We thank Patrice Jegouzo for the head devices and headpost development and production. We also thank P. Calvo, A. Mialot, and E. Idoux for their help in the development of previous versions of the device and VVM protocol.
This work was funded by the Centre National des Etudes Spatiales, the CNRS, and the Universit&#233; Paris Descartes. J. C. and M. B. receive support from the French ANR-13-CESA-0005-02. F. F. B. and M. B. receive support from the French ANR-15-CE32-0007.

All animal procedures followed the Paris Descartes University animal regulations.
1. Device assembly
NOTE: The device used in this protocol is a helmet-like structure fixed on mice skulls by means of an implanted headpost.
<ol>
	<li>Using a 3D printer and white opaque poly (lactic acid) (PLA) plastic, print using the design and specification files provided here (see Table of Materials) for both the device and headpost. 
	NOTE: The dimensions of the device are shown in Figure 1 and dimensions of the headpost shown in Figure 2.</li>
	<li>A striped as well as sham device are to be tested (Figure 2A11). To obtain the striped model, using black nail polish, draw 3 mm large vertical stripes on the external surface of the device. The sham condition does not require any modification to the printed device.</li>
</ol>
2. Headpost implantation surgery
All the materials used in this protocol are detailed in the materials list in the supplementary information. Steps 2.7-2.9 use the biomaterials provided in the implantation kit (see Table of Materials). Ensure the use of sterile instruments and arrange surgery and recovery in different zones. Once mastered, the implantation procedure lasts about 30 min.
<ol>
	<li>For analgesia, 30 min before the beginning of the surgery, subcutaneously inject buprenorphine (0.05 mg/kg) and put back the animal in its home cage. 
	NOTE: Buprenorphine&#39;s analgesic effects last approximately 12 h, long after the end of the procedure. In our experience, mice do not show any signs of distress related to this intervention&#160;but a subsequent dose of 0.05mg/kg buprenorphine is recommended 24h after the surgery.&#160;</li>
	<li>Anesthetize the animal in a chamber with 2.5%-3% isoflurane gas. Wait 3 min and check if the mouse is properly anesthetized by observing respiration and lack of movement inside the chamber. Pass the mouse to a nose cone on a surgical table with a heating pad and, by interdigital pinching, verify that there is no withdrawal reflex and lower the isoflurane to 1.5%.</li>
	<li>Shave the head of the mouse using an electric razor. To obtain a sterile environment, rub the shaved area with iodine solution and after with 70% alcohol. Repeat this procedure two more times.</li>
	<li>Inject lidocaine hydrochloride (2%, 2 mg/kg) under the skin of the head for local anesthesia and wait 5 min for the effects to begin. To avoid eye damage due to dryness, cover the mouse&#39;s eyes with topical ophthalmic vet ointment.</li>
	<li>With a pair of blunt forceps, grab the skin at the back of the head, and with a pair of blunt scissors (or scalpel), make a longitudinal incision of about 1.5 cm to expose the skull.</li>
	<li>With the help of a scalpel, scratch the periosteum. Be careful not to scratch too hard, as the fixation of the headpost can be compromised if the skull starts to bleed slightly.</li>
	<li>Apply a drop of the green activator on the middle of the skull. This will improve the fixation of the cement by increasing bone permeability.</li>
	<li>Prepare the cement: mix one spoon (provided in the implantation kit) of polymer with five drops of monomer and one drop of catalyzer. With the help of a brush, apply a generous amount of the cement mix between the lambda and bregma skull landmarks;</li>
	<li>Quickly place the headpost on the cement with a swiping motion going from lambda to bregma. After the headpost has been placed, reapply more cement around the inferior part to ensure that the headpost properly sticks to the skull. To guarantee proper fixation, make sure the cement is applied abundantly and that it dries before continuing to the next step. 
	NOTE: With this fixation procedure, the headpost will not come off and allow for long-term, repeated tests; in our hands, headpost removal is &#60;10%.</li>
	<li>Prepare the resin mix by applying a powder-to-liquid ratio that enables a smooth consistency of the mixture. Apply the resin where the cement was applied as well as around the headpost in order to protect its surface.</li>
	<li>Wait 3 min for the resin to dry and close the skin at the back of the ears with monofilament suture. With a cotton swab, apply diluted (10%-20%) iodine solution to the operated area. 
	NOTE: Make sure the skin does not get stuck to the resin.</li>
	<li>Turn off the anesthesia and place the animal under a red warm light to avoid hypothermia. Place moistened food and&#160;hydrogel or another water source based in gel in the cage&#39;s floor. Do not leave the mouse unattended until it regains consciousness. As soon as the animal fully recovers from the procedure (usually, 30 min to 1 h after), place it in a cage with groups of three or four to stimulate social interactions.</li>
</ol>
3. Device fixation
<ol>
	<li>48 h following the surgery, secure the custom-built head device onto the headpost.
	<ol>
		<li>Using a pair of 1.2 mm screws and a screwdriver (1.3 mm hex), align the holes in the striped device with the holes in the headpost, place the screws and secure them. To fix the sham condition, turn the device upside down and, with the back part (Figure 1A) of the device facing the rostral direction, align the holes in the device with the holes in the headpost. 
		NOTE: It is recommended that this step be done by two operators, one holding the mouse with a one-handed mouse restraint, while the other securing the device to the headpost. If the fixation is done by a single operator, the device can be placed while the mouse is under gas anesthesia.</li>
		<li>Check that the device is well-secured and cannot be removed by the animal and that the device does not apply pressure directly on the mouse&#39;s nose, which could potentially cause pain, difficulty to breath, or skin injury. 
