This work was funded by internal funds of the University Clinic Freiburg, Department of Psychiatry and Psychotherapy and the Berta-Ottenstein Program for Clinician Scientists (to SV). TS is funded by the grants of Medical Research Foundation (FRM) (AJE201912009450) and the University of Strasbourg Institute of Advance Studies (USIAS) (2020-035), as well as Centre National de la Recherche Scientifique (CNRS), France.

All experiments were performed in agreement with European guidelines (EU 2010/63) and in accordance with the German animal protection law (TierSchG), FELASA (www.felasa.eu/guidelines.php), the national animal welfare body GV-SOLAS (www.gv-solas.de/index.html) guide for the care and use of laboratory animals, and were approved by the animal welfare committee of the University of Freiburg and by the Comite d&#8217;Ethique en Matiere d&#8217;Experimentation Animale de Strasbourg (CREMEAS, CEEA35), as well as local authoriti...

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All the authors declare no conflicts of interest.

The CDM model represents a relevant and established model for testing the anti-depressive potency of new interventions and opens an extended time window for molecular or electrophysiological experiments to elucidate the pathophysiology of depression. Especially when combined with other tests to assess a depression-like state, CDM has a high face and concept validity. It combines subchronic stress and acquired helplessness for induction and produces a long-lasting depressive-like state. It is insensitive to the single app...

Affective disorders, such as major depressive disorder, are among the most frequent and challenging mental illnesses and are associated with high individual suffering1, an increase of suicide risk2, and cause a considerable socioeconomic burden3 for society. Despite its impact, treatment options are limited, and there is an urgent need for the development of novel antidepressive interventions, especially due to the innovation crisis in psychopharmacology over the last decades. In order to understand the pathophysiology of depression and test potential new agents, rational and valid animal models are urgently needed4. For almost half a century, the classical forced swim test (FST), originally described by Porsolt5, was used as induction and read-out for screening of potential novel antidepressants. It consists of a forced swim period for 5-15 min on day 1, subsequent one-time drug application, and evaluation of the portion mice spend immobile in water in another swim period on the following day. The immobility time was considered to represent a missing natural escape behavior and was thought to correlate with the degree of a depression-like state in the mice5.
The classical FST has been heavily criticized, not only in the scientific community6,7,8 but also in public media8. Most controversies around the FST are due to the short induction and treatment periods of only 1 day in the classical paradigm. It was argued that FST represents rather an acute trauma model than a state comparable to human depression. Moreover, the Porsolt test might be suitable as a screening tool for potential antidepressive agents, but it ignores the delayed onset of action of many antidepressants.
The chronic despair model (CDM)9,10,11,12,13,14,15, which is derived from the original FST, represents a more appropriate animal model for depression. In CDM, repeated swim stress over 5 consecutive days avoids acute traumatic effects. By failing to escape from a repeated and ongoing stressful situation, mice are thought to develop a state of helplessness, surrender, and ultimately despair. This paradigm is more comparable to current psychological theories for the development of depression in humans than a single acute trauma, which is commonly experienced at the onset of a posttraumatic stress disorder. The resulting depression-like state in CDM is stable for up to 4 weeks9 and therefore opens the possibility for longer treatment periods, which are better comparable to clinical conditions, where antidepressants usually need 2-4 weeks to show a benefit16.
The evaluation of the depressive-like state should then be multidimensional. The measurement of immobility time, such as in the classical FST, is useful, but should not be used as the only outcome parameter. Various methods, which are described below, should be able to map different dimensions of a depressive state in line with symptoms usually found in depressed humans. Suitable read-out assessments could include escape behavior (immobility time9,10,17), tail suspension test (TST)9, anhedonia (classical sucrose preference test (SPT)18), motivation-oriented behavior (nose-poke sucrose preference test (NPSPT)10), expectation/exploration-behavior (response to ambiguous signal19; Y-maze test9), electrophysiology (measurements of long-term plasticity (long-term potentiation, LTP; long-term depression, LTD)20), molecular assessments (activation patterns of immediate early genes (IEGs); further stress patterns21).
Theoretically, a repeated swim test can be used to induce a depressed state without any assessment of immobility time. However, it is strongly recommended to provide at least a proof-of-concept experimental series with immobility times. Additionally, CDM represents a suitable model to assess the development of a depressive-like state by measuring immobility time during the induction phase. Specific mouse strains or mice treated before swimming can be evaluated with respect to resilience or vulnerability to stress and the induction of behavioral despair.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Beaker, 2000 mL</td>
			<td>Kimble Kimax</td>
			<td>14000-2000</td>
			<td>any vessel &#62;2000ml and diameter of 24-26 cm possible</td>
		</tr>
		<tr>
			<td>Digital Thermometer</td>
			<td>Hanna Instruments</td>
			<td>846-4708</td>
			<td>any digital thermometer possible</td>
		</tr>
		<tr>
			<td>Digitalwaage 200 g Dipse</td>
			<td>DIPSE</td>
			<td>tp200</td>
			<td>any digital scale possible</td>
		</tr>
		<tr>
			<td>Lenovo ThinkCentre V50a-24IMB AiO 11FJ00DVGE - 60,5 cm</td>
			<td>Lenovo</td>
			<td>A 908278</td>
			<td>any standard Personalcomputer possible</td>
		</tr>
		<tr>
			<td>Logitech PTZ Pro</td>
			<td>Logitech</td>
			<td>1000005246</td>
			<td>any high resolution camera possible</td>
		</tr>
		<tr>
			<td>Stopwatch ROTILABO</td>
			<td>Carl Roth</td>
			<td>L423.1</td>
			<td>any stopwatch possible</td>
		</tr>
		<tr>
			<td>Timer ROTILABO</td>
			<td>Carl Roth</td>
			<td>A802.1</td>
			<td>any timer possible</td>
		</tr>
	</tbody>
</table>

