Movement Disorders, Second Editionhttp://dx.doi.org/10.1016/B978-0-12-405195-9.00047-0 © 2015 Elsevier Inc. All rights reserved.

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C H A P T E R

47Animal Models of Tourette Syndrome and Obsessive-Compulsive Disorder

Christopher PittengerYale University School of Medicine, New Haven, CT, USA

O U T L I N E

47.1 TS Models 74847.1.1 Basal Ganglia Dysregulation in TS 74847.1.2 Assessing TS-Relevant Behaviors

in Animal Models 74947.1.3 Amphetamine-Induced Stereotypy 750

47.1.3.1 Validity as a TS Model 75047.1.4 Transgenic Potentiation of the Corticostriatal

Circuitry 75147.1.4.1 Validity as a TS Model 751

47.1.5 Knockout Models 75147.1.6 Interneuronal Manipulations 75247.1.7 Targeted Inhibition within the Striatum

in a Primate Model 75247.1.7.1 Validity as a Model of TS 752

47.1.8 Autoimmune Models of TS 75347.1.8.1 Validity as a Model of TS 753

47.2 OCD Models 75347.2.1 Assessing OCD-Relevant Behaviors

in Animal Models 75447.2.1.1 Anxiety 75447.2.1.2 Grooming 75447.2.1.3 Prepulse Inhibition 75447.2.1.4 Perseverative Behaviors 75547.2.1.5 Predictive Validity 755

47.2.2 Spontaneous OCD-like Behaviors in Animals 75547.2.2.1 Validity as a Model of OCD 755

47.2.3 Behaviorally Induced OCD-Like Behaviors in Rodents 75647.2.3.1 The Signal Attenuation Model 75647.2.3.2 Schedule-Induced Polydipsia 756

47.2.4 Pharmacological Models of OCD-Like Behavior 75747.2.4.1 Quinpirole-Induced Checking 75747.2.4.2 Neonatal Clomipramine Exposure 75747.2.4.3 5-HT1b Agonist Treatment 757

47.2.5 Genetic Models 75747.2.5.1 Slc1a1 Knockout Mice 75747.2.5.2 HoxB8 Knockout Mice 75847.2.5.3 Dlgap3 Knockout Mice 75847.2.5.4 Slitrk5 Knockout Mice 758

47.2.6 Targeted Manipulations of the Corticostriatal Circuitry 759

47.3 Conclusions 759

References 760

Tourette syndrome (TS) is a complex developmental neuropsychiatric condition that was first described by the French neurologist Gilles de la Tourette in 1885. It was once thought to be rare, but recent epidemiological studies have found a prevalence of 0.3–1% (Robertson et al., 2009). Its pathognomonic symptoms are episodic, spasmodic, semivoluntary stereotyped movements—motor and vocal tics. TS represents the more severe end

of a spectrum of tic disorders, which are typically cat-egorized on the basis of the onset, type (motor or vocal), and chronicity of tics; tic disorders, broadly defined, have an estimated prevalence of 5% (Dooley, 2006). Tics typically have their onset in early childhood, peak in mid-childhood, and improve with age; roughly 75% of patients with childhood TS show substantial improve-ment in adulthood (Bloch and Leckman, 2009).

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As detailed in earlier chapters, the symptomatology of TS extends well beyond these movements. Roughly 90% of patients with TS describe a “premonitory urge” that precedes their motor tics: a sensation of discomfort in the affected part of the body that builds up with time and is discharged by the release of the tic. Patients have a certain amount of voluntary control; for example, chil-dren with tics can often with effort restrain tics in school and then release them in private. Tics are improved by concentration and vanish during sleep; they are wors-ened by stress and sleep deprivation (Du et al., 2010). Patients with TS show other sensory abnormalities; in particular, they have a deficit in sensorimotor gating, as measured by the phenomenon of prepulse inhibi-tion (PPI) (Swerdlow, 2013). Some patients with TS describe complex subjective phenomenology, including “ sensations without sources” and “irresistible urges to pause in mid-sentence” (Hollenbeck, 2001).

