This study was supported in part by an Israel Science Foundation (ISF) grant (297/18). The authors thank M. Bronfeld for establishing the acute rodent model and M. Israelashvili for her comments.

<ol>
	<li>American Psychiatric Association. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=DSM-5.">DSM-5.</a> American Psychiatric Association. , (2013).</li><li>Peterson, B. S., Leckman, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+temporal+dynamics+of+tics+in+Gilles+de+la+Tourette+syndrome.">The temporal dynamics of tics in Gilles de la Tourette syndrome.</a> Biol.Psychiatry. 44, 1337-1348 (1998).</li><li>Ganos, 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=The+somatotopy+of+tic+inhibition:+where+and+how+much.">The somatotopy of tic inhibition: where and how much.</a> Movement Disorders. , (2015).</li><li>Barnea, 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=Subjective+versus+objective+measures+of+tic+severity+in+Tourette+syndrome+-+The+influence+of+environment.">Subjective versus objective measures of tic severity in Tourette syndrome - The influence of environment.</a> Psychiatry Research. 242, 204-209 (2016).</li><li>Silva, R. R., Munoz, D. M., Barickman, J., Friedhoff, A. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Environmental+Factors+and+Related+Fluctuation+of+Symptoms+in+Children+and+Adolescents+with+Tourette's+Disorder.">Environmental Factors and Related Fluctuation of Symptoms in Children and Adolescents with Tourette's Disorder.</a> Journal of Child Psychology and Psychiatry. 36 (2), 305-312 (1995).</li><li>Rothenberger, 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=Sleep+and+Tourette+syndrome.">Sleep and Tourette syndrome.</a> Advances in Neurology. 85, 245-259 (2001).</li><li>Conelea, C. a., Woods, D. W., Brandt, B. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+impact+of+a+stress+induction+task+on+tic+frequencies+in+youth+with+Tourette+Syndrome.">The impact of a stress induction task on tic frequencies in youth with Tourette Syndrome.</a> Behaviour Research and Therapy. 49 (8), 492-497 (2011).</li><li>Ganos, C., Rothwell, J., Haggard, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Voluntary+inhibitory+motor+control+over+involuntary+tic+movements.">Voluntary inhibitory motor control over involuntary tic movements.</a> Movement Disorders. 33 (6), 937-946 (2018).</li><li>Yael, D., Vinner, E., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pathophysiology+of+tic+disorders.">Pathophysiology of tic disorders.</a> Movement Disorders. 30 (9), 1171-1178 (2015).</li><li>Kurvits, L., Martino, D., Ganos, C., Eddy, C. 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W., Bronfeld, M., Belelovsky, K., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+neurophysiological+correlates+of+motor+tics+following+focal+striatal+disinhibition.">The neurophysiological correlates of motor tics following focal striatal disinhibition.</a> Brain. 132 (8), 2125-2138 (2009).</li><li>Worbe, Y., 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=Behavioral+and+movement+disorders+induced+by+local+inhibitory+dysfunction+in+primate+striatum.">Behavioral and movement disorders induced by local inhibitory dysfunction in primate striatum.</a> Cerebral Cortex. 19 (8), 1844-1856 (2009).</li><li>Pogorelov, V., Xu, M., Smith, H. R., Buchanan, G. F., Pittenger, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Corticostriatal+interactions+in+the+generation+of+tic-like+behaviors+after+local+striatal+disinhibition.">Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition.</a> Experimental Neurology. 265, 122-128 (2015).</li><li>Bronfeld, M., Yael, D., Belelovsky, K., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Motor+tics+evoked+by+striatal+disinhibition+in+the+rat.">Motor tics evoked by striatal disinhibition in the rat.</a> Frontiers in Systems Neuroscience. 7, 50 (2013).</li><li>Vinner, E., Israelashvili, M., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prolonged+striatal+disinhibition+as+a+chronic+animal+model+of+tic+disorders.">Prolonged striatal disinhibition as a chronic animal model of tic disorders.</a> Journal of Neuroscience Methods. 292, 20-29 (2017).</li><li>Paxinos, G., Watson, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The Rat Brain in Stereotaxic Coordinates. 6, (2007).</li><li>Flecknell, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Analgesia+and+Post-Operative+Care.">Analgesia and Post-Operative Care.</a> Laboratory Animal Anaesthesia. , (2016).</li><li>Israelashvili, M., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Corticostriatal+divergent+function+in+determining+the+temporal+and+spatial+properties+of+motor+tics.">Corticostriatal divergent function in determining the temporal and spatial properties of motor tics.</a> Journal of Neuroscience. 35 (50), 16340-16351 (2015).</li><li>Bronfeld, M., Belelovsky, K., Bar-Gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spatial+and+temporal+properties+of+tic-related+neuronal+activity+in+the+cortico-basal+ganglia+loop.">Spatial and temporal properties of tic-related neuronal activity in the cortico-basal ganglia loop.</a> Journal of Neuroscience. 31 (24), 8713-8721 (2011).</li><li>McCairn, K. 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=A+Primary+Role+for+Nucleus+Accumbens+and+Related+Limbic+Network+in+Vocal+Tics.">A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.</a> Neuron. 89 (2), 300-307 (2016).</li><li>Rizzo, F., 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=Aripiprazole+Selectively+Reduces+Motor+Tics+in+a+Young+Animal+Model+for+Tourette's+Syndrome+and+Comorbid+Attention+Deficit+and+Hyperactivity+Disorder.">Aripiprazole Selectively Reduces Motor Tics in a Young Animal Model for Tourette's Syndrome and Comorbid Attention Deficit and Hyperactivity Disorder.</a> Frontiers in Neurology. 9, 1-11 (2018).</li><li>Vinner, E., Matzner, A., Belelovsky, K., Bar-gad, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dissociation+of+tic+expression+from+its+neuronal+encoding+in+the+striatum+during+sleep.">Dissociation of tic expression from its neuronal encoding in the striatum during sleep.</a> bioRxiv. , (2020).</li><li>Webster, K. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cortico-striate+interrelations+in+the+albino+rat.">Cortico-striate interrelations in the albino rat.</a> Journal of Anatomy. 95, 532-544 (1961).</li><li>Ebrahimi, A., Pochet, R., Roger, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Topographical+organization+of+the+projections+from+physiologically+identified+areas+of+the+motor+cortex+to+the+striatum+in+the+rat.">Topographical organization of the projections from physiologically identified areas of the motor cortex to the striatum in the rat.</a> Neuroscience Research. 14, 39-60 (1992).</li><li>Brown, L. L., Sharp, F. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metabolic+mapping+of+rat+striatum:+somatotopic+organization+of+sensorimotor+activity.">Metabolic mapping of rat striatum: somatotopic organization of sensorimotor activity.</a> Brain Research. 686, 207-222 (1995).</li><li>Brown, L. L., Smith, D. M., Goldbloom, L. 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The authors have nothing to disclose.

