亚慢性和温和的社会失败应激的小鼠模型理解应激诱导行为和生理赤字
Summary
这里，为了开发亚慢性和轻度社会败应力的小鼠模型中的方法描述和用于研究抑郁症的致病特性，包括hyperphagia-和烦渴样症状以下增加体重。
Abstract
Stressful life events often increase the incidence of depression in humans. To study the mechanisms of depression, the development of animal models of depression is essential. Because there are several types of depression, various animal models are needed for a deeper understanding of the disorder. Previously, a mouse model of subchronic and mild social defeat stress (sCSDS) using a modified chronic social defeat stress (CSDS) paradigm was established. In the paradigm, to reduce physical injuries from aggressors, the duration of physical contact between the aggressor and a subordinate was reduced compared to in the original CSDS paradigm. sCSDS mice showed increased body weight gain, food intake, and water intake during the stress period, and their social behaviors were suppressed after the stress period. In terms of the face validity of the stress-induced overeating and overdrinking following the increased body weight gain, the sCSDS mice may show some features related to atypical depression in humans. Thus, a mouse model of sCSDS may be useful for studying the pathogenic mechanisms underlying depression. This protocol will help establish the sCSDS mouse model, especially for studying the mechanisms underlying stress-induced weight gain and polydipsia- and hyperphagia-like symptoms.
Introduction
多种压力事件发生在整个人类的生活。过大的应力常导致在人类和动物有害的生理后果。在人类中，压力事件是主要危险因素沉淀精神障碍，例如抑郁症1。疾病研究的全球负担表明，抑郁症是最致残性疾病的伤残调整寿命年（DALY）和多年居住残疾2项之一。此外，抑郁症占自杀的DALY 3的比例最大。患有抑郁症很难管理自己的生活，作为一个结果，他们的生活质量往往恶化。因此，强烈需要开发有效的治疗剂，以改善生活在这些患者中的质量。
许多研究的重大抑郁症被执行，并揭示了疾病susceptibilit的遗传贡献y为约30〜40％，这是由多个位点的小的影响4的作用进行说明。由于抑郁症背后的复杂的致病机理，疾病的病因的详细仍不清楚。临床报告显示，有抑郁症，亚型如忧郁和非典型抑郁症5，其显示降低的和分别6增加体重。虽然25-30％和抑郁症患者15-30％为纯忧郁和非典型特征，分别大多有两种亚型7的混合特征。因此，严重抑郁症有广泛的症状。为了找到生物标志物和开发目标的治疗剂的各类人类的抑郁症的，它建立凹陷8的几个不同的动物模型是重要的。
抑郁症的动物模型用几种方法已经建立了一个包括学无奈，慢性应激和慢性社会的失败应力（CSDS）9-12。丰田和同事建立大鼠和小鼠13-17的CSDS模型，以阐明代谢和与抑郁症相关的行为。由于抑郁症的动物模型是由表面效度18评估，在其中模型建立的环境是很重要的。此外，金等 19报道的方法进行详细创建CSDS小鼠。已知的是，在CSDS小鼠的社会行为的缺陷可以通过慢性治疗中回收，而不是由急性治疗，与抗抑郁药，而且它们在脑源性神经营养的调节方面共享的症状类似于在抑郁症患者因素6。
Goto等13以前开发的亚慢性和轻度社会败应力（sCSDS）小鼠模型通过修改方法金等人 。19。该sCSDS小鼠显示以下收益体重和增加身体水分含量13 polydipsia-和亢进样症状。在这份报告中，提供了协议建立sCSDS小鼠模型和我们讨论这个模型的效用。
Protocol
Representative Results
Discussion
有sCSDS小鼠和CSDS小鼠进行标准CSDS协议19（与每天侵略者物理接触5至10分钟）之间的差异确定的体重。时的应力期间sCSDS小鼠显示增加BWG，而标准CSDS小鼠显示体重降低时的应力期间21,22,23。有这两种协议之间的侵略者与身体接触的总时长方面在10天的期限压力很大差异。而原来的CSDS范例包括侵略者和从属小鼠中总（全面CSDS）之间的物理相互作用的50或100分钟时，sCSDS方法包含这种相?…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
作者感谢博士。长冈健太郎（东京农工大学）和饭尾涉（茨城县）的有益的讨论。这项研究是由农业和医学科学（IUCAM）（文部科学省，日本）和研究项目上的农产品和健康促进的好处食品的发展（NARO）之间的茨城大学合作的部分资助（农林水产省，日本） 。
Materials
| single cage | Charles River Laboratories Japan | width [W] × depth [D] × height [H] = 143 × 293 × 148 mm | |
| M cage | Natsume Seisakusho | W × D × H = 220 × 320 × 135 mm | |
| Whiteflake | Charles River Laboratories Japan | Wood-shaving chips made from spruce trees | |
| AIN-93G | Oriental Yeast | purified-diet food pellets | |
| Kimtowel | Nippon Paper Crecia Co. | Paper towels | |
| open-field arena | O’Hara & Co. | made of gray polyvinylchloride |
Riferimenti
- 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 (1), 102-111 (2012).
- Whiteford, H. A., et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 382 (9904), 1575-1586 (2013).
- Ferrari, A. J., et al. The Burden Attributable to Mental and Substance Use Disorders as Risk Factors for Suicide: Findings from the Global Burden of Disease Study 2010. PLoS ONE. 9 (4), e91936 (2014).
- Flint, J., Kendler, K. S. The genetics of major depression. Neuron. 81 (3), 484-503 (2014).
- Nestler, E. J., et al. Neurobiology of Depression. Neuron. 34 (1), 13-25 (2002).
- Gold, P. W., Chrousos, G. P. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol. Psychiatry. 7 (3), 254-275 (2002).
- 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 (10), 1589-1599 (2012).
- Nestler, E. J., Hyman, S. E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13 (10), 1161-1169 (2010).
- Katz, R. J. Animal models and human depressive disorders. Neurosci. Biobehav. Rev. 5 (2), 231-246 (1981).
- Krishnan, V., Nestler, E. J. Animal models of depression: molecular perspectives. Curr. Top. Behav. Neurosci. 7, 121-147 (2011).
- Kudryavtseva, N. N., Bakshtanovskaya, I. V., Koryakina, L. A. Social model of depression in mice of C57BL/6J strain. Pharmacol. Biochem. Behav. 38 (2), 315-320 (1991).
- Miczek, K. A., Yap, J. J., Covington, H. E. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol. Ther. 120 (2), 102-128 (2008).
- Goto, T., et al. Subchronic and mild social defeat stress accelerates food intake and body weight gain with polydipsia-like features in mice. Behav. Brain Res. 270, 339-348 (2014).
- Goto, T., Kubota, Y., Toyoda, A. Plasma and Liver Metabolic Profiles in Mice Subjected to Subchronic and Mild Social Defeat Stress. J. Proteome Res. , (2014).
- Iio, W., Matsukawa, N., Tsukahara, T., Kohari, D., Toyoda, A. Effects of chronic social defeat stress on MAP kinase cascade. Neurosci. Lett. 504 (3), 281-284 (2011).
- Iio, W., et al. Effects of chronic social defeat stress on peripheral leptin and its hypothalamic actions. BMC Neurosci. 15 (72), (2014).
- Iio, W., et al. Anorexic behavior and elevation of hypothalamic malonyl-CoA in socially defeated rats. Biochem. Biophys. Res. Commun. 421 (2), 301-304 (2012).
- Crawley, J. N. . What’s Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice. , 978-970 (2007).
- Golden, S. A., Covington, H. E., Berton, O., Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6 (8), 1183-1191 (2011).
- Miczek, K. A., Maxson, S. C., Fish, E. W., Faccidomo, S. Aggressive behavioral phenotypes in mice. Behav. Brain Res. 125, 167-181 (2001).
- Krishnan, V., et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 131 (2), 391-404 (2007).
- Chuang, J. C., et al. A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress. Biol. Psychiatry. 67 (11), 1075-1082 (2010).
- Warren, B. L., et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol. Psychiatry. 73 (1), 7-14 (2013).
- Savignac, H. M., et al. Increased sensitivity to the effects of chronic social defeat stress in an innately anxious mouse strain. Neuroscienze. 192, 524-536 (2011).
- Green, J. G., et al. Childhood Adversities and Adult Psychiatric Disorders in the National Comorbidity Survey Replication I: associations with first onset of DSM-IV disorders. Arch. Gen. Psychiatry. 67 (2), 113-123 (2010).
- Miniati, M., et al. Clinical characteristics and treatment outcome of depression in patients with and without a history of emotional and physical abuse. J. Psychiatr. Res. 44 (5), 302-309 (2010).
- Tao, M., et al. Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women. J. Affect. Disord. 135 (1-3), 95-99 (2011).
- Valente, S., Fisher, D. Recognizing and managing psychogenic polydipsia in mental health. J. Nurse Pract. 6 (7), 546-550 (2010).
- Dundas, B., Harris, M., Narasimham, M. Psychogenic Polydipsia Review: Etiology, Differential, and Treatment. Curr. Psychiatry Rep. 9 (3), 236-241 (2007).
- Tsumura, K., et al. Downregulation of AQP2 expression in the kidney of polydipsic STR/N mice. Am. J. Physiol. Renal Physiol. 290 (2), F478-F485 (2006).
- Flores, P., et al. Schedule-Induced Polydipsia: Searching for the Endophenotype of Compulsive Behavior. World J. Neurosci. 4, 253-260 (2014).
- Cryan, J. F., Dinan, T. G. Mind-altering microorganisms: the impact of the gut microbiota on brain and and behaviour. Nat. Rev. Neurosci. 13 (10), 701-712 (2012).
