
[86]
Hu, H., Cui, Y., Yang, Y. Circuits and functions of the lateral habenula in health and in disease. Nature Reviews Neuroscience, 2020, 21(5): 277-295.
Crossref Google Scholar
[87]
Lecourtier, L., Kelly, P. H. A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition. Neuroscience & Biobehavioral Reviews, 2007, 31(5): 658-672.
Crossref Google Scholar
[88]
Shumake, J., Gonzalez-Lima, F. Brain systems underlying susceptibility to helplessness and depression. Behavioral and Cognitive Neuroscience Reviews, 2003, 2(3): 198-221.
Crossref Google Scholar
[89]
Herkenham, M., Nauta, W. J. H. Efferent connections of the habenular nuclei in the rat. In: Neuroanatomy. Contemporary Neuroscientists (Selected Papers of Leaders in Brain Research). Boston: Birkhäuser, 1979.
[90]
Jhou, T. C., Geisler, S., Marinelli, M., Degarmo, B. A., Zahm, D. S. The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. The Journal of Comparative Neurology, 2009, 513(6): 566-596.
Crossref Google Scholar
[91]
Aghajanian, G. K., Wang, R. Y. Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique. Brain Research, 1977, 122(2): 229-242.
Crossref Google Scholar
[92]
Yang, Y., Wang, H., Hu, J., Hu, H. L. Lateral habenula in the pathophysiology of depression. Current Opinion in Neurobiology, 2018, 48: 90-96.
Crossref Google Scholar
[93]
Groenewegen, H. J., Ahlenius, S., Haber, S. N., Kowall, N. W., Nauta, W. J. H. Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus in the rat. The Journal of Comparative Neurology, 1986, 249(1): 65-102.
Crossref Google Scholar
[94]
Zhang, J., Tan, L., Ren, Y., Liang, J., Lin, R., Feng, Q., Zhou, J., Hu, F., Ren, J., Wei, C. et al. Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression. Cell, 2016. 166(3): 716-728.
Crossref Google Scholar
[95]
Stern, W. C., Johnson, A., Bronzino, J. D., Morgane, P. J. Effects of electrical stimulation of the lateral habenula on single-unit activity of raphe neurons. Experimental Neurology, 1979, 65(2): 326-342.
Crossref Google Scholar
[96]
Baratta, M. V., Kodandaramaiah, S. B., Monahan, P. E., Yao, J., Weber, M. D., Lin, P. A., Gisabella, B., Petrossian, N., Amat, J., Kim, K. et al. Stress enables reinforcement-elicited serotonergic consolidation of fear memory. Biological Psychiatry, 2016, 79(10): 814-822.
Crossref Google Scholar
[97]
Pandey, S., Shekhar, K., Regev, A., Schier, A. F. Comprehensive identification and spatial mapping of habenular neuronal types using single-cell RNA-seq. Current Biology, 2018, 28(7): 1052-1065.e7.
Crossref Google Scholar
[98]
Cerniauskas, I., Winterer, J., de Jong, J. W., Lukacsovich, D., Yang, H., Khan, F., Peck, J. R., Obayashi, S. K., Lilascharoen, V., Lim, B. K., et al. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors. Neuron, 2019, 104(5): 899-915.e8.
Crossref Google Scholar
[99]
Matsumoto, M., Hikosaka, O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature, 2009, 459(7248): 837-841.
Crossref Google Scholar
[100]
Shumake, J., Edwards, E., Gonzalez-Lima, F. Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Research, 2003, 963(1-2): 274-281.
Crossref Google Scholar
[101]
Park, H., Rhee, J., Park, K., Han, J. S., Malinow, R., Chung, C. Exposure to stressors facilitates long-term synaptic potentiation in the lateral habenula. The Journal of Neuroscience, 2017, 37(25): 6021-6030.
Crossref Google Scholar
[102]
Park, H., Rhee, J., Lee, S., Chung, C. Selectively impaired endocannabinoid-dependent long-term depression in the lateral habenula in an animal model of depression. Cell Reports, 2017, 20(2): 289-296.
Crossref Google Scholar
[103]
Cui, Y., Yang, Y., Ni, Z., Dong, Y., Cai, G., Foncelle, A., Ma, S., Sang, K., Tang, S., Li, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature, 2018, 554(7692): 323-327.