This complex symptomatology raises substantial challenges for the production and analysis of animal models; these difficulties are general to efforts to model neuropsychiatric disorders with substantial subjective phenomenology (Pittenger, 2011; Nestler and Hyman, 2010). Face validity is difficult to convincingly estab-lish: not all repetitive movements are tics; convincingly characterizing repetitive movements in an animal as a tic, as opposed to some other neurological entity, is thus problematic on the basis of appearance alone. Of course the subjective symptomatology of the disorder, such as the premonitory urges, cannot readily be assessed in an animal. Predictive validity is likewise an uncertain guide in the development and assessment of animal models of TS. The most effective pharmacological treatment is a low dose of a D2 antagonist such as haloperidol or pimo-zide; however, these treatments have a small to medium effect size in most studies, and nonresponse is common ( Scahill et al., 2006). As D2 blockade is also used for many other movement disorders and neuropsychiatric condi-tions, response of a target behavior in an animal model is thus neither a sensitive nor a specific validator of the model. The other well-established pharmacotherapy consists of alpha-2 adrenergic agonists such as clonidine and guanfacine, but these have a substantially smaller effect size (Scahill et al., 2006). Finally, a specialized form of psychotherapy, habit reversal therapy, has been found to be highly effective (Piacentini et al., 2010); but it is dif-ficult or impossible to recapitulate such behavioral inter-ventions in an animal model.

Informative models of TS are therefore best based on robust etiological or construct validity. Unfortunately, our limited insight into the pathophysiology of the dis-order—the very condition that a robust animal model would do much to alleviate—has substantially limited progress in this area. Several models have been described, based on different etiopathological hypotheses, but none

has yet proven robust or yielded substantial novel insight into the disorder. In this chapter, we summarize the most prominent models that have been described in the litera-ture, and we assess the strengths and weaknesses of each.

TS is frequently comorbid with other psychiatric conditions; indeed, 60–90% of children presenting for evaluation or treatment of TS meet criteria for at least one additional psychiatric disorder. The most frequent comorbidities are attention deficit hyperactivity disor-der, with a prevalence of 50% in patients with transient or chronic tic disorders and 60–75% in those with full TS, and obsessive-compulsive disorder (OCD), with 30–50% of individuals with TS meeting criteria for a diagnosis of OCD at some point during their lives (Du et al., 2010). There has recently been substantial interest in several proposed animal models of OCD, which we summarize in the second half of this chapter (Fineberg et al., 2011; Albelda and Joel, 2012a,b). The difficulties with face, pre-dictive, and construct validity are if anything more acute in modeling OCD than in modeling TS (Pittenger, 2011); nevertheless, several intriguing genetic, pharmacologi-cal, and behavioral models have recently emerged and received substantial attention.

47.1 TS MODELS

47.1.1 Basal Ganglia Dysregulation in TS

The neurobiology of TS is summarized in detail else-where in this volume; here we recapitulate key details that are central to the construct validity of the behavioral models that are described subsequently.

Convergent data implicate the basal ganglia circuitry in the pathophysiology of TS. In particular, functional neu-roimaging studies—PET and fMRI—have consistently shown abnormalities in this circuitry, both at rest and con-current with tic release (Leckman et al., 2010). Structural MRI has shown a small but significant reduction in cau-date and putamen volume in children and adults with TS (e.g., Peterson et al., 2003); childhood volumetric abnormalities predict adult symptom severity, arguing for the causal importance of the observed small morpho-logical changes for pathophysiology (Bloch et al., 2005). Postmortem investigations have revealed a reduction in specific populations of striatal interneurons in brains of individuals with particularly severe and refractory TS, providing a possible explanation for the observed volu-metric changes in the caudate and putamen (Kataoka et al., 2010; Kalanithi et al., 2005). The etiology of these abnormalities—be it a deficit in neuronal differentiation, migration, or survival—has not yet been elucidated.

Cortical development and activity have also been found to be abnormal in patients with TS. Dorsal prefrontal corti-ces are increased in thickness in children with TS, but this

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evolves over ontogeny into prefrontal cortical thinning in adults (Leckman et al., 2010). Abnormalities in cortical thickness have been observed in other regions, includ-ing premotor and parietal-occipital cortices, where corti-cal thickness correlates inversely with symptomatology (Peterson et al., 2001). Particular attention has focused on the supplementary motor area, where metabolic activity is dysregulated and is positively correlated with tic severity (Felling and Singer, 2011).

Abnormal modulatory neurotransmission of basal ganglia and cortex has been implicated in TS and is a tar-get of pharmacotherapy. Dysregulation of dopaminergic (DA) neurotransmission figures prominently in most models of TS pathophysiology, due to the prominent role DA modulation plays in regulating information flow through the basal ganglia circuitry and due to the efficacy of D2 antagonists as pharmacotherapy (Bloch, 2008). Several PET studies—though not all—have shown increased dopamine release in the striatum after amphet-amine challenge in patients with TS, relative to controls; other studies have revealed increased expression of the dopamine transporter, also consistent with enhanced dopamine release (Rickards, 2009). Some attention has also focused on noradrenergic modulation, because α2 adrenergic agonists are used as pharmacotherapy. More recently, genetic findings implicating abnormalities in histaminergic neurotransmission (Ercan-Sencicek et al., 2010; Fernandez et al., 2012) have generated new inter-est in the possible contribution of dysregulated hista-minergic modulation of the basal ganglia circuitry in the pathophysiology of TS (Bloch et al., 2011).

