The authors thank Drs. Kentaro Nagaoka (Tokyo University of Agriculture and Technology) and Wataru Iio (Ibaraki Prefecture) for the helpful discussion. This research was supported in part by Ibaraki University Cooperation between Agriculture and Medical Science (IUCAM) (The MEXT, Japan) and the Research Project on the Development of Agricultural Products and Foods with Health-promoting Benefits (NARO) (The MAFF, Japan).

The animal studies were approved by and met the guidelines of both the Animal Care and Use Committee of Ibaraki University and the Ministry of Education Culture, Sports, Science, and Technology (MEXT), Japan (Notification No.71). A complete overview of the protocol is shown in Figure 1.
1. Apparatus
<ol>
	<li>Prepare two kinds of cages: a single cage (width [W] &#215; depth [D] &#215; height [H] = 143 mm &#215; 293 mm &#215; 148 mm), and a &#8220;social defeat (SD)&#8221; ca...

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	<li>Heim, C., Binder, E. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Current+research+trends+in+early+life+stress+and+depression:+Review+of+human+studies+on+sensitive+periods,+gene-environment+interactions,+and+epigenetics.">Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics.</a> Exp. Neurol. 233 (1), 102-111 (2012).</li><li>Whiteford, H. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Global+burden+of+disease+attributable+to+mental+and+substance+use+disorders:+findings+from+the+Global+Burden+of+Disease+Study+2010.">Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.</a> Lancet. 382 (9904), 1575-1586 (2013).</li><li>Ferrari, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Burden+Attributable+to+Mental+and+Substance+Use+Disorders+as+Risk+Factors+for+Suicide:+Findings+from+the+Global+Burden+of+Disease+Study+2010.">The Burden Attributable to Mental and Substance Use Disorders as Risk Factors for Suicide: Findings from the Global Burden of Disease Study 2010.</a> PLoS ONE. 9 (4), e91936 (2014).</li><li>Flint, J., Kendler, K. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+genetics+of+major+depression.">The genetics of major depression.</a> Neuron. 81 (3), 484-503 (2014).</li><li>Nestler, E. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neurobiology+of+Depression.">Neurobiology of Depression.</a> Neuron. 34 (1), 13-25 (2002).</li><li>Gold, P. W., Chrousos, G. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Organization+of+the+stress+system+and+its+dysregulation+in+melancholic+and+atypical+depression:+high+vs+low+CRH/NE+states.">Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states.</a> Mol. Psychiatry. 7 (3), 254-275 (2002).</li><li>O'Keane, V., Frodl, T., Dinan, T. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+review+of+atypical+depression+in+relation+to+the+course+of+depression+and+changes+in+HPA+axis+organization.">A review of atypical depression in relation to the course of depression and changes in HPA axis organization.</a> Psychoneuroendocrinology. 37 (10), 1589-1599 (2012).</li><li>Nestler, E. J., Hyman, S. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+neuropsychiatric+disorders.">Animal models of neuropsychiatric disorders.</a> Nat. Neurosci. 13 (10), 1161-1169 (2010).</li><li>Katz, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+and+human+depressive+disorders.">Animal models and human depressive disorders.</a> Neurosci. Biobehav. Rev. 5 (2), 231-246 (1981).</li><li>Krishnan, V., Nestler, E. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+depression:+molecular+perspectives.">Animal models of depression: molecular perspectives.</a> Curr. Top. Behav. Neurosci. 7, 121-147 (2011).</li><li>Kudryavtseva, N. N., Bakshtanovskaya, I. V., Koryakina, L. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Social+model+of+depression+in+mice+of+C57BL/6J+strain.">Social model of depression in mice of C57BL/6J strain.</a> Pharmacol. Biochem. Behav. 38 (2), 315-320 (1991).</li><li>Miczek, K. A., Yap, J. J., Covington, H. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Social+stress,+therapeutics+and+drug+abuse:+preclinical+models+of+escalated+and+depressed+intake.">Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake.</a> Pharmacol. Ther. 120 (2), 102-128 (2008).</li><li>Goto, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subchronic+and+mild+social+defeat+stress+accelerates+food+intake+and+body+weight+gain+with+polydipsia-like+features+in+mice.">Subchronic and mild social defeat stress accelerates food intake and body weight gain with polydipsia-like features in mice.</a> Behav. Brain Res. 270, 339-348 (2014).</li><li>Goto, T., Kubota, Y., Toyoda, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Plasma+and+Liver+Metabolic+Profiles+in+Mice+Subjected+to+Subchronic+and+Mild+Social+Defeat+Stress.">Plasma and Liver Metabolic Profiles in Mice Subjected to Subchronic and Mild Social Defeat Stress.</a> J. Proteome Res. , (2014).</li><li>Iio, W., Matsukawa, N., Tsukahara, T., Kohari, D., Toyoda, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+chronic+social+defeat+stress+on+MAP+kinase+cascade.">Effects of chronic social defeat stress on MAP kinase cascade.