		NOTE: It is also important to ensure the device is symmetrically inserted on the mouse face, so that eyes are completely covered by the head device. Check that the animal does not show any signs of abnormal pain or distress.</li>
	</ol>
	</li>
	<li>Leave the device on the mouse for 14 days.</li>
</ol>
4. Animal care and surveillance
<ol>
	<li>Once back in their cages, mice will exhibit certain abnormalities in behavior. At first, the animal may stay prostrated and try to remove the device using its forepaws, but this should stop after the first hour. During the next following hours, the animal will usually display difficulties orienting itself inside the cage and reaching for food and water. Therefore, during the 48 h following implantation, monitor the mice and provide easy access to water and food, by placing both directly on the cage floor, for example.</li>
	<li>Keep track of mice&#39;s weights during the duration of the protocol. Weigh the mice right after implantation and again every 24 h. Special attention should be given to animals wearing the striped device, as they normally experience body weight loss (1-2 g) during the first 48 h, but start gaining weight again at a normal pace following that initial period (see Figure 2B11).</li>
	<li>After 2 days, mice are expected to return to their regular faculties. Depending on the system used in animal facilities, the device might be preventing access to the food and water. Ensure the animal is at ease while eating and drinking or adapt the dispensing system accordingly. 
	NOTE: The range of head movements produced by the animals after a few days with the device on is not modified by the device (see Figure 211) (i.e., the range of head movements produced remains similar to natural head movements).</li>
	<li>To further ensure mice&#39;s well-being, ensure daily surveillance and apply the qualitative scale (Table 1) of well-being throughout the duration of the protocol.</li>
	<li>Remove a mouse from the ongoing protocol if one or more of the following criteria apply:
	<ol>
		<li>Mice that have a total score higher than 4 points on the aforementioned qualitative scale must immediately be excluded from the experiment (see Table 1). Regardless of the score, if the mouse does not regain its initial weight after 6 days, the procedure must be stopped.</li>
		<li>The device is not correctly fixed to the headpost if, for instance, the headpost shakes when touched or a part starts to come off. This causes the headpost to come off the mouse&#39;s head and consequently interrupts the learning, which explains why daily surveillances are necessary.</li>
		<li>When a mouse has its headpost ripped off during any part of the protocol. Due to the skull bleeding associated to this detachment, the reimplantation surgery has a low success rate and is not worth attempting.</li>
	</ol>
	</li>
</ol>
5. Removal of the device
<ol>
	<li>After the learning period (in this protocol 14 days), remove the device following the same instructions as for its fixation (section 3). As soon as the device is removed, test the mice with experiments such as video-oculography tests, or, for instance, with in vitro electrophysiology as described previously11. 
	NOTE: As soon as the device is taken off, mice are exposed back to the standard, visually unobstructed environment. Therefore, perform experiments that aim to test the learning effects of this device directly after its removal.</li>
</ol>
6. Video-oculography sessions
NOTE: Video-oculography experiments are performed to record the generated eye movements while the animal is being rotated in the dark (vestibulo-ocular reflex, VOR) or by rotating the animal&#39;s surroundings while the animal is still (optokinetic reflex, OKR). Each mouse was tested for both these reflexes before and after the adaptation protocol. For more details about the video-oculography set-up, see previously published reports12,13.&#160;In order to habituate the mice to the restrained recording conditions, the day before the beginning of the recording, place the animal on the tube at the center of the turntable for 10minutes without performing any test.
<ol>
	<li>Secure the mouse on the turntable by head-fixing it with the help of screws inserted into the headpost. Place a screen dome surrounding the animal and turn off all the lights in the room except for the optokinetic projector. 
	NOTE: Video-oculography recordings require the animal to be still and with its eyes open. Interrupt the recording session and put the animal back on its cage in case the mouse does not voluntarily keep its eyes open, or if the appearance of the eye deteriorates during the recording session. Another attempt can be made following a resting period of at least 12h.</li>
	<li>Start the OKR full-field stimulation (white dot pattern projection) and record at several different velocities in both clockwise and counter clockwise directions. As soon as the recordings are over, remove the dome.</li>
	<li>To be able to record the VOR in pitch dark, apply a drop of 2% pilocarpine to the eyes14. Wait at least 5 min for it to act and gently remove it with a cotton swab. The pilocarpine will keep the pupil constricted with a constant size throughout the measurements, allowing proper quantification of movements in the dark.</li>
	<li>Turn off all the lights in the room and add a box on top of the turntable to keep the animal in pitch dark. Start the horizontal VOR using sinusoidal angular rotations around a vertical axis with different frequencies and/or different velocities.</li>
	<li>Once the recording session is finished, return the mouse to a cage properly illuminated with an infrared lamp. The heat will prevent hypothermia caused by the secondary vasodilator effects of pilocarpine on the body of the mouse. 
	NOTE: Due to the animal being restrained, recording sessions can&#8217;t last more than 90 min. When additional test sessions are needed, let the animal rest for 24h between sessions.</li>
</ol>