Crossref Google Scholar
[104]
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., Hu, H. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 2018, 554(7692): 317-322.
Crossref Google Scholar
[105]
Shelton, L., Pendse, G., Maleki, N., Moulton, E. A., Lebel, A., Becerra, L., Borsook, D. Mapping pain activation and connectivity of the human habenula. Journal of Neurophysiology, 2012, 107(10): 2633-2648.
Crossref Google Scholar
[106]
Paulson, P. E., Morrow, T. J., Casey, K. L. Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat. Pain, 2000, 84(2-3): 233-245.
Crossref Google Scholar
[107]
Goto, M., Canteras, N. S., Burns, G., Swanson, L. W. Projections from the subfornical region of the lateral hypothalamic area. The Journal of Comparative Neurology, 2005, 493(3): 412-438.
Crossref Google Scholar
[108]
Yu, L. C., Han, J. S. Habenula as a relay in the descending pathway from nucleus accumbens to periaqueductal grey subserving antinociception. The International Journal of Neuroscience, 1990, 54(3-4): 245-251.
Crossref Google Scholar
[109]
Shelton, L., Becerra, L., Borsook, D. Unmasking the mysteries of the habenula in pain and analgesia. Progress in Neurobiology, 2012, 96(2): 208-219.
Crossref Google Scholar
[110]
Cohen, S. R., Melzack, R. Morphine injected into the habenula and dorsal posteromedial thalamus produces analgesia in the formalin test. Brain Research, 1985, 359(1-2): 131-139.
Crossref Google Scholar
[111]
Ma, Q. P., Shi, Y. S., Han, J. S. Further studies on interactions between periaqueductal gray, nucleus accumbens and habenula in antinociception. Brain Research, 1992, 583(1-2): 292-295.
Crossref Google Scholar
[112]
Bhatnagar, S., Viau, V., Chu, A., Soriano, L., Meijer, O. C., Dallman, M. F. A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function. The Journal of Neuroscience, 2000, 20(14): 5564-5573.
Crossref Google Scholar
[113]
Hsu, D. T., Kirouac, G. J., Zubieta, J. K., Bhatnagar, S. Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood. Front Behav Neurosci, 2014, 8: 73.
Crossref Google Scholar
[114]
Spencer, S. J., Fox, J. C., Day, T. A. Thalamic paraventricular nucleus lesions facilitate central amygdala neuronal responses to acute psychological stress. Brain Research, 2004, 997(2): 234-237.
Crossref Google Scholar
[115]
Penzo, M. A., Robert, V., Tucciarone, J., De Bundel, D., Wang, M., Van Aelst, L., Darvas, M., Parada, L. F., Palmiter, R. D., He, M. et al. The paraventricular thalamus controls a central amygdala fear circuit. Nature, 2015, 519(7544): 455-459.
Crossref Google Scholar
[116]
Zhang, Y., Liu, W., Lebowitz, E. R., Zhang, F., Hu, Y., Liu, Z., Yang, H., Wu, J., Wang, Y., Silverman, W. K. et al. Abnormal asymmetry of thalamic volume moderates stress from parents and anxiety symptoms in children and adolescents with social anxiety disorder. Neuropharmacology, 2020, 180: 108301.
Crossref Google Scholar
[117]
Philip, N. S., Tyrka, A. R., Albright, S. E., Sweet, L. H., Almeida, J., Price, L. H., Carpenter, L. L. Early life stress predicts thalamic hyperconnectivity: A transdiagnostic study of global connectivity. Journal of Psychiatric Research, 2016, 79: 93-100.
Crossref Google Scholar
[118]
Liao, M., Yang, F., Zhang, Y., He, Z., Song, M., Jiang, T., Li, Z., Lu, S., Wu, W., Su, L. et al. Childhood maltreatment is associated with larger left thalamic gray matter volume in adolescents with generalized anxiety disorder. PLoS One, 2013, 8(8): e71898.
Crossref Google Scholar
[119]
Qin, S., Young, C. B., Duan, X., Chen, T., Supekar, K., Menon, V. Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood. Biological Psychiatry, 2014, 75(11): 892-900.
Crossref Google Scholar
[120]
Babaev, O., Piletti Chatain, C., Krueger-Burg, D. Inhibition in the amygdala anxiety circuitry. Experimental & Molecular Medicine, 2018, 50(4): 1-16.