In this manuscript, we detailed the protocols of the acute and chronic models for tic induction in a freely behaving rat. These protocols describe the preparation of all components, the surgery and the experimental process which can be adapted for customization to meet specific research needs. The primary principle underlying these models is the direct local application of bicuculline to the motor areas of the striatum, which is known to play a key role in the pathophysiology of tic disorders10,11,12. In both models, bicuculline is delivered to the target through custom-made implanted cannulas. The specific cannula implantation target depends on the desired body location of tic expression. The striatum is somatotopically organized27,28,29,30. Application of bicuculline to its anterior parts leads to tic expression in the forelimb, jaw, and head, whereas its application to the posterior parts results in hindlimb tics18. Moreover, application to the ventral striatum (nucleus accumbens &#8211; NAc) leads to hyperactivity31. The models enable the implantation of cannulas in both hemispheres and in both striatal targets for simultaneous injection to produce bilateral symptoms. This method is not only applicable to tic expression models, but also valid in other neuroscience models that require injection of neuroactive compounds.
In the acute model, we suggest implanting the cannula 2 mm (0.079&#39;&#39;) above the injection target to prevent tissue damage to the target area. To minimize subsequent damage by the injection-cannula, we use a thin 30 G tube to reach the final target. Note that multiple injections to the same target will eventually lead to tissue necrosis from mechanical stress, which will cause decreased tic expression. One possible solution is to insert the injector to deeper targets during the subsequent injections, as long as they remain localized in the motor areas of the striatum. This tissue necrosis does not occur in the chronic model, since the bicuculline infusion is ongoing through a static directly implanted infusion-cannula into the striatal target. To minimize potential tissue damage from chronic infusion-cannula implantation, we also used a 30 G tube. However, to connect the infusion-cannula to the flow-moderator via flexible-catheter tubing, we needed to use a tubing-adapter, creating a potential failing point in the process. Thicker flexible-catheter tubing can be used to fit the flow-moderator, leading to a reasonable cost of a larger tissue damage from the larger infusion-cannula.
Ongoing research over the last 10 years has enabled us to define specific concentrations and delivery rates of bicuculline15,18,22,23, resulting in a reproducible behavioral phenomenon of observable tic expression. Deviation from these values towards higher volumes, concentrations or injection rates, may cause episodic seizures15,18,32 and unilateral rotations of the rats. Lower concentrations result in more subtle, less detectable tics, expressed over shorter periods of time. In the chronic model, no seizures were observed throughout the whole period; however, extensive tic expression and tendency to unilateral rotations were observed on the first day after the bicuculline-filled pump implantation, which stabilized during the second day. This, combined with post brain surgery recovery, interferes with the animal&#8217;s comfort level and wellbeing. To dissociate the recovery period from tic expression, we suggest implanting an ACSF-filled pump first19. This period of ACSF infusion can also be used to conduct control experiments prior to tic induction. Control experimental sessions may also be carried out in the acute model, utilizing ACSF injections18,33.
Both the acute and the chronic models can be used to study the kinematic characteristics and neural correlates of tic expression. Tics can be identified by frame-by-frame offline video analysis, which however is time-consuming and less accurate. More sensitive evaluation methods include electromyography (EMG) and kinematic sensors (accelerometer and gyroscopes) (Figure 4). For this purpose, the kinematic devices need to be located near the tic-expressing site on the body for accurate movement assessment. The neural correlates of tic expression may be captured by neurophysiological recordings throughout the CBG pathway (Figure 4). When considering the implantation of additional recording devices, their locations both inside and outside the brain need to be planned carefully to prevent interference with the injection.
The nature of the experimental query should dictate the choice of model of tic expression. The acute model is simple and easy to implement. Multiple transient injections can be conducted over a relatively long period of time, can be run simultaneously in several brain regions and enable combining control and experimental sessions. The chronic model is more complicated and requires daily monitoring of the rat&#39;s wellbeing. Yet, the constant and prolonged bicuculline application provides the opportunity to address the dynamics of tic expression and its modulation over time.