</a> Neurosci. Lett. 504 (3), 281-284 (2011).</li><li>Iio, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+chronic+social+defeat+stress+on+peripheral+leptin+and+its+hypothalamic+actions.">Effects of chronic social defeat stress on peripheral leptin and its hypothalamic actions.</a> BMC Neurosci. 15 (72), (2014).</li><li>Iio, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anorexic+behavior+and+elevation+of+hypothalamic+malonyl-CoA+in+socially+defeated+rats.">Anorexic behavior and elevation of hypothalamic malonyl-CoA in socially defeated rats.</a> Biochem. Biophys. Res. Commun. 421 (2), 301-304 (2012).</li><li>Crawley, J. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> What's Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice. , 978-970 (2007).</li><li>Golden, S. A., Covington, H. E., Berton, O., Russo, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+standardized+protocol+for+repeated+social+defeat+stress+in+mice.">A standardized protocol for repeated social defeat stress in mice.</a> Nat. Protoc. 6 (8), 1183-1191 (2011).</li><li>Miczek, K. A., Maxson, S. C., Fish, E. W., Faccidomo, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Aggressive+behavioral+phenotypes+in+mice.">Aggressive behavioral phenotypes in mice.</a> Behav. Brain Res. 125, 167-181 (2001).</li><li>Krishnan, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Molecular+adaptations+underlying+susceptibility+and+resistance+to+social+defeat+in+brain+reward+regions.">Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.</a> Cell. 131 (2), 391-404 (2007).</li><li>Chuang, J. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+beta3-adrenergic-leptin-melanocortin+circuit+regulates+behavioral+and+metabolic+changes+induced+by+chronic+stress.">A beta3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress.</a> Biol. Psychiatry. 67 (11), 1075-1082 (2010).</li><li>Warren, B. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neurobiological+sequelae+of+witnessing+stressful+events+in+adult+mice.">Neurobiological sequelae of witnessing stressful events in adult mice.</a> Biol. Psychiatry. 73 (1), 7-14 (2013).</li><li>Savignac, H. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increased+sensitivity+to+the+effects+of+chronic+social+defeat+stress+in+an+innately+anxious+mouse+strain.">Increased sensitivity to the effects of chronic social defeat stress in an innately anxious mouse strain.</a> Neuroscience. 192, 524-536 (2011).</li><li>Green, J. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Childhood+Adversities+and+Adult+Psychiatric+Disorders+in+the+National+Comorbidity+Survey+Replication+I:+associations+with+first+onset+of+DSM-IV+disorders.">Childhood Adversities and Adult Psychiatric Disorders in the National Comorbidity Survey Replication I: associations with first onset of DSM-IV disorders.</a> Arch. Gen. Psychiatry. 67 (2), 113-123 (2010).</li><li>Miniati, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+characteristics+and+treatment+outcome+of+depression+in+patients+with+and+without+a+history+of+emotional+and+physical+abuse.">Clinical characteristics and treatment outcome of depression in patients with and without a history of emotional and physical abuse.</a> J. Psychiatr. Res. 44 (5), 302-309 (2010).</li><li>Tao, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Examining+the+relationship+between+lifetime+stressful+life+events+and+the+onset+of+major+depression+in+Chinese+women.">Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women.</a> J. Affect. Disord. 135 (1-3), 95-99 (2011).</li><li>Valente, S., Fisher, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recognizing+and+managing+psychogenic+polydipsia+in+mental+health.">Recognizing and managing psychogenic polydipsia in mental health.</a> J. Nurse Pract. 6 (7), 546-550 (2010).</li><li>Dundas, B., Harris, M., Narasimham, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychogenic+Polydipsia+Review:+Etiology,+Differential,+and+Treatment.">Psychogenic Polydipsia Review: Etiology, Differential, and Treatment.</a> Curr. Psychiatry Rep. 9 (3), 236-241 (2007).</li><li>Tsumura, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Downregulation+of+AQP2+expression+in+the+kidney+of+polydipsic+STR/N+mice.">Downregulation of AQP2 expression in the kidney of polydipsic STR/N mice.</a> Am. J. Physiol. Renal Physiol. 290 (2), F478-F485 (2006).</li><li>Flores, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Schedule-Induced+Polydipsia:+Searching+for+the+Endophenotype+of+Compulsive+Behavior.">Schedule-Induced Polydipsia: Searching for the Endophenotype of Compulsive Behavior.</a> World J. Neurosci. 4, 253-260 (2014).</li><li>Cryan, J. F., Dinan, T. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mind-altering+microorganisms:+the+impact+of+the+gut+microbiota+on+brain+and+and+behaviour.">Mind-altering microorganisms: the impact of the gut microbiota on brain and and behaviour.</a> Nat. Rev. Neurosci. 13 (10), 701-712 (2012).</li></ol>

The authors declare that they have no competing financial interests.