Crossref Google Scholar
[121]
Do-Monte, F. H., Quiñones-Laracuente, K., Quirk, G. J. A temporal shift in the circuits mediating retrieval of fear memory. Nature, 2015, 519(7544): 460-463.
Crossref Google Scholar
[122]
Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M. Rebushi, N., Pfau, M. et al. Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature Neuroscience, 2015, 18(7): 962-964.
Crossref Google Scholar
[123]
Zhu, Y., Wienecke, C. F., Nachtrab, G., Chen, X. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature, 2016, 530(7589): 219-222.
Crossref Google Scholar
[124]
Do-Monte, F. H., Minier-Toribio, A., Quiñones-Laracuente, K., Medina-Colón, E. M., Quirk, G. J. Thalamic regulation of sucrose seeking during unexpected reward omission. Neuron, 2017, 94(2): 388-400.e4.
Crossref Google Scholar
[125]
Betley, J. N., Cao, Z. F., Ritola, K. D., Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell, 2013, 155(6): 1337-1350.
Crossref Google Scholar
[126]
Zhang, X., van den Pol, A. N. Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation. Science, 2017, 356(6340): 853-859.
Crossref Google Scholar
[127]
Giber, K., Diana, M. A., Plattner, V., Dugué, G. P., Bokor, H., Rousseau, C. V., Maglóczky, Z., Havas, L., Hangya, B., Wildner, H. et al. A subcortical inhibitory signal for behavioral arrest in the thalamus. Nature Neuroscience, 2015, 18(4): 562-568.
Crossref Google Scholar
[128]
Halassa, M. M., Acsády, L. Thalamic inhibition: Diverse sources, diverse scales. Trends in Neuroscience, 2016, 39(10): 680-693.
Crossref Google Scholar
[129]
Beas, B. S., Wright, B. J., Skirzewski, M., Leng, Y., Hyun, J. H., Koita, O., Ringelberg, N., Kwon, H. B., Buonanno, A., Penzo, M. A. The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nature Neuroscience, 2018, 21(7): 963-973.
Crossref Google Scholar
[130]
Miller, O. H., Bruns, A., Ammar, I. B., Mueggler, T., Hall, B. J. Synaptic regulation of a thalamocortical circuit controls depression-related behavior. Cell Reports, 2017. 20(8): 1867-1880.
Crossref Google Scholar
[131]
Baek, J., Lee, S., Cho, T., Kim, S.-W., Kim, M., Yoon, Y., Kim, K. K., Byun, J., Kim, S. J., Jeong, J., Shin, H.-S. Neural circuits underlying a psychotherapeutic regimen for fear disorders. Nature, 2019, 566(7744): 339-343.
Crossref Google Scholar
Stress and Brain
Volume 1 Issue 2,
December 2021
Pages 108-127
DOI: 10.26599/SAB.2021.9060001
Cite this article:
Ma M, Chang X, Wu H. Animal models of stress and stress-related neurocircuits: A comprehensive review. Stress and Brain, 2021, 1(2): 108-127. https://doi.org/10.26599/SAB.2021.9060001
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10.26599/SAB.2021.9060001.T001Classification and characteristics of various animal models of stress.