animal models of depression - chronic despair model (cdm)

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. Despite its importance, current pharmacological treatment is limited, and novel treatment options are urgently needed. One key factor in the search for potential new drugs is evaluating their anti-depressive potency in appropriate animal models. The classical Porsolt forced swim test was used for this purpose for decades to induce and assess a depressive-like state. It consists of two short periods of forced swimming: the first to induce a depressed state and the second on the following day to evaluate the antidepressant effect of the agent given in between the two swim sessions. This model might be suitable as a screening tool for potential antidepressive agents but ignores the delayed onset of action of many antidepressants. The CDM was recently established and represented a modification of the classical test with notable differences. Mice are forced to swim for 5 consecutive days, following the idea that in humans, depression is induced by chronic rather than by acute stress. In a resting period of several days (1-3 weeks), animals develop sustained behavioral despair. The standard read-out method is the measurement of immobility time in an additional delayed swim session, but several alternative methods are proposed to get a broader view of the mood status of the animal. Multiple analysis tools can be used targeting behavioral, molecular, and electrophysiological changes. The depressed phenotype is stable for at least 4 weeks, providing a time window for rapid but also subchronic antidepressant treatment strategies. Furthermore, alterations in the development of a depressive-like state can be addressed using this approach. CDM, therefore, represents a useful tool to better understand depression and to develop novel treatment interventions.

In the first swim session of the induction phase of CDM, mice usually show a mean immobility time between 190 s and 230 s, which constantly rises with every additional swim session (Figure 1A). This increase is more pronounced in the first 3 days and reaches a plateau-like phase during the last 2-3 days. The immobility-time measured on day 5 remains stable over up to 4 weeks, indicating stable behavioral despair. The antidepressant potency of an intervention ...

Watch this Scientific Journal Video about Animal Models of Depression - Chronic Despair Model CDM at JoVE.com

Animal Models of Depression - Chronic Despair Model CDM

The chronic despair mouse model (CDM) of depression consists of repetitive forced swim sessions and another delayed swim phase as a read-out. It represents a suitable model for induction of a chronic depressive-like state stable for at least 4 weeks, amendable to evaluate subchronic and acute treatment interventions.