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The authors declare no conflicts of interest.

The long-term sensory perturbation described here consists of a visuo-vestibular mismatch produced in freely-behaving mice. To implant the device that mice wear for 14 days, a simple and short surgery using a commercially available surgical kit is performed. Mice recover in less than 1 h from this headpost implantation procedure and show no associated signs of distress from it. Subsequently, in the given example of application of this protocol, VOR and OKR are measured using the video-oculography technique. Nonetheless, this device-induced long-term learning protocol could be used in a variety of experiments such as in vitro electrophysiology1, neuronal imaging, and various behavioral assays. The rationale behind the development of this technique was inspired by the prism-based methodology used in humans and monkeys. This technique, however, differs because it impairs rather than modifies vision. Thus, it constitutes (in its current form) an extreme case of visuo-vestibular mismatch. The authors believe that the provided technical information may be useful for designing a prism-like version of the device or further developing specific feature-restricting devices16.
Made of a light (0.9 g) poly (lactic acid) plastic, the head device was designed to fit the head of a young adult mouse, allowing protection of the snout and leaving enough space laterally to let the animal groom. The front part of this device exposes the end of the snout to permit feeding and grooming behaviors. The device is slightly opaque, so that the animal is deprived of precise vision of the surrounding but still receives luminance stimulation. The striped and sham implantations are tested to ensure that the measured effects are due primarily to the visuo-vestibular mismatch caused by the high-contrast visual signal during self-generated movements of the striped device and not by proprioceptive modification (i.e, the weight of the device applied in the mouse&#180;s head and neck).
Experimentally, mice that wore the striped device showed a significant VOR gain decrease of 50% after the learning period; still, there can be an inter-individual variability for absolute gain values. Sham mice showed no significant VOR gain alterations, thus demonstrating that the VOR reduction is caused by the sensory conflict and not by motor impairment. Furthermore, young mice (&#60;P26) showed VOR and OKR gain values lower than older animals17. For that reason, animal age has to be taken into account while planning the experiment. Finally, the aforementioned mice exclusion criteria (section 4.5) are a crucial step that should be followed to ensure well-being as well as establish reliable results.
One of the advantages of this protocol is the time that it saves experimenters during the learning period, compared to other types of VOR/OKR adaptation protocols. So far, VOR adaptation in mice has been studied by head-fixing and training the animal on a rotating turntable6,8,18,19, which is time-consuming, especially when a lot of animals must be trained. The presented protocol allows the training of several animals at once and saves time. In addition, in these classical experiments the trainings are typically limited to 1 h per day, leaving long periods of putative unlearning that cause adaptation to be an iterated alternation of learning/unlearning with different dynamics20. Here, the head-fixation of the device allows for uninterrupted learning. Another advantage is that since the learning period is generated in a freely behaving head-free situation, mice are able to learn through a range of natural head movements that are actively generated. In the classical protocols, the animal is head-fixed while being passively rotated on the turntable so that the learning occurs at a determined stimulation (one frequency, one velocity)21 that does not reflect the natural range of head movements. It is important to note that the vestibular system encodes movements differently when they are actively generated by the subject or when externally applied10; thus, the cellular mechanisms triggered in both situations may also differ.
Overall, the described methodology is suitable for combined in vivo/in vitro studies on long-term sensory adaptations occurring after a visual conflict and/or visuo-vestibular mismatch in freely behaving mice. Sensory conflicts are a recognized cause of motion sickness, which is a field that has recently attracted use of mice22,23. It was recently demonstrated that the gain adaptation caused by the use of this device offers protection against motion sickness when mice are exposed to a provocative stimulus15. Hence, this protocol could be used to identify the cellular mechanisms underlying adaptation to a sensory conflict as well as to develop anti-motion sickness treatments.