Tics are the defining symptom of Tourette syndrome (TS) and other tic disorders. Tics are described as sudden, rapid, recurrent movements (motor tics), or vocalizations (vocal tics)1. Tic expression typically fluctuates in its temporal (frequency)2 and spatial (intensity, body location)3 properties over multiple time scales (hours, days, months, and years). These changes are affected by different factors, such as environmental features4,5, behavioral states6,7, and voluntary and temporary suppression8.
Although the neuronal mechanism governing motor tics is still not fully understood, an increasing number of theoretical and experimental studies have provided new evidence as to its nature9. Currently, the pathophysiology of tic generation is thought to involve the cortico-basal ganglia (CBG) loop, and specifically is associated with abnormal inhibition of the striatum, the primary basal ganglia input nucleus10,11,12. Previous studies in rodents and primates have demonstrated that the striatum can be disinhibited by local application of different GABAA antagonists, such as bicuculline and picrotoxin13,14,15,16,17,18. This pharmacological intervention leads to transient motor tic expression in the contralateral side to the injection, thus establishing a robust acute model of tic disorders with face and construct validity. The acute model is simple to induce and makes it possible to study the effects of short-term modulation such as electrical and optical stimulation concurrent with electrophysiological and kinematic recordings before, during and after tic expression. However, the acute model is limited to the short time period following the injection. Based on the acute model, we recently proposed a chronic model of tic generation in rats that utilizes a prolonged, fixed-rate infusion of bicuculline to the striatum via a subcutaneous-implanted mini-osmotic pump19. This model extends the period of tic expression to multiple days/weeks. The constant release of bicuculline over a lengthy period of time allows for the examination of the effects of a variety of factors such as pharmacological treatments and behavioral states on tic expression.
Here, we present protocols for generating the acute and chronic models of tic expression in rats. As a function of the specific research question, the protocols enable the fine-tuning of the parameters including unilateral versus bilateral implantation, the site of the tics (according to the somatotopic organization of the striatum)18 and the angle of the implant-cannula (depending on the location of additional implanted devices). The method used in the chronic model is partially based on commercial products but with critical adjustments to fit the tic model. This article details the adjustments needed to custom tailor these tic models.