There were definitive differences in body weight between sCSDS mice and CSDS mice subjected to the standard CSDS protocol (5 to 10 min of physical contact with aggressors per day)19. The sCSDS mice showed increased BWG during the stress period, whereas the standard CSDS mice showed a decrease in body weight during the stress period21,22,23. There is a substantial difference between the two protocols in terms of the total duration of physical contact with aggressors during the 10-day stress period. W...

Many kinds of stressful events occur throughout the lives of humans. Excessive stress often leads to harmful physiological consequences in humans and animals. In humans, stressful events are major risk factors for precipitating psychiatric disorders such as depression1. A Global Burden of Disease study indicated that depression is one of the most disabling disorders in terms of disability-adjusted life years (DALYs) and years lived with disability2. In addition, depression accounts for the largest proportion of suicide DALYs3. People suffering from depression find it difficult to manage their lives, and as a result, their quality of life often worsens. Therefore, there is a strong need to develop effective therapeutics to improve the quality of life in these patients.
Many studies have been performed on major depressive disorders, and have revealed that the genetic contribution to disease susceptibility is approximately 30&#8211;40%, which is explained by the effects of multiple loci of small effects4. Because of the complex pathogenic mechanisms underlying depression, the detailed etiology of the disease remains elusive. Clinical reports indicate that there are subtypes of depression such as melancholic and atypical depression5, which show reduced and increased body weight, respectively6. Although 25&#8211;30% and 15&#8211;30% of patients with depression represent pure melancholic and atypical features, respectively, most of them have mixed features of both subtypes7. Therefore, major depression has a wide range of symptoms. In order to find biomarkers and develop objective therapeutics for the various types of depression in humans, it is important to establish several different animal models of depression8.
Animal models of depression have been established using several approaches including learned helplessness, chronic unpredictable mild stress, and chronic social defeat stress (CSDS)9-12. Toyoda and colleagues established the CSDS models of rats and mice13-17 in order to elucidate the metabolism and behaviors that are associated with depression. Given that animal models of depression are evaluated by face validity18, the context within which the model is established is important. Moreover, Golden et al.19 reported the methods for creating CSDS mice in detail. It is known that the deficits in social behavior of CSDS mice can be recovered by chronic treatment, but not by acute treatment, with antidepressants, and that they share symptoms similar to those in patients with depression in terms of the regulation of brain-derived neurotrophic factor6.
Goto et al.13 previously developed the subchronic and mild social defeat stress (sCSDS) mouse model by modifying the methods of Golden et al.19. The sCSDS mice show polydipsia- and hyperphagia-like symptoms following gains in body weight and increased body water content13. In this report, the protocol for establishing the sCSDS mouse model is provided and we discuss the utility of this model.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>single cage</td>
			<td>Charles River Laboratories Japan</td>
			<td></td>
			<td>width [W] &#215; depth [D] &#215; height [H] = 143 &#215; 293 &#215; 148 mm</td>
		</tr>
		<tr>
			<td>M cage</td>
			<td>Natsume Seisakusho</td>
			<td></td>
			<td>W &#215; D &#215; H = 220 &#215; 320 &#215; 135 mm</td>
		</tr>
		<tr>
			<td>Whiteflake</td>
			<td>Charles River Laboratories Japan</td>
			<td></td>
			<td>Wood-shaving chips made from spruce trees</td>
		</tr>
		<tr>
			<td>AIN-93G</td>
			<td>Oriental Yeast</td>
			<td></td>
			<td>purified-diet food pellets</td>
		</tr>
		<tr>
			<td>Kimtowel</td>
			<td>Nippon Paper Crecia Co.</td>
			<td></td>
			<td>Paper towels</td>
		</tr>
		<tr>
			<td>open-field arena</td>
			<td>O&#8217;Hara &#38; Co.</td>
			<td></td>
			<td>made of gray polyvinylchloride</td>
		</tr>
	</tbody>
</table>

a mouse model of subchronic and mild social defeat stress for understanding stress-induced behavioral and physiological deficits

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.

To monitor the degree of physical stress for over the 10-day periods, the number of attack bites by ICR mice was manually counted by a researcher. Figure 5A indicates the individual values for the number of attack bites received. There was considerable variability in the early stage (approximately 10&#8211;120 bites on day 1), but this variability was reduced in the later stage (approximately 5&#8211;20 bites on day 10). Figure 5B&#160;indicates that the average number of attack bites re...

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A Mouse Model of Subchronic and Mild Social Defeat Stress for Understanding Stress-induced Behavioral and Physiological Deficits

Here, methods for developing a mouse model of subchronic and mild social defeat stress are described and used to investigate the pathogenic features of depression including hyperphagia- and polydipsia-like symptoms following increased body weight.

Stressful life events often increase the incidence of depression in humans. To study the mechanisms of depression, the development of animal models of ...

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19.4K ビュー.  Ibaraki University. ここでは、亜慢性軽度ソーシャル敗北ストレスのマウスモデルを開発するための方法が記載され、体重増加、以下hyperphagia-および多渇症様症状を含むうつ病の病原性の特徴を調べるために使用されます。 