There is an intriguing but still controversial literature suggesting an autoimmune pathogenesis for a subset of cases of TS. Abnormalities of peripheral measures of immune function have been documented in TS patients (Murphy et al., 2010). The association between neuroim-munological dysregulation and tic disorders remains unclear, but this proposed pathophysiological link opens an additional avenue for potential modeling in animals (Hornig and Lipkin, 2013).

47.1.2 Assessing TS-Relevant Behaviors in Animal Models

As described, assessing the face validity of tics poses significant challenges. Rodent models are generally characterized in terms of their expression of stereotypies—sequences of simple or complex behaviors that are repeated excessively, invariantly, and apparently without purpose (Ridley, 1994). Stereotypies can emerge sponta-neously, especially in animals in the restricted environ-ment of vivarium housing, in which they do not receive environmental feedback that would normally modulate instinctual behaviors under more naturalistic conditions, and especially under conditions of stress (Dantzer, 1986).

Stereotypies have been associated with basal ganglia dysfunction and, in particular, with increased DA tone; they are potentiated by prodopaminergic agents such as amphetamine and methamphetamine (Garner and Mason, 2002). Rodents display a wide variety of ste-reotypies, such as increased and fragmented grooming, head-bobbing, orofacial movements such as chewing and tongue protrusion, repetitive rearing, rotational behavior, and thigmotaxic locomotion (Kelley, 2001).

Such stereotypical movements have a degree of face validity for tics. Like tics, they are repetitive, stereotyped, and apparently purposeless, and they can interfere with the execution of normal behavioral programs. Like tics, they have been interpreted as fragmentary component parts of normal patterns of behavior. Their potentiation by prodopaminergic pharmacological treatments is con-sistent with hypotheses about the role of dopamine in TS, as summarized. Recent data indicate that rodents can learn to suppress amphetamine-induced stereotypy (Wolgin, 2012); this phenomenon may be analogous to the ability of TS patients to suppress tics during acts requiring focused concentration.

However, the equation of behavioral stereotypies in rodents with tics in humans with TS faces several challenges. Stereotypies are multiform, and not all repetitive behaviors respond equivalently to pharma-cological manipulations; for example, with increasing doses of amphetamine, the observed repertoire of ste-reotypical behaviors qualitatively changes (Lyon and Robbins, 1975). It is unclear which quantifiable stereo-typical behaviors, if any, are best considered to be iso-morphic to tics. It is of course impossible to assess in a rodent the premonitory urge that is characteristic of tics in up to 90% of patients (Du et al., 2010). Stereotypical behaviors, broadly defined, are seen in a wide variety of neuropsychiatric conditions—not only TS, but also trichotillomania and other grooming disorders, schizo-phrenia, autism, certain genetic syndromes such as Lesch-Nyhan and Prader-Willi, and certain intoxicated states, as well as after some neurological insults such as basal ganglia strokes. When repetitive behaviors are observed in an animal, it is unclear which of these patho-logical states, if any, they may recapitulate. Finally, to the extent that stereotypies recapitulate autonomous frag-ments of normal behavior patterns, they may be highly species-specific; the extrapolation from a stereotyped behavior in a rodent to tics in a patient with TS is thus fraught with conceptual peril.

Stereotypies are typically measured observationally, either online or in a video recording, by an observer blind to experimental condition. They can be scored either continuously or discretely, and either over time or by instantaneous sampling (Creese and Iversen, 1973; Fray et al., 1980; Kelley, 2001). It is generally necessary to individually score qualitatively distinct stereotypies,

47. ANIMAL MODELS OF TOURETTE SYNDROME AND OBSESSIVE-COMPULSIVE DISORDER750

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as they may be differentially modulated by experimen-tal manipulations (Lyon and Robbins, 1975). Automated approaches to the scoring of stereotypies have been described, but they have limitations due to the qualita-tively variable nature of different stereotypies and have not entered into widespread use.

Because of the conceptual challenges attendant to the use of stereotypies as a behavioral model of tics, it is valuable to use convergent evidence from other behav-ioral measures in the evaluation of animal models of TS. This has been done to only a limited extent in the literature to date. One behavior of considerable transla-tional validity is PPI, a measure of sensorimotor gating. PPI deficits are not specific to TS; they are also seen in schizophrenia and OCD, and they have been variably reported in other conditions (Swerdlow, 2013). However, PPI is reduced in TS (Swerdlow et al., 2001), and it has the advantage of being readily measurable in animals using approaches nearly identical to those employed in animals. PPI is impaired by amphetamine, increased by D2 DA blockers, and disrupted by lesions of the striatum (Swerdlow, 2013; Baldan Ramsey et al., 2011). It is to be hoped that PPI and similarly translational valid behav-ioral measures will be more widely used to supplement the scoring of behavioral stereotypies in future assess-ments of animal models of TS and related disorders than they have been hitherto.