<table>
	<tbody>
		<tr>
			<td>Anchor screws</td>
			<td>Micro Fasteners</td>
			<td>SMPPS0002</td>
			<td>#0 x 1/8 - Pan Head Sheet Metal Screws</td>
		</tr>
		<tr>
			<td>Bicuculline methiodide</td>
			<td>Sigma Aldrich</td>
			<td>14343</td>
			<td></td>
		</tr>
		<tr>
			<td>Cyanoacrylate (CA) accelerator</td>
			<td>Zap</td>
			<td>PT29</td>
			<td></td>
		</tr>
		<tr>
			<td>Cyanoacrylate (CA) glue</td>
			<td>BSI</td>
			<td>IC-2000</td>
			<td>This glue was found to be stronger than others</td>
		</tr>
		<tr>
			<td>Dental cement</td>
			<td>Coltene</td>
			<td>H00322</td>
			<td>Hygenic Perm Repair Material Reline Resin Self Cure</td>
		</tr>
		<tr>
			<td>Glue gel</td>
			<td>Loctite</td>
			<td></td>
			<td>Ultra Gel Control</td>
		</tr>
		<tr>
			<td>Hemostat</td>
			<td>WPI</td>
			<td>501242</td>
			<td>Any hemostat sized approximately 14 cm would be sufficient</td>
		</tr>
		<tr>
			<td>Hypo-tube, extra-thin wall 25G</td>
			<td>Component supply company</td>
			<td>HTX-25X</td>
			<td></td>
		</tr>
		<tr>
			<td>Hypo-tube, regular wall 22G</td>
			<td>Component supply company</td>
			<td>HTX-22R</td>
			<td></td>
		</tr>
		<tr>
			<td>Hypo-tube, regular wall 30G</td>
			<td>Component supply company</td>
			<td>HTX-30R</td>
			<td></td>
		</tr>
		<tr>
			<td>Infusion pump machine</td>
			<td>New Era Pump Systems</td>
			<td>NE-1000</td>
			<td></td>
		</tr>
		<tr>
			<td>Mini-osmotic pump</td>
			<td>ALZET</td>
			<td>2001</td>
			<td>1.0&#181;l per hour, 7 days</td>
		</tr>
		<tr>
			<td>PE compatible adhesive</td>
			<td>CEYS</td>
			<td></td>
			<td>Special difficult plastics (suitable for PE)</td>
		</tr>
		<tr>
			<td>PE-10 Catheter Tubing</td>
			<td>ALZET</td>
			<td>PE-10</td>
			<td>ID = 0.28mm, OD = 0.61mm</td>
		</tr>
		<tr>
			<td>Precision glass microsyringe, 10&#181;l</td>
			<td>Hamilton</td>
			<td>80065</td>
			<td>1701 RNR 10&#181;l syr (22s/51/3)</td>
		</tr>
		<tr>
			<td>Tissue adhesive</td>
			<td>3M</td>
			<td>1469Sb</td>
			<td>Vetbond</td>
		</tr>
		<tr>
			<td>Tubing-adapter</td>
			<td>CMA</td>
			<td>3409500</td>
			<td></td>
		</tr>
		<tr>
			<td>Tygon micro bore tubing, 0.02 inch ID * 0.06 OD</td>
			<td>Component supply company</td>
			<td>TND80-020</td>
			<td></td>
		</tr>
		<tr>
			<td>Wire 0.005-inch</td>
			<td>Component supply company</td>
			<td>GWX-0050</td>
			<td></td>
		</tr>
		<tr>
			<td>Wire 0.013-inch</td>
			<td>Component supply company</td>
			<td>GWX-0130</td>
			<td></td>
		</tr>
	</tbody>
</table>

generating acute and chronic experimental models of motor tic expression in rats

Motor tics are sudden, rapid, recurrent movements that are the key symptoms of Tourette syndrome and other tic disorders. The pathophysiology of tic generation is associated with abnormal inhibition of the basal ganglia, particularly its primary input structure, the striatum. In animal models of both rodents and non-human primates, local application of GABAA antagonists, such as bicuculline and picrotoxin, into the motor parts of the striatum induces local disinhibition resulting in the expression of motor tics.
Here, we present acute and chronic models of motor tics in rats. In the acute model, bicuculline microinjections through a cannula implanted in the dorsal striatum elicit the expression of tics lasting for short time periods of up to an hour. The chronic model is an alternative enabling the extension of tic expression to periods of several days or even weeks, utilizing continuous infusion of bicuculline via a sub-cutaneous mini-osmotic pump.
The models enable the study of the behavioral and neural mechanisms of tic generation throughout the cortico-basal ganglia pathway. The models support the implantation of additional recording and stimulation devices in addition to the injection cannulas, thus allowing for a wide variety of usages such as electrical and optical stimulation and electrophysiological recordings. Each method has different advantages and shortcomings: the acute model enables the comparison of the kinematic properties of movement and the corresponding electrophysiological changes before, during and after tic expression and the effects of short-term modulators on tic expression. This acute model is simple to establish; however, it is limited to a short period of time. The chronic model, while more complex, makes feasible the study of tic dynamics and behavioral effects on tic expression over prolonged periods. Thus, the type of empirical query drives the choice between these two complementary models of tic expression.

