The authors would like to thank Thomas Grace for constructing Y-mazes, barriers, and social defeat cages. The authors would like to thank Jay Lee, Karina Stech, and Prachi Srivastava for assistance with data collection. This work was funded by NIMH Grant R01 MH112861 (BAS).

These experiments were conducted in compliance with NIH laboratory animal care guidelines and approved by the Rutgers University Institutional Animal Care and Use Committee.
1. Chronic corticosterone (CORT)
<ol>
	<li>Randomly assign mice to treatment groups. Randomly divide adult male C57BL/6J mice into Vehicle and Corticosterone (CORT) groups.
	<ol>
		<li>House vehicle mice in distinct cages, and CORT mice in others, as their treatment is delivered via the cage&#8217;s water bottle.</li>
		...

<ol>
	<li>Kessler, R. 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=Lifetime+and+12-month+prevalence+of+DSM-III-R+psychiatric+disorders+in+the+United+States.+Results+from+the+National+Comorbidity+Survey.">Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.</a> Arch Gen Psychiatry. 51 (1), 8-19 (1994).</li><li>Breslau, N., Davis, G. 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The authors have nothing to disclose.

While the chronic CORT paradigm provides a constant CORT dose in the drinking water, from experience there can be some variability in amount consumed by mice. Further, consumption can only be assessed for the total cage, and an average taken based on the number of mice in the cage. Additionally, spillage can occur when weighing the bottles, transferring the mice for behavior testing, or when changing to a fresh cage. However, tracking Vehicle and CORT consumption is still feasible and accurate across weeks of treatment a...