Animal Models of Depression - Chronic Despair Model (CDM)

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. ...

The chronic despair model represents a suitable model for the induction of a chronic depressive-like state in mice in order to better understand the path of physiology of mood disorders and to evaluate potential antidepressive treatment interventions. Repetitive stress is used to induce a depressive-like state, following the idea that in humans depression is induced by chronic rather than acute stress. Since the effects of CDM induction are stable for up to four weeks, it is not only possible to investigate rapid acting antidepressants, but also substances with a delayed onset like most conventional antidepressants.Before inducing the chronic depressive-like state, visually observe the mice for abnormalities including signs of biting or barbering. Exclude the whole cage from the experimental series if an animal shows signs of injury. To perform paired parametric tests afterward, make sure that each mouse is clearly marked or labeled.Additionally weigh each mouse before starting the experiment. To perform a forced swim session, fill up a beaker or cylinder with room temperature water to a height of at least 20 centimeters from the bottom, leaving a minimum of 10 centimeters between the water surface and the upper border of the vessel. Then gently transfer the mouse into the water and set a timer for 10 minutes.To prevent the mouse from drowning, continuously observe the mouse while it is in the water from a position where it cannot see the experimenter. After 10 minutes, take the mouse out of the water by simply grabbing its tail. Gently dry the mouse with a paper towel, and put it either under a heating light or on a heating mat.Perform the forced swim session on each mouse every day for five consecutive days. After five swim sessions, transfer the animals back to their home cages and allow them to rest for at least two days. To use immobility time as read out method, record each swim session using a camera.Then watch the offline video recordings and use a stopwatch to measure the total time spent by the mouse in the three different behavioral conditions during the swim test, struggling, swimming and immobility. The animal is considered to be struggling when it actively tries to escape from the threatening situation. This involves pawing the side of the cylinder with head oriented toward the wall and moving all limbs.The water surface is typically slightly turbulent. The animal is considered to be swimming when it moves at least both hide paws and travels a distance through the water. It actively searches for a way out but does not lift its paws above the water surface or try to overcome the glass wall of the vessel.In this condition animals frequently turn around or move in circles. Lastly, the animal is considered to be in the immobility stage. If it keeps still in a freezing-like position and does not move at all, or only moves the tail, or the forepaws to keep its head above the water surface, no distance is actively traveled except for passive floating, and no directed movement of the front paws is observed.In the induction phase of the chronic despair model, during the first swim session, mice usually show a mean immobility time between 190 and 230 seconds, which then constantly increases with every additional swim session. The immobility time measured on day five remains stable over four weeks indicating stable behavioral despair. Antidepressive interventions, such as imipramine, sleep deprivation and ketamine, significantly reduce the immobility time.While sleep deprivation combined with a recovery sleep does not show a significant change of the depressive-like phenotype. Since each treatment group has different mean values of immobility time on day five, different treatments should be compared using normalized mean values instead of absolute values. If immobility time remains unchanged during all five days, the applied stress could not change the behavior relevantly, and thus these mice cannot be used to evaluate treatment effects.Other readout methods such as tail suspension test, nose poke sucrose preference test, and assessment of long term potentiation during the patch clamp technique can be used to describe a broader view of the behavioral despair of the animals. Measurement of the immobility time is an important part of the chronic despair model, but it should never be the only readout method. Multiple other assessments like the tail suspension test or sucrose preference test should be used.

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6.7K visualizações.  University of Freiburg. O modelo de desespero crônico representa um modelo adequado para a indução de um estado crônico depressivo em camundongos, a fim de entender melhor o caminho da fisiologia dos transtornos de humor e avaliar possíveis intervenções de tratamento antidepressivo. O estresse repetitivo é usado para induzir um estado depressivo, seguindo a ideia de que a depressão humana é induzida por estresse crônico e não agudo. Como os efeitos da indução do MDL são estáveis por até quatro seman...