Sensory conflicts, such as visual ones, are present in daily life, for instance, when one wears glasses or during an entire lifespan (developmental growth, changes in sensory acuity, etc.). Due to a well-described circuit anatomy, easily controlled sensory inputs, quantifiable motor outputs, and precise quantification methods1, gaze stabilization reflexes have been used as models of motor learning in many species. In humans and monkeys, the vestibulo-ocular reflex (VOR) adaptation is studied through the use of prisms that the subject wears for several days2,3,4,5. Since the rodent model allows the combination of behavioral and cellular experiments, we developed a new method to create long-term sensory conflict in freely behaving mice with a helmet-like device. Inspired by the methodology used in humans and monkeys, the protocol generates a mismatch between the vestibular and visual inputs (i.e., visuo-vestibular mismatch, VVM) that leads to a decrease in VOR gain.
Classical protocols triggering a VOR gain-down adaptation in rodents consist of rotating the head-fixed animal on a turntable while rotating the visual field in phase. This paradigm creates a visuo-vestibular conflict, which makes the VOR counter-productive. Long-term adaptation protocols consist of an iteration of this procedure over the course of several consecutive days6,7,8. As a result, when a large group of animals needs to be tested, classical methodology requires a great amount of time. In addition, because the animal is head-fixed, the learning is mostly limited to a discrete frequency/velocity and consist of discontinuous trainings interrupted by intertrial intervals of variable duration6. Finally, classical protocols use passive learning, as the vestibular stimulation is not actively generated by the animal&#39;s voluntary movements, a situation that greatly shapes vestibular processing9,10.
The aforementioned experimental constraints are surpassed by the presented innovative methodology. The required surgical approach is straightforward, and the materials used are readily available commercially. The sole part that relies on more expensive material is the quantification of the behavior; nonetheless, the fundamentals of the protocol may be used for any experiment, from in vitro investigations to other behavioral studies of learning. Overall, by generating a temporary visual impairment and a visuo-vestibular conflict over several days, this methodology can easily be transposed to any study concerned with sensory perturbation or motor learning.

<table><tbody><tr><td>3D printer</td><td>Ulimaker, USA</td><td>S5</td><td></td></tr><tr><td>Blunt scissors</td><td>FST</td><td>14079-10</td><td></td></tr><tr><td>Catalyst V</td><td>Sun Medical, Japan</td><td>LX22</td><td>Parkell bio-materials, Kit n&amp;deg;S380</td></tr><tr><td>Dentalon Plus</td><td>Heraeus</td><td>37041</td><td></td></tr><tr><td>Eyetracking system and software</td><td>Iscan</td><td>ETN200</td><td></td></tr><tr><td>Green activator</td><td>Sun Medical, Japan</td><td>VE-1</td><td>Parkell bio-materials, Kit n&amp;deg;S380</td></tr><tr><td>Monomer</td><td>Sun Medical, Japan</td><td>MF-1</td><td>Parkell bio-materials, Kit n&amp;deg;S380</td></tr><tr><td>Ocrygel</td><td>TvmLab</td><td>10779</td><td>Ophtalmic vet ointment</td></tr><tr><td>Polymer L-type clear (cement)</td><td>Sun Medical, Japan</td><td>TT12F</td><td>Parkell bio-materials, Kit n&amp;deg;S380</td></tr><tr><td>Sketchup</td><td>Trimble</td><td></td><td>3D modeling software used for the device&#039;s ready-to-print design file</td></tr><tr><td>Turntable</td><td></td><td></td><td>Not commercially available</td></tr></tbody></table>

long-term sensory conflict in freely behaving mice

Long-term sensory conflict protocols are a valuable means of studying motor learning. The presented protocol produces a persistent sensory conflict for experiments aimed at studying long-term learning in mice. By permanently wearing a device fixed on their heads, mice are continuously exposed to a sensory mismatch between visual and vestibular inputs while freely moving in home cages. Therefore, this protocol readily enables the study of the visual system and multisensory interactions over an extended timeframe that would not be accessible otherwise. In addition to lowering the experimental costs of long-term sensory learning in naturally behaving mice, this approach accommodates the combination of in vivo and in vitro experiments. In the reported example, video-oculography is performed to quantify the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) before and after learning. Mice exposed to this long-term sensory conflict between visual and vestibular inputs presented a strong VOR gain decrease but exhibited few OKR changes. Detailed steps of device assembly, animal care, and reflex measurements are hereby reported.