Mood disorders such as depression and anxiety are highly prevalent in today&#8217;s society. Decades of work has continuously searched for improved treatments and relevant rodent models to study these complex disorders1. Chronic stress is a contributing factor for mood disorders like depression2. Therefore, chronic stress paradigms such as chronic social defeat stress (SDS) and chronic corticosterone administration (CORT) were developed in male mice and are now widely used to assess the neurobiological and behavioral effects of chronic stress exposure. The most widely used behavioral tests for assessing chronic stress effects include tasks associated with avoidance behavior, such as elevated plus maze, open field, and novelty suppressed feeding, or with antidepressant efficacy, such as forced swim test. However, these behaviors in rodents arguably lack face and, more importantly, predictive validity and translational relevance for human disorders such as depression.
A popular chronic stress paradigm, chronic unpredictable mild stress (CUMS), has been validated extensively using behaviors such as sucrose preference3. CUMS reduces preference for a 1% sucrose solution compared to water and is historically interpreted as anhedonia-related behavior4,5. However, this reduction in sucrose preference is not observed in humans with major depressive disorder6,7. In addition, sucrose preference does not allow for the study of effortful reward motivation.
Recently, some research has shifted focus to other behaviors associated with motivation and reward8,9. These tasks have promising translational value because relatively similar behavior assessments can be conducted in both humans and rodents. Here, we describe the CORT and SDS paradigms and their effects in a Y-maze barrier behavioral task that measures motivation to exert effort for reward. We then discuss a new chronic stress paradigm that we developed, chronic non-discriminatory social defeat stress (CNSDS), which is effective in both male and female mice.
Chronic corticosterone administration (CORT) is a paradigm designed to mimic chronic stress without actual stress exposures. Activation of the hypothalamus-pituitary-adrenal axis by stress results in the endogenous release of the adrenal steroid cortisol in humans10,11,12 and corticosterone in mice13,14. Delivery of corticosterone through the drinking water of adult male mice for at least 4 weeks results in maladaptive behavioral responses in avoidance tasks such as open field, elevated plus maze, and novelty suppressed feeding10,11,12,13,14,15,16. Interestingly, CORT also affects reward processing in instrumental tasks16,17,18,19. The CORT paradigm described here produces a consistent serum concentration of below 100 ng/mL CORT, which is more than five times less than that produced by an acute stressor such as forced swim15. Therefore, chronic CORT administration is unlikely to cause hypercortisolemia. While chronic CORT is only effective in male mice20, we recently demonstrated that it produces a robust shift in effortful responding in the Y-maze barrier task21. To our knowledge, this was one of the first studies to examine the effects of chronic stress on an effort-related choice behavior in male mice21. One previous study first demonstrated the impact of acute restraint stress on effort-based decision making in rats22. In effort-related choice behaviors, an animal chooses to either exert effort for a high-value reward or accept a lower-value reward that is more freely available. In humans, the effort-expenditure for rewards task (EEfRT), is a computer game developed to be analogous to effort-related choice tasks in mice23. Depression results in maladaptive responses in EEfRT (decreased likelihood of choosing hard tasks for high-value rewards). Therefore, effort-related choice tasks in rodents are particularly interesting because of their translational relevance.
Chronic social defeat stress (SDS) is one of the more widely used preclinical stress models in male mice. It is a 10-day protocol where large, aggressive retired breeder CD-1 males attack experimental mice, typically C57BL/6J, in 5 min daily sessions24. This produces a robust maladaptive behavioral phenotype in a subset of experimental mice. A social interaction test is used to stratify mice into resilient or susceptible populations to the defeat stress, and several studies have used this unique characteristic of SDS to probe the molecular and neural circuit mechanisms underlying stress reliance and susceptibility. Here we describe the details of the CORT paradigm and its implementation for the Y-maze barrier behavioral task. We also discuss SDS effects in the Y-maze barrier task. The Y-maze barrier task is based on the T-maze barrier task, which is used primarily in rats to measure motivation to expend effort for high or low rewards present in the two arms of the maze8,9,25. This task has also been implemented to study effortful responding in mice administered caffeine or dopamine antagonists in mice26. Rodents can either expend greater effort by climbing barriers of progressively increasing height in one arm of the maze for a higher reward value, typically 4 reward pellets, or expend significantly less effort in the other arm of the maze to receive only 2 reward pellets9. 10-day social defeat paradigms produce a robust maladaptive phenotype in susceptible mice that lasts approximately 30 days, so we modified the Y-maze barrier task to more rapidly train and test animals in order to complete all experiments within this 30-day timeframe24. Therefore, here we also detail a Y-maze barrier behavioral task protocol containing condensed training sessions and single barrier test sessions to measure motivation to expend effort for reward in chronic stress-exposed mice.
Unfortunately, both chronic corticosterone and chronic social defeat stress were developed in male mice and are less effective in female mice. This is highly problematic as women are more likely than men to be diagnosed with mood disorders such as depression1. Clever adaptations to SDS have allowed usage in female mice but require difficult surgeries or tedious urine collection26,27. We recently described a simple modification to the SDS paradigm, called chronic non-discriminatory social defeat stress (CNSDS). CNSDS allows susceptible and resilient stratification of both experimental male and female mice28. Both female and male susceptible mice exposed to CNSDS show increased avoidance of open arms in elevated-plus maze and of the center in open field and display increased latency to eat in novelty-suppressed feeding. CNSDS also is more efficient than other modifications to SDS, as both sexes are combined in defeat sessions. This results in an increased yield of experimental mice without an associated increase in time and effort required to complete the protocol. Therefore, we conclude this manuscript with an in-depth presentation of this recently developed chronic stress paradigm.

<table>
	<tbody>
		<tr>
			<td>Acrylic Sheet</td>
			<td>McMaster Carr</td>
			<td>8560K215</td>
			<td>Clear, 3/16&#34; thick, 24&#34; X 36&#34;</td>
		</tr>
		<tr>
			<td>Beta-cyclodextrin</td>
			<td>Sigma-Aldrich</td>
			<td>C4767</td>
			<td>500 mg</td>
		</tr>
		<tr>
			<td>C57BL/6J Mice</td>
			<td>Jackson Labs</td>
			<td>000664</td>
			<td>Adults age 7-8 weeks</td>
		</tr>
		<tr>
			<td>Corticosterone</td>
			<td>Sigma-Aldrich</td>
			<td>C2505 or C27840</td>
			<td>100 or 500 mg</td>
		</tr>
		<tr>
			<td>Male CD-1 Mice</td>
			<td>Charles River</td>
			<td>022</td>
			<td>&#34;Retired Breeders&#34;</td>
		</tr>
		<tr>
			<td>PVC Acrylic Sheet</td>
			<td>McMaster Carr</td>
			<td>8560K215</td>
			<td>White, 3/16&#34; thick, 48&#34; X 48&#34;</td>
		</tr>
		<tr>
			<td>Solidstate Ultrasonic Cleaner</td>
			<td>Fisher Scientific</td>
			<td>FS-28</td>
			<td>Must reach 40 kHz</td>
		</tr>
		<tr>
			<td>Steel Wire Cloth</td>
			<td>McMaster Carr</td>
			<td>9219T143</td>
			<td>1 ft X 2 ft</td>
		</tr>
	</tbody>
</table>