Animal model/distinctionClinical manifestationAdvantages of the modelDisadvantages of the modelEvaluation methodsAnimal speciesExperimental replicability
Chronic restraint stress (CRS)Physiological and psychological stress, Simulate occurrence of human diseasesModeling conditions are relatively safe without body harmfulnessThe modeling is easy, and the stimulus is very different from the real human stressSugar water preference; autonomous activity assay; novel object exploration; open field testMice; ratsEasier to implement, the process takes 21 days or longer
Chronic unpredictable mild stress (CUMS)The classic symptoms of depression namely anhedoniaThe change of stress factors leads to the decrease of the adaptive ability of animals and has a more significant stimulus effectThe modeling method is complex, and a variety of stimulus environments need to be prepared randomlySugar-water preference, open-field, forced swimming test (rats/mice); tail suspension test (mice)SD and Wistar rats; miceRelatively difficult to replicate the same phenotype in different environments
Chronic social defeat stress (CSDS)Simulation of human social environmental stress and the main symptoms of human mental illness; social withdrawalThe modeling time is short; the operation process is simple; and the construction scheme is relatively clearUsed only for male animals, ignoring the effects of the animal’s sex; the quality and quantity of pressure sources are difficult to controlSugar water preference test (SPT); open field testing (OFT); FST; tail suspension test (TST); elevated cross maze test (EPM)Mice; SD and Wistar ratsTen consecutive days of chronic stress stimulation; easy to produce the effect of depression
Learned helplessness (LH)Subjecting the animal to unpredictable and inevitable stress and leaving the animal helplessSimple operation; Short consumption time; It\'s a good way to simulate the helpless symptoms of depressionBehavioral changes induced by the model are temporary and return to normal in a week or soOFT; FST; TST; Morris mazeMice; rats; dogs; rhesus monkeysThe model has high repeatability and can be obtained in a short time
Deprivation model (MD)The abandonment of hope of escape followed by despair results in low mood and loss of interest as the main symptoms of depressionLow cost, simple, fast and reliable; preliminary screening of antidepressants or evaluation of behavioral changes in other models of depressionIt is also doubtful whether the acute stress process can produce depressive state, which is inconsistent with the clinical course of depressionClimbing; tail upright; foraging; grooming and other activities were less than that of the normal groupMice; rats; dogsThe model can be established quickly and sensitively, with high repeatability and consistent depression phenotype
Olfactory bulbectomy (OBX)Causes abnormalities in the nervous and endocrine systems, similar to those seen in clinical depression; it has some similarities with the clinical manifestations of Alzheimer’s diseaseChronic administration reverses the behavioral and biochemical changes caused by OBX, similar to the clinical effects of antidepressantsThe postoperative recovery time was longer (2 weeks), and there were more differences from the etiology of clinical depressionOFT; Morris maze; elevated cross maze experiment; FST; TSTMice; ratsThe consistency of surgical operation and the repeatability of experimental operation are not high

Note: Classification and characterization of neural circuits associated with various stress models. In response to stress exposure, the body will produce a variety of clinical manifestations of stress, such as depression, anxiety, loss of pleasure, and other symptoms. In order to better simulate the pathogenesis of depression, various stress models have been generated, including chronic stress model, acute stress model, surgical stress mode, and so on. The advantages and disadvantages of various stress models, evaluation methods, commonly used animal species, and the replicability of modeling were briefly evaluated in the table.

10.26599/SAB.2021.9060001.T002Classification of neural circuit characteristics related to stress models.

Animal modelClassificationRelated major brain nucleiInvolved neural circuits or molecular signalsActivation effects: Antidepres-sant effectActivation effects: Induction of depressive-like behaviors
Acute stress models· Foot shock model· Tail suspension model· Forced swimming model· Paraventricular nucleus of hypothalamus (PVN)· DRN· BLA· mPFC· NAc· ILTmPFC-BLA—√
mPFC-DRN—√
ILT-NAc—√
HPA—√
Chronic stress models· CRS· CSDS· LH· CUMS· mPFC· DRN· Amygdala· vHip· NAc· LHb· MHb· IPN· Hypothalamic–Pituitary–Adrenal axis (HPA)· VTATmPFC-Amygdala—√
mPFC-NAc√—
DRN-VTAT√—
vHip-NAc—√
BLA-NAc√—
VTAT-mPFC√—
VTAT-NAc—√
MHb-IPN√—
LHb-DRN/MRN—√
HPA—√
Surgical modeling· OBX· Post-stroke depression (PSD)· Ovariectomized (OVX)· Vascular depression (VD)· Cortex· vHip· Amygdala· BLA· NAcvHip-NAc—√
mPFC-NAc√—
BLA-NAc√—
Limbic–hypothalamic axis—√
Drug modeling· Depression model induced by reserpine· Depression model induced by repeated injection of glucocorticoid· Hippocampus· HPAHPA—√
Reduced catecholamine and 5-hydroxytryptamine—√
Decreased monoamine transmitters—√
Elevated glucocorticoids—√

Note: Classification of neural circuits associated with stress. Important advances have been made in identifying the causal role of neural circuits in stress-induced depression-like behavior through optogenetic and chemogenetic manipulation. Thus, several key brain regions and neural circuits involved in stress-induced depression-like behavior are described in the table, such as brain regions and their nuclei are mainly involved in different stress models, and the molecular pathways mediated by different neural circuits in different models, as well as whether the activation or inhibition of circuits will moderate or strengthen the regulation of depressive behavior, etc.