The following figures illustrate the results obtained with mice that underwent the 2 week adaptation protocol wearing either a striped or sham device. Figure 3 shows an example of raw traces seen during recording sessions. As shown by comparing the traces, the VOR response decreases after the VVM protocol (Figure 3A, before vs. after striped). The VOR of sham mice remained unaltered after the adaptation (Figure 3A, before vs. after sham). The OKR of mice wearing the striped device (Figure 3B) is comparable to the period prior to the VVM protocol and to sham mice. Figure 4 shows a quantification example of the mean VOR gains at a fixed frequency of 0.5 Hz and at 40 degrees per second, before and after the VVM protocol, for both striped and sham devices. There is a strong gain decrease after mice wore the striped device, while the sham mice did not have significant gain changes. Effects of VOR decrease tested at different velocities/frequencies have been reported by Carcaud et al.11 and Idoux et al.15.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/59135/59135fig1.jpg" /> 
Figure 1: Head device depicted with dimensions, in millimeters. Views: (A) back, (B) side, (C) bottom, and (D) aerial. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/59135fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/59135/59135fig2.jpg" /> 
Figure 2: Headpost depicted with dimensions, in millimeters. Fixed in the implantation surgery, this light (0.2 g) poly (lactic acid) plastic headpost allows the locking of the adaptation device to the mouse and head-fixing of the animal on the turntable during the video-oculography sessions. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/59135fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/59135/59135fig3v2.jpg" /> 
Figure 3: Example raw traces of eye movements during VOR and OKR stimulations. (A, left) Left: VOR performed at 0.5 Hz at 40 &#176;/s and (B, right) optokinetic stimulation at a constant velocity of 10 &#176;/s (black line), in a clockwise direction, before (green lines) and after (yellow) wearing the striped or sham (purple) device. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/59135fig3v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/59135/59135fig4v2.jpg" /> 
Figure 4: Example mean VOR and OKR gain values after adaptation to either striped or sham device. Gains were plotted according to time (days) for the striped (n = 10) and sham (n = 6) devices at stimulations of 40&#176;/s and 0.5 Hz for the VOR (left), and 10 &#176;/s clockwise direction for the OKR (right). On the timescale, &#34;before&#34; day represents the day immediately prior to the adaptation and &#34;day 0&#34; represents the day when the device is removed. Error bars represent the standard deviation, ***p &#60; 0.001, not significant. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/59135fig4v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table fo:keep-together.within-page="1">
	<tbody>
		<tr>
			<td>Points</td>
			<td>Body weight alterations</td>
			<td>Physical appearance</td>
			<td>Behavior</td>
		</tr>
		<tr>
			<td>0</td>
			<td>none or weight gain</td>
			<td>standard</td>
			<td>no signs of distress and normal locomotion</td>
		</tr>
		<tr>
			<td>1</td>
			<td>weight loss &#60;10%</td>
			<td>no body grooming</td>
			<td>impaired locomotion or cage orientation</td>
		</tr>
		<tr>
			<td>2</td>
			<td>weight loss between 10%-20%</td>
			<td>dehydration</td>
			<td>--</td>
		</tr>
		<tr>
			<td>3</td>
			<td>weight loss &#62;20%</td>
			<td>wounds</td>
			<td>nervous ticks (e.g. scratching, biting)</td>
		</tr>
	</tbody>
</table>
Table 1: Qualitative scale for the well-being assessment. Listed are the qualitative parameters that must be assessed during the duration of the protocol. The sum weight alterations, physical appearance, and behavior scores should not be greater than four points.
Supplemental File 1. Device.stl.&#160;<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/Device.stl" target="_blank">Please click here to download this file.</a>
Supplemental File 2. Headpost.stl.&#160;<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59135/Headpost.stl" target="_blank">Please click here to download this file.</a>

Watch this Scientific Journal Video about Long-term Sensory Conflict in Freely Behaving Mice at JoVE.com

Long-term Sensory Conflict in Freely Behaving Mice

The presented protocol produces a persistent sensory conflict for experiments aimed at studying long-term learning. By permanently wearing a fixed device on their heads, mice are continuously exposed to a sensory mismatch between visual and vestibular inputs while freely moving in home cages.

Long-term sensory conflict protocols are a valuable means of studying motor learning. The presented protocol produces a persistent sensory conflict for ...

long-term-sensory-conflict-in-freely-behaving-mice

Nanyang Technological University

Research

JoVE Journal

Neuroscience

6.6K Views.  CNRS. Het algemene doel van dit protocol is het produceren van een hardnekkig zintuiglijk conflict voor de studie van langdurig leren bij vrij gedragende muizen. Door de experimentele kosten en tijd van zintuiglijk leren te verlagen, is deze aanpak geschikt voor de combinatie van in vivo en in vitro experimenten. Na bevestiging van een gebrek aan reactie op teen knijpen in een verdoofde muis, gebruik maken van een paar stompe tangen om de huid te grijpen aan de achterkant van het hoofd en gebruik s...