chronic stress shifts effort-related choice behavior in a y-maze barrier task in mice

Mood disorders, including major depressive disorder, can be precipitated by chronic stress. The Y-maze barrier task is an effort-related choice test that measures motivation to expend effort and obtain reward. In mice, chronic stress exposure significantly impacts motivation to work for a higher value reward when a lesser value reward is freely available compared to unstressed mice. Here we describe the chronic corticosterone administration paradigm, which produces a shift in effortful responding in the Y-maze barrier task. In the Y-maze task, one arm contains 4 food pellets, while the other arm contains only 2 pellets. After mice learn to select the high reward arm, barriers with progressively increasing height are then introduced into the high reward arm over multiple test sessions. Unfortunately, most chronic stress paradigms (including corticosterone and social defeat) were developed in male mice and are less effective in female mice. Therefore, we also discuss chronic non-discriminatory social defeat stress (CNSDS), a stress paradigm we developed that is effective in both male and female mice. Repeating results with multiple distinct chronic stressors in male and female mice combined with increased usage of translationally relevant behavior tasks will help to advance the understanding of how chronic stress can precipitate mood disorders.

Chronic CORT was administered for 4 weeks followed by Y-maze barrier training and testing (Figure 1A). In a separate cohort, the 10-day SDS paradigm was similarly followed by training and testing in the Y-maze barrier task (Figure 1C), to determine the effect of these chronic stress paradigms on effort-related choice behavior in male mice. Chronic CORT and SDS both reduced mean body weight compared to Vehicle mice and SDS Control mice as determined by t...

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Chronic Stress Shifts Effort-Related Choice Behavior in a Y-Maze Barrier Task in Mice

The Y-maze barrier task is a behavior test that examines motivation to expend effort for reward. Here, we discuss testing multiple well-validated chronic stressors including chronic corticosterone and social defeat stress with this behavior, as well as the novel chronic non-discriminatory social defeat stress (CNSDS), which is effective in females.

Mood disorders, including major depressive disorder, can be precipitated by chronic stress. The Y-maze barrier task is an effort-related choice test that ...