47.1.3 Amphetamine-Induced Stereotypy

The basic characteristics of amphetamine-induced stereotypy, and the strengths and conceptual weak-nesses of these behaviors as a model of TS symptom-atology, have been discussed. Ultimately, the value of stimulant-induced stereotypy for TS research rests on the ability of this pharmacological model to shed light on the pathophysiology of the disorder. In this regard, investigations of differential striosomal activa-tion by amphetamine, principally from the Graybiel laboratory, are of particular interest. The striosomes are patches within the dorsal striatum, constituting 6–8% of the total area of the striatum, whose connec-tivity differs from that of the predominant matrix (or “ matrisomes”); they are neurochemically distinct from the matrix, being relatively low in cholinesterase and high in μ-opioid receptor staining (Crittenden and Graybiel, 2011). Striosomes receive afferent projections from limbic cortical structures and project predomi-nantly to the ventral midbrain, including to the dopa-minergic substantia nigra and ventral tegmental area.

Upon amphetamine administration, striosomes are preferentially activated (as indicated by increased immediate early gene expression), and the degree of differential striosome-matrix activation correlates well with the intensity of stereotypies (Canales and

Graybiel, 2000). The striosome-matrix relationship is incompletely understood, and its association with tics in TS remains unclear. Indeed, more recent work has associated striosome-matrix imbalance with dyskinetic movements in a variety of neurological conditions, so it may represent a general principle of the control of movement by the basal ganglia circuitry rather than a specific pathophysiological mechanism of TS ( Crittenden and Graybiel, 2011).

The intensity of stereotypies increases in parallel with amphetamine dose, and the nature of the stereotypies qualitatively changes. The emission of these stereotypies competes with locomotor activation, which increases at lower amphetamine doses but then declines as the dose increases and more stereotypy emerges (Norman and Shallice, 1986). The duration of individual bouts of ste-reotypy increases, and the gap between bouts decreases. At very high amphetamine doses, locomotion entirely ceases and mice can become nearly immobile (Lyon and Robbins, 1975). Amphetamine-induced stereotypy exhibits the intriguing phenomenon of sensitization: that is, with repeated administration of amphetamine the behavioral consequences are potentiated and the associated increase in DA within the basal ganglia is enhanced (Vezina, 2004). Sensitization of the response to psychostimulants has been examined in the context of drug addiction and schizophrenia (Featherstone et al., 2007); its specific relevance to the understanding of TS remains unclear.

47.1.3.1 Validity as a TS ModelThe validity of amphetamine-induced sensitization

as a model of TS has been challenged. Its face validity is based on the resemblance of behavioral stereotypies to tics. However, while behavioral stereotypies share some characteristics with tics, such as their repetitive nature and apparent purposelessness, they do not reca-pitulate the temporal structure of tics (Peterson and Leckman, 1998), following instead the acute rise and fall of amphetamine dose after administration. The behavioral excitation that accompanies psychostimu-lant administration does not resemble core phenom-enology of TS. Amphetamine-induced stereotypy can be attenuated by neuroleptic treatment (Roux et al., 2001); however, this provides little guidance as to the underlying validity of the model: since the stereotypies are produced by increasing dopamine, their reduction by a DA antagonist is unsurprising. The construct or etiological validity of amphetamine stereotypies in the context of TS rests on the notion that TS is a hyperdopa-minergic state. However, dysregulation of DA in TS has not been seen in all studies and is likely to be relatively subtle. It is unclear that the dramatic DA excess pro-duced by acute amphetamine treatment recapitulates this pathophysiology.

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Irrespective of its validity as a model of the patho-physiology of TS, amphetamine stereotypy has proven valuable in the identification of core principles of stria-tal organization in the context of movement disorders – particularly in the notion of striosome–matrix imbalance (Crittenden and Graybiel, 2011). It may also be useful in the context of other models as a way to stress the basal ganglia or “push the system,” revealing stereotypies and other relevant behaviors that may not be evident at baseline.

47.1.4 Transgenic Potentiation of the Corticostriatal Circuitry

As noted, dysregulated activity in the corticostriatal circuitry has been implicated in both TS and OCD. The D1CT-7 transgenic mouse was one early attempt to reca-pitulate this circuit-level abnormality (Campbell et al., 1999a; Nordstrom and Burton, 2002). In these mice, the firing of glutamatergic afferents