Video: Long-term Sensory Conflict in Freely Behaving Mice

Low-stress Route Learning Using the Lashley III Maze in Mice

Many behavior tests designed to assess learning and memory in rodents, particularly mice, rely on visual cues, food and/or water deprivation, or other aversive stimuli to motivate task acquisition. As animals age, sensory modalities deteriorate. For example, many strains of mice develop hearing deficits or cataracts. Changes in the sensory systems required to guide mice during task acquisition present potential confounds in interpreting learning changes in aging animals. Moreover, the use of aversive stimuli to motivate animals to learn tasks is potentially confounding when comparing mice with differential sensitivities to stress. To minimize these types of confounding effects, we have implemented a modified version of the Lashley III maze. This maze relies on route learning, whereby mice learn to navigate a maze via repeated exposure under low stress conditions, e.g. dark phase, no food/water deprivation, until they navigate a path from the start location to a pseudo-home cage with 0 or 1 error(s) on two consecutive trials. We classify this as a low-stress behavior test because it does not rely on aversive stimuli to encourage exploration of the maze and learning of the task. The apparatus consists of a modular start box, a 4-arm maze body, and a goal box. At the end of the goal box is a pseudo-home cage that contains bedding similar to that found in the animal&#x2019;s home cage and is specific to each animal for the duration of maze testing. It has been demonstrated previously that this pseudo-home cage provides sufficient reward to motivate mice to learn to navigate the maze1. Here, we present the visualization of the Lashley III maze procedure in the context of evaluating age-related differences in learning and memory in mice along with a comparison of learning behavior in two different background strains of mice. We hope that other investigators interested in evaluating the effects of aging or stress vulnerability in mice will consider this maze an attractive alternative to behavioral tests that involve more stressful learning tasks and/or visual cues.

The Lashley III maze is a route-learning task that does not rely on aversive stimuli or visual cues. It is thus a highly attractive option for evaluating learning and memory, especially in aging mice or otherwise where stress is a consideration.

Many behavior tests designed to assess learning and memory in rodents, particularly mice, rely on visual cues, food and/or water deprivation, or other ...

T-maze Forced Alternation and Left-right Discrimination Tasks for Assessing Working and Reference Memory in Mice

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in rodents. In our laboratory, we evaluated the two types of memory in more than 30 strains of genetically engineered mice using the automated version of this apparatus. Here, we present the modified T-maze apparatus operated by a computer with a video-tracking system and our protocols in a movie format. The T-maze apparatus consists of runways partitioned off by sliding doors that can automatically open downward, each with a start box, a T-shaped alley, two boxes with automatic pellet dispensers at one side of the box, and two L-shaped alleys. Each L-shaped alley is connected to the start box so that mice can return to the start box, which excludes the effects of experimenter handling on mouse behavior. This apparatus also has an advantage that in vivo microdialysis, in vivo electrophysiology, and optogenetics techniques can be performed during T-maze performance because the doors are designed to go down into the floor. In this movie article, we describe T-maze tasks using the automated apparatus and the T-maze performance of &alpha;-CaMKII+/- mice, which are reported to show working memory deficits in the eight-arm radial maze task. Our data indicated that &alpha;-CaMKII+/- mice showed a working memory deficit, but no impairment of reference memory, and are consistent with previous findings using the eight-arm radial maze task, which supports the validity of our protocol. In addition, our data indicate that mutants tended to exhibit reversal learning deficits, suggesting that &alpha;-CaMKII deficiency causes reduced behavioral flexibility. Thus, the T-maze test using the modified automatic apparatus is useful for assessing working and reference memory and behavioral flexibility in mice.

This article presents the protocol of T-maze tests using a modified automated apparatus for assessing the learning and memory functions in mice.

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in ...

A Behavioral Assay for Investigating the Role of Spatial Memory During Instinctive Defense in Mice

Evolution has selected a repertoire of defensive behaviors that are essential for survival across all animal species. These behaviors are often stereotyped actions elicited in response to innately aversive sensory stimuli, but their success requires enough flexibility for adapting to different spatial environments, which can change rapidly. Here, we describe a behavioral assay to evaluate the influence of learned spatial knowledge on defensive behaviors in mice. We have adapted the widely used Barnes maze spatial memory assay to investigate how mice navigate to a shelter during escape responses to innately aversive sensory stimuli in a novel environment, and how they adapt to acute changes in the environment. This new assay is an ethological paradigm that does not require training and exploits the natural exploration patterns and navigation strategies in mice. We propose that the set of protocols described here are a powerful means of studying goal-directed behaviors and stimulus-triggered navigation, which should be of interest to both the fields of instinctive behaviors and spatial memory.