This protocol allows researchers to examine the effects of chronic stress on effortful responding in both male and female mice. An advantage of this technique is that both male and female mice can simultaneously undergo a validated chronic social defeat paradigm allowing reward behaviors to be directly compared. Historically, preclinical research into mood disorders has utilized behavioral tasks that involve avoidance of threatening environments.However, reward and motivation tasks, such as effort-related choice, may offer more translational relevance. To prepare the vehicle solution, dissolve 3.375 grams of beta-cyclodextrin in 750 milliliters of tap water in a one liter screw top glass container. To prepare the corticosterone solution, dissolve 3.375 grams of beta-cyclodextrin in 750 milliliters of tap water, followed by the addition of 26.25 milligrams of corticosterone.Dissolve the corticosterone in solution in an ultrasonic cleaner water bath for approximately 30 minutes at 40 kilohertz until the liquid demonstrates a clear appearance, then fill the water bottles of the vehicle and corticosterone mouse group with the appropriate solutions and record the volume of liquid consumed twice a week. To habituate the mice to the Y-maze, the day after food deprivation, place a large number of 20 milligram grain-based food pellets in the caps of two 50 milliliter centrifuge tubes and place one cap at the end of each arm of the Y-maze, then place a mouse in the start box of the Y-maze with the start box divider in place for a few seconds before removing the divider and allowing the mouse to explore the Y-maze for 15 minutes. After two days of Y-maze habituation, place for pellets in a cap for the high reward arm and place two pellets in a cap for the low reward arm.For a high reward forced choice trial, block access to the low reward arm and place the mouse in the start box for a few seconds before removing the divider, allowing the mouse 60 seconds to enter the high reward arm to consume the available pellets. For a low reward forced choice trial, block access to the high reward arm. For free choice training, begin each session with one high and one low arm forced choice trial before completing 10 free choice trials.Allow the mouse to select either maze arm. Once the mouse has traveled to the end of the arm to the cap of pellets, place an arm divider behind the mouse, locking in the animal until it has consumed the pellets. Record which arm is selected for all 10 free choice trials daily.Once a mouse has selected the high reward arm for 7 out of 10 trials in a free choice training day, place a 10 centimeter barrier halfway down the high reward arm in the Y-maze and perform at least two high and low arm forced choice trials with the barrier in place. After completing all four trials, place the mouse in the start box and allow the mouse to select an arm for 10 free choice trials with the 10 centimeter barrier to the high reward arm in place. On the following day, habituate and test the mouse as demonstrated, but use a 15 centimeter barrier in the high reward arm.The next day, test the mouse with a 20 centimeter barrier as demonstrated. For chronic nondiscriminatory social defeat stress testing, align the cages of CD1 males with C57BL/6J males and females with CD1 cages in the front and C57BL/6J cages adjacent to the CD1 male mice in the social defeat room. To start the trial, place one adult male and one adult female experimental C57BL/6J mouse into the home cage of each CD1 aggressor male for a five-minute social defeat session and record the attack latency and frequency of attack for both male and female experimental animals.At the end of the session, transfer the male C57BL/6J mouse into the cage of co-housed CD1 males separated by a clear perforated plexiglass barrier. Separate the attacking CD1 and female C57BL/6 mice with a similar clear perforated plexiglass barrier. For a control session, place one control female mouse in the home cage of one control male C57BL/6 mouse.After five minutes, place a clear perforated plexiglass divider between the animals. At the end of the first experiment, rotate the mice for the remaining nine defeat sessions, such that each C57BL/6 male and female pair is rotated one cage to the left to provide a new interaction with novel CD1 mice for each session. Chronic corticosterone and chronic nondiscriminatory social defeat stress mice both exhibit a reduced mean body weight compared to vehicle and control animals.These mice also consumed less mean home cage lab chow. Vehicle and corticosterone-administered mice consume a similar volume of liquid over four weeks of treatment and three weeks of behavior testing. Chronic nondiscriminatory social defeat stress produces a maladaptive phenotype in susceptible mice compared to either resilient or control mice not exposed to chronic nondiscriminatory social defeat stress displaying a reduction in time spent in the interaction zone containing a novel CD1 mouse.Both chronic corticosterone and chronic nondiscriminatory social defeat stress mice produce a shift in effortful responding when the barrier height increases to 15 and 20 centimeters. High and low reward arm latency with the 15 centimeter barrier is not impacted by corticosterone administration and is similar for both groups with both low and high reward arms. Importantly, if chronic corticosterone or chronic nondiscriminatory social defeat stress impairs learning of the Y-maze barrier task, these mice may fail to reach the criterion in free choice training sessions, impacting subsequent barrier result interpretation.In addition, the social interaction task can be used to stratify the mice into resilient and susceptible populations, as well as by sex. When conducting the Y-maze barrier task, it is critical to record both the selected arm and the latency to reach the food pellet reward in each individual trial. Other important and translationallly relevant reward-related behaviors, such as outcome devaluation or progressive ratio, can be performed following the chronic corticosterone social defeat or chronic nondiscriminatory social defeat protocols.

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Research

JoVE Journal

Behavior

10.8K visualizações.  The State University of New Jersey. Este protocolo permite que os pesquisadores examinem os efeitos do estresse crônico na resposta esforçada em camundongos machos e femininos. Uma vantagem dessa técnica é que tanto camundongos machos quanto fêmeas podem sofrer simultaneamente um paradigma de derrota social crônica validado, permitindo que comportamentos de recompensa sejam diretamente comparados. Historicamente, pesquisas pré-científicas sobre transtornos de humor têm utilizado tarefas comportamentais que envolvem evi...