Protocols for generating the acute and chronic models for tic induction in rats were presented above. The protocols cover the full preparation for surgery and experiments (Figure 1 for the acute model, Figure 2 for the chronic model). The application of bicuculline into the motor areas of the striatum results in the expression of ongoing motor tics. Tics appear on the contralateral side to the application and are characterized by brief and repetitive muscle contractions. After bicuculline application to the anterior parts of the striatum, tics are typically expressed in the rat&#8217;s forelimb, head and/or jaw, whereas after posterior injections, tics are expressed in the hindlimb18. In the acute model (Figure 3A), tics start to appear several minutes after the bicuculline microinjection, last for dozens of minutes and eventually decay and cease18. In the chronic model (Figure 3B), tics typically start to appear on the first day following the bicuculline-filled pump implantation19. Tics fluctuate during the day and are most clearly observable during the quiet-waking state19. Tic expression remains ongoing over a period of multiple days and up to a few weeks, depending on the type of mini-osmotic pump.
Tic expression may be monitored and quantified by simultaneous recordings of video, kinematic sensors and neural activity15,19,22. Motor tics have a stereotypic kinematic signature that can be detected in the accelerometer and gyroscope signals (Figure 4), thus enabling the measurement of their frequency and intensity. Tic timing can also be assessed using the local field potential (LFP) signal throughout the CBG pathway, because of the appearance of large amplitude LFP transient spikes15 (Figure 4). The results presented here and additional implementations of the acute and chronic models are described in detail in our previous works15,18,19,22,23. The striatal disinhibition model in both rodents and non-human primates replicated key properties of tic expression in Tourette syndrome and other tic disorders concerning both motor15,18 and vocal24 tics and their expression following a different behavioral, environmental and pharmacological interventions22,25,26. However, existing findings form only the tip of the iceberg of the complex manifestation of tic disorders.&#160; We believe that the model will enable the study of a wide range of such factors, ranging from environmental effects such as sensory input, behavioral effects such as concurrent action performance and clinical effects such as the response to different treatments.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/61743/61743fig01.jpg" /> 
Figure 1: Schematic representation of the custom-made devices used in the acute model.&#160;(1) Implant-cannula which is chronically implanted in the striatum. (2) Dummy, a removable inner wire, is used to seal the implanted cannula. (3) Injector, composed of (3.1) flexible tube and (3.2) injection-cannula, is used for acute delivery of the bicuculline into the striatum. (4) Cannula-holder, composed of (4.1) base and (4.2) lead, is used to hold the implant-cannula during the implantation. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/61743/61743fig01large.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/61743/61743fig02.jpg" /> 
Figure 2: Schematic representation of the custom-made devices and the mini-osmotic pump used in the chronic model.&#160;(1) Cannula-guide is used to hold the infusion-cannula during the implantation. (2) Infusion-cannula is chronically implanted in the striatum. (3) Flexible catheter-tubing connects the infusion-cannula to the mini-osmotic pump. (4) Tubing-adapter connects the flexible catheter-tubing to the flow moderator. (5) Flow-moderator is composed of (5.1) short cannula-part, (5.2) white flange and (5.3) long cannula-part. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/61743/61743fig02large.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/61743/61743fig03.jpg" /> 
Figure 3: Schematic representation of the experimental setups.&#160;In the acute model, tics are induced following a bicuculline injection using a pump-infusion machine (A). In the chronic model, ongoing tics are achieved by prolonged infusion of bicuculline via mini-osmotic pump implantation (B). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/61743/61743fig03large.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/61743/61743fig04.jpg" /> 
Figure 4: An example of synchronized signals from the kinematic and neurophysiological recordings.&#160;Accelerometer, gyroscope and the corresponding LFP from the primary motor cortex during tic expression. Dashed gray line: tic onset time as detected by the LFP signal. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/61743/61743fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats

We present protocols for generating acute and chronic experimental models of tic expression in freely behaving rats. The models are based on striatal cannula implantation and subsequent GABAA antagonist application. The acute model uses transient injections whereas the chronic model utilizes prolonged infusions via a subcutaneous implanted mini-osmotic pump.

Motor tics are sudden, rapid, recurrent movements that are the key symptoms of Tourette syndrome and other tic disorders. The pathophysiology of tic ...

generating-acute-chronic-experimental-models-motor-tic-expression

Nanyang Technological University

Research

JoVE Journal

Behavior

7.4K Views.  Bar-Ilan University. We present protocols for generating acute and chronic experimental models of tic expression in freely behaving rats. The models are based on striatal cannula implantation and subsequent GABAA antagonist application. The acute model uses transient injections whereas the chronic model utilizes prolonged infusions via a subcutaneous implanted mini-osmotic pump.