This protocol describes a behavioral assay, based on the Barnes maze test, to study how instinctive defensive actions are modified by the knowledge of spatial environment.

Evolution has selected a repertoire of defensive behaviors that are essential for survival across all animal species. These behaviors are often ...

Behavior

Analyzing Spatial Learning and Prosocial Behavior in Mice Using the Barnes Maze and Damsel-in-Distress Paradigms

The Barnes maze is a reliable measure of spatial learning and memory that does not require food restriction or exposure to extremely stressful stimuli. The Barnes maze can also assess other mouse behaviors, such as general motivation to escape from the maze platform and exploratory behavior. The Barnes maze can measure whether a genetic mutation or environmental variable can impact the acquisition and retention of spatial memories, as well as provide information about the search strategy employed by the mice. Here we use the Barnes maze to detect a memory deficit in adult mice following a single developmental ethanol exposure event. The newly described Damsel-in-Distress paradigm exposes a male mouse to a female mouse trapped in a chamber in the open center field of the arena. It provides an opportunity for the mouse to socially respond to the trapped female and exhibit prosocial behavior. The Damsel-in-Distress paradigm can also be used to examine mouse behavior in a novel arena and measure locomotor activity. Both the Barnes Maze and the Damsel-in-Distress protocols require minimal financial investment and most aspects of the tests can be constructed from common lab supplies. These flexible and accessible tools can also be used to detect behavioral changes over the course of development.

This protocol measures spatial learning and memory using the Barnes maze. A novel Damsel-in-Distress paradigm is used to assess locomotor activity and prosocial behavior in mice.

The Barnes maze is a reliable measure of spatial learning and memory that does not require food restriction or exposure to extremely stressful stimuli. ...

Novel Object Recognition and Object Location Behavioral Testing in Mice on a Budget

Ethologically relevant behavioral testing is a critical component of any study that uses mouse models to study the cognitive effects of various physiological or pathological changes. The object location task (OLT) and the novel object recognition task (NORT) are two effective behavioral tasks commonly used to reveal the function and relative health of specific brain regions involved in memory. While both of these tests exploit the inherent preference of mice for the novelty to reveal memory for previously encountered objects, the OLT primarily evaluates spatial learning, which relies heavily on hippocampal activity. The NORT, in contrast, evaluates non-spatial learning of object identity, which relies on multiple brain regions. Both tasks require an open-field-testing arena, objects with equivalent intrinsic value to mice, appropriate environmental cues, and video recording equipment and the software. Commercially available systems, while convenient, can be costly. This manuscript details a simple, cost-effective method for building the arenas and setting up the equipment necessary to perform the OLT and NORT. Furthermore, the manuscript describes an efficient testing protocol that incorporates both OLT and NORT and provides typical methods for data acquisition and analysis, as well as representative results. Successful completion of these tests can provide valuable insight into the memory function of various mouse model systems and appraise the underlying neural regions that support these functions.

Here we provide a protocol which includes comprehensive instructions for the economical establishment of murine object location and novel object recognition behavioral testing, including the design, cost, and construction of required equipment as well as execution of behavioral testing, data collection, and analysis.

Ethologically relevant behavioral testing is a critical component of any study that uses mouse models to study the cognitive effects of various ...

Two Different Real-Time Place Preference Paradigms Using Optogenetics within the Ventral Tegmental Area of the Mouse

Understanding how neuronal activation leads to specific behavioral output is fundamental for modern neuroscience. Combining optogenetics in rodents with behavioral testing in validated paradigms allows the measurement of behavioral consequences upon stimulation of distinct neurons in real-time with high spatial and temporal selectivity, and thus the establishment of causal relationships between neuronal activation and behavior. Here, we describe a step-by-step protocol for a real-time place preference (RT-PP) paradigm, a modified version of the classical conditioned place preference (CPP) test. The RT-PP is performed in a three-compartment apparatus and can be utilized to answer if optogenetic stimulation of a specific neuronal population is rewarding or aversive. We also describe an alternative version of the RT-PP protocol, the so-called neutral compartment preference (NCP) protocol, which can be used to confirm aversion. The two approaches are based on extensions of classical methodology originating from behavioral pharmacology and recent implementation of optogenetics within the neuroscience field. Apart from measuring place preference in real time, these setups can also give information regarding conditioned behavior. We provide easy-to-follow step-by-step protocols alongside examples of our own data and discuss important aspects to consider when applying these types of experiments.

Here we present two easy-to-follow step-by-step protocols for place preference paradigms using optogenetics in mice. Using these two different setups, preference and avoidance behaviors can be solidly assessed within the same apparatus with high spatial and temporal selectivity, and in a straightforward manner.

Understanding how neuronal activation leads to specific behavioral output is fundamental for modern neuroscience. Combining optogenetics in rodents with ...

Optogenetic Manipulation of Neuronal Activity to Modulate Behavior in Freely Moving Mice

Optogenetic modulation of neuronal circuits in freely moving mice affects acute and long-term behavior. This method is able to perform manipulations of single neurons and region-specific transmitter release, up to whole neuronal circuitries in the central nervous system, and allows the direct measurement of behavioral outcomes. Neurons express optogenetic tools via an injection of viral vectors carrying the DNA of choice, such as Channelrhodopsin2 (ChR2). Light is brought into specific brain regions via chronic optical implants that terminate directly above the target region. After two weeks of recovery and proper tool-expression, mice can be repeatedly used for behavioral tests with optogenetic stimulation of the neurons of interest.
Optogenetic modulation has a high temporal and spatial resolution that can be accomplished with high cell specificity, compared to the commonly used methods such as chemical or electrical stimulation. The light does not harm neuronal tissue and can therefore be used for long-term experiments as well as for multiple behavioral experiments in one mouse. The possibilities of optogenetic tools are nearly unlimited and enable the activation or silencing of whole neurons, or even the manipulation of a specific receptor type by light.
The results of such behavioral experiments with integrated optogenetic stimulation directly visualizes changes in behavior caused by the manipulation. The behavior of the same animal without light stimulation as a baseline is a good control for induced changes. This allows a detailed overview of neuronal types or neurotransmitter systems involved in specific behaviors, such as anxiety. The plasticity of neuronal networks can also be investigated in great detail through long-term stimulation or behavioral observations after optical stimulation. Optogenetics will help to enlighten neuronal signaling in several kinds of neurological diseases.

With optogenetic manipulation of specific neuronal populations or brain regions, behavior can be modified with high temporal and spatial resolution in freely moving animals. By using different optogenetic tools in combination with chronically implanted optical fibers, a variety of neuronal modulations and behavioral testing can be performed.

Optogenetic modulation of neuronal circuits in freely moving mice affects acute and long-term behavior. This method is able to perform manipulations of ...

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.

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 ...

Investigating Migraine-Like Behavior Using Light Aversion in Mice

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as photophobia. Whilst it is impossible to confirm that a mouse is experiencing migraine, light aversion can be used as a behavioral surrogate for the migraine symptom of photophobia. To test for light aversion, we utilize the light/dark assay to measure the time mice freely choose to spend in either a light or dark environment. The assay has been refined by introducing two critical modifications: pre-exposures to the chamber prior to running the test procedure and adjustable chamber lighting, permitting the use of a range of light intensities from 55 lux to 27,000 lux. Because the choice to spend more time in the dark is also indicative of anxiety, we also utilize a light-independent anxiety test, the open field assay, to distinguish anxiety from light-aversive behavior. Here, we describe a modified test paradigm for the light/dark and open field assays. The application of these assays is described for intraperitoneal injection of calcitonin gene-related peptide (CGRP) in two mouse strains and for optogenetic brain stimulation studies.

Rodents are not able to report migraine symptoms. Here, we describe a manageable test paradigm (light/dark and open field assays) to measure light aversion, one of the most common and bothersome symptoms in patients with migraines.

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as ...

Assessment of Mouse Judgment Bias through an Olfactory Digging Task

Judgment biases (JB) are differences in the way that individuals in positive and negative affective/emotional states interpret ambiguous information. This phenomenon has long been observed in humans, with individuals in positive states responding to ambiguity 'optimistically' and those in negative states instead showing 'pessimism'. Researchers aiming to assess animal affect have taken advantage of these differential responses, developing tasks to assess judgment bias as an indicator of affective state. These tasks are becoming increasingly popular across diverse species and fields of research. However, for laboratory mice, the most widely used vertebrates in research and a species heavily relied upon to model affective disorders, only one JB task has been successfully validated as sensitive to changes in affective state. Here, we provide a detailed description of this novel murine JB task, and evidence of its sensitivity to mouse affect. Though refinements are still necessary, assessment of mouse JB opens the door for answering both practical questions regarding mouse welfare, and fundamental questions about the impact of affective state in translational research.

This article provides a detailed description of a novel mouse judgment bias protocol. Evidence of this olfactory digging task's sensitivity to affective state is also demonstrated and its utility across diverse research fields is discussed.

Judgment biases (JB) are differences in the way that individuals in positive and negative affective/emotional states interpret ambiguous information. This ...

Long-term Sensory Conflict in Freely Behaving Mice

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