Video: Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats

The Successive Alleys Test of Anxiety in Mice and Rats

The plus-maze was derived from the early work of Montgomery. He observed that rats tended to avoid the open arms of a maze, preferring the enclosed ones. Handley, Mithani and File et al. performed the first studies on the plus-maze design we use today, and in 1987 Lister published a design for use with mice. 
Time spent on, and entries into, the open arms are an index of anxiety; the lower these indices, the more anxious the mouse is. Alternatively, a mouse that spends most of its time in the closed arms is classed as anxious. 
One of the problems of the plus-maze is that, while time spent on, and entries into, the open arms is a fairly unambiguous measure of anxiety, time in the central area is more difficult to interpret, although time spent here has been classified as &#x201C;decision making&#x201D;. In many tests central area time is a considerable part of the total test time.
Shepherd et al. produced an ingenious design to eliminate the central area, which they called the &#x201C;zero maze&#x201D;. However, although used by several groups, it has never been as widely adopted as the plus-maze. 
In the present article I describe a modification of the plus-maze design that not only eliminates the central area but also incorporates elements from other anxiety tests, such as the light-dark box and emergence tests. It is a linear series of four alleys, each having increasing anxiogenic properties. It has given similar results to the plus-maze in general. Although it may not be more sensitive than the plus-maze (more data is needed before a firm conclusion can be reached on this point), it provides a useful confirmation of plus-maze results which would be useful when, for example, only a single example of a mutant mouse was available, as, for example, in ENU-based mutagenesis programs.

The plus-maze measures anxiety-like behaviour in rodents. There are two opposite closed and two opposite open arms; anxious rodents avoid the open arms. The central area is neither completely open nor closed, so time spent here is ambiguous and difficult to interpret. Here a modification of the plus-maze protocol eliminating this area is described.

The plus-maze was derived from the early work of Montgomery. He observed that rats tended to avoid the open arms of a maze, preferring the enclosed ones.  ...

Nest Building as an Indicator of Health and Welfare in Laboratory Mice

The minimization and alleviation of suffering has moral and scientific implications. In order to mitigate this negative experience one must be able to identify when an animal is actually in distress. Pain, illness, or distress cannot be managed if unrecognized. Evaluation of pain or illness typically involves the measurement of physiologic and behavioral indicators which are either invasive or not suitable for large scale assessment. The observation of nesting behavior shows promise as the basis of a species appropriate cage-side assessment tool for recognizing distress in mice. Here we demonstrate the utility of nest building behavior in laboratory mice as an ethologically relevant indicator of welfare. The methods presented can be successfully used to identify thermal stressors, aggressive cages, sickness, and pain. Observation of nest building behavior in mouse colonies provides a refinement to health and well-being assessment on a day to day basis.

We demonstrate the utility of nest building behavior in laboratory mice as an indicator of welfare. Nest scoring is a sensitive technique that is altered by temperature, illness, and aggression. The time to integrate into nest test (TINT) is a simple cage-side assessment that can detect postoperative pain.

The minimization and alleviation of  suffering has moral and scientific implications. In order to mitigate this  negative experience one must be able to ...

Stimulating the Lip Motor Cortex with Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) has proven to be a useful tool in investigating the role of the articulatory motor cortex in speech perception. Researchers have used single-pulse and repetitive TMS to stimulate the lip representation in the motor cortex. The excitability of the lip motor representation can be investigated by applying single TMS pulses over this cortical area and recording TMS-induced motor evoked potentials (MEPs) via electrodes attached to the lip muscles (electromyography; EMG). Larger MEPs reflect increased cortical excitability. Studies have shown that excitability increases during listening to speech as well as during&#160;viewing speech-related movements. TMS can be used also to disrupt the lip motor representation. A 15-min train of low-frequency sub-threshold repetitive stimulation has been shown to suppress motor excitability for a further 15-20 min. This TMS-induced disruption of the motor lip representation impairs subsequent performance in demanding speech perception tasks and modulates auditory-cortex responses to speech sounds. These findings are consistent with the suggestion that the motor cortex contributes to speech perception. This article describes how to localize the lip representation in the motor cortex and how to define the appropriate stimulation intensity for carrying out both single-pulse and repetitive TMS experiments.

Transcranial magnetic stimulation (TMS) has proven to be a useful tool in investigating the role of the articulatory motor cortex in speech perception.&#160; This article describes how to record motor evoked potentials (MEPs) from the lip muscles and how to disrupt the motor lip representation using repetitive TMS.

Transcranial magnetic stimulation (TMS) has proven to be a useful tool in investigating the role of the articulatory motor cortex in speech perception. ...

The Modified Hole Board - Measuring Behavior, Cognition and Social Interaction in Mice and Rats

This protocol describes the modified hole board (mHB), which combines features from a traditional hole board and open field and is designed to measure multiple dimensions of unconditioned behavior in small laboratory mammals (e.g., mice, rats, tree shrews and small primates). This paradigm is a valuable alternative for the use of a behavioral test battery, since a broad behavioral spectrum of an animal&#8217;s behavioral profile can be investigated in one single test.
The apparatus consists of a box, representing the &#8216;protected&#8217; area, separated from a group compartment. A board, on which small cylinders are staggered in three lines, is placed in the center of the box, representing the &#8216;unprotected&#8217; area of the set-up. The cognitive abilities of the animals can be measured by baiting some cylinders on the board and measuring the working and reference memory. Other unconditioned behavior, such as activity-related-, anxiety-related- and social behavior, can be observed using this paradigm. Behavioral flexibility and the ability to habituate to a novel environment can additionally be observed by subjecting the animals to multiple trials in the mHB, revealing insight into the animals&#8217; adaptive capacities.
Due to testing order effects in a behavioral test battery, na&#239;ve animals should be used for each individual experiment. By testing multiple behavioral dimensions in a single paradigm and thereby circumventing this issue, the number of experimental animals used is reduced. Furthermore, by avoiding social isolation during testing and without the need to food deprive the animals, the mHB represents a behavioral test system, inducing if any, very low amount of stress.

This protocol describes the modified hole board, which is a behavioral test set-up that comprises the characteristics of an open field and a traditional hole board. This set-up enables the differential analysis of unconditioned behavior of small laboratory mammals as well as the analysis of cognitive abilities.

This protocol describes the modified hole board (mHB), which combines features from a traditional hole board and open field and is designed to measure ...

The Social Dimension of Stress: Experimental Manipulations of Social Support and Social Identity in the Trier Social Stress Test

In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations supportive behavior of other people as well as positive social relationships can act as powerful resources to cope with stress. In order to study the interplay between these variables, this protocol describes two effective experimental manipulations of social relationships and supportive behavior in the laboratory. In the present article, these two manipulations are implemented in the Trier Social Stress Test (TSST)&#8212;a standard stress induction paradigm in which participants are subjected to a simulated job interview. More precisely, we propose (a) a manipulation of the relationship between different protagonists in the TSST by making a shared social identity salient and (b) a manipulation of the behavior of the TSST-selection committee, which acts either supportively or unsupportively. These two experimental manipulations are designed in a modular fashion and can be applied independently of each other but can also be combined. Moreover, these two manipulations can also be integrated into other stress protocols and into other standardized social interactions such as trust games, negotiation tasks, or other group tasks.

Previous research on the social dimension of stress has focused on two important variables: social identity and social support. This protocol introduces an effective experimental manipulation of these two social variables and describes their implementation in a standard stress induction paradigm (Trier Social Stress Test).

In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations ...

A Protocol of Manual Tests to Measure Sensation and Pain in Humans

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study demonstrates a quantitative sensory testing protocol using techniques to measure tactile sensation and pain threshold for pressure and heat using portable and easily accessed equipment. These techniques and equipment are ideal for new laboratories and clinics where cost is a concern or a limiting factor. We demonstrate measurement techniques for the following: cutaneous mechanical sensitivity on the arms and legs (von-Frey filaments), radiant and contact heat sensitivity (with both threshold and qualitative assessments using the Visual Analog Scale (VAS)), and mechanical pressure sensitivity (algometer, with both threshold and the VAS). The techniques and equipment described and demonstrated here can be easily purchased, stored, and transported by most clinics and research laboratories around the world. A limitation of this approach is a lack of automation or computer control. Thus, these processes can be more labor intensive in terms of personnel training and data recording than the more sophisticated equipment. We provide a set of reliability data for the demonstrated techniques. From our description, a new laboratory should be able to set up and run these tests and to develop their own internal reliability data.

The goal of this procedure is to demonstrate a battery of quantitative techniques for sensory and pain measurement in humans. The equipment and techniques described are commonly found in pain clinics or are easy to obtain.

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study ...

A Wireless, Bidirectional Interface for In Vivo Recording and Stimulation of Neural Activity in Freely Behaving Rats

In vivo electrophysiology is a powerful technique to investigate the relationship between brain activity and behavior at a millisecond and micrometer scale. However, current methods mostly rely on tethered cable recordings or only use unidirectional systems, allowing either recording or stimulation of neural activity, but not at the same time or same target. Here, a new wireless, bidirectional device for simultaneous multichannel recording and stimulation of neural activity in freely behaving rats is described. The system operates through a single portable head stage that both transmits recorded activity and can be targeted in real-time for brain stimulation using a telemetry-based multichannel software. The head stage is equipped with a preamplifier and a rechargeable battery, allowing stable long-term recordings or stimulation for up to 1 h. Importantly, the head stage is compact, weighs 12 g (including battery) and thus has minimal impact on the animal&#180;s behavioral repertoire, making the method applicable to a broad set of behavioral tasks. Moreover, the method has the major advantage that the effect of brain stimulation on neural activity and behavior can be measured simultaneously, providing a tool to assess the causal relationships between specific brain activation patterns and behavior. This feature makes the method particularly valuable for the field of deep brain stimulation, allowing precise assessment, monitoring, and adjustment of stimulation parameters during long-term behavioral experiments. The applicability of the system has been validated using the inferior colliculus as a model structure.

A Wireless, Bidirectional Interface for In Vivo Recording and Stimulation of Neural Activity in Freely Behaving Rats

A wireless, bidirectional system for multi-channel neural recordings and stimulation in freely behaving rats is introduced. The system is light and compact, thus having minimal impact on the animal&#180;s behavioral repertoire. Moreover, this bidirectional system provides a sophisticated tool to assess causal relationships between brain activation patterns and behavior.

In vivo electrophysiology is a powerful technique to investigate the relationship between brain activity and behavior at a millisecond and micrometer ...

The "Motor" in Implicit Motor Sequence Learning: A Foot-stepping Serial Reaction Time Task

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that involves finger-pressing movements while sitting, the modified SRT task requires participants to step with both feet while maintaining a standing posture. This stepping task necessitates whole body actions that impose postural challenges. The foot-stepping task complements the classic SRT task in several ways. The foot-stepping SRT task is a better proxy for the daily activities that require ongoing postural control, and thus may help us better understand sequence learning in real-life situations. In addition, response time serves as an indicator of sequence learning in the classic SRT task, but it is unclear whether response time, reaction time (RT) representing mental process, or movement time (MT) reflecting the movement itself, is a key player in motor sequence learning. The foot-stepping SRT task allows researchers to disentangle response time into RT and MT, which may clarify how motor planning and movement execution are involved in sequence learning. Lastly, postural control and cognition are interactively related, but little is known about how postural control interacts with learning motor sequences. With a motion capture system, the movement of the whole body (e.g., the center of mass (COM)) can be recorded. Such measures allow us to reveal the dynamic processes underlying discrete responses measured by RT and MT, and may aid in elucidating the relationship between postural control and the explicit and implicit processes involved in sequence learning. Details of the experimental set-up, procedure, and data processing are described. The representative data are adopted from one of our previous studies. Results are related to response time, RT, and MT, as well as the relationship between the anticipatory postural response and the explicit processes involved in implicit motor sequence learning.

We introduce the foot-stepping serial reaction time (SRT) task. This modified SRT task, complementing the classic SRT task that involves only finger-pressing movement, better approximates daily sequenced activities and allows researchers to study the dynamic processes underlying discrete response measures and disentangle the explicit process operating in implicit sequence learning.

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that ...

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 ...

A Task for Assessing the Impact of a Partner on the Speed and Accuracy of Motor Performance in Rats

To our knowledge, no study has examined the effect of mere presence on accuracy of performance in animals. Therefore, we developed an experimental task to measure rats&#8217; motor performance (speed and accuracy) in a social condition. Rats were trained to run on a runway and pull down a lever at the end of the runway. In testing, rats performed the task solitarily (single) or in the presence of a confederate rat beyond the lever (pair or a social condition). As indices of the performance speed, we measured the time needed to start running, run through the runway, and pull down the lever. As the index of performance accuracy, we counted the number of trials in which rats could pull down the lever during their first attempt. One-way and two-way repeated-measure analyses of variance were used to analyze the data. This run-and-pull task enabled us to examine the effect of the presence of another conspecific on both speed and accuracy of motor performance in one experiment. The results showed that rats performed the task faster but less accurately in pair sessions than in single sessions. This protocol would be a valid animal model to examine the effect of mere presence on speed and accuracy of motor performance in rats.

A procedure to measure the speed and accuracy of rats&rsquo; motor performance in a social condition is described. The protocol enables us to investigate the effect of the mere presence of others on speed and accuracy of motor performance in one experiment.

To our knowledge, no study has examined the effect of mere presence on accuracy of performance in animals. Therefore, we developed an experimental task to ...

Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats

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The Successive Alleys Test of Anxiety in Mice and Rats

Nest Building as an Indicator of Health and Welfare in Laboratory Mice

Stimulating the Lip Motor Cortex with Transcranial Magnetic Stimulation

The Modified Hole Board - Measuring Behavior, Cognition and Social Interaction in Mice and Rats

The Social Dimension of Stress: Experimental Manipulations of Social Support and Social Identity in the Trier Social Stress Test

A Protocol of Manual Tests to Measure Sensation and Pain in Humans

A Wireless, Bidirectional Interface for In Vivo Recording and Stimulation of Neural Activity in Freely Behaving Rats

The "Motor" in Implicit Motor Sequence Learning: A Foot-stepping Serial Reaction Time Task

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

A Task for Assessing the Impact of a Partner on the Speed and Accuracy of Motor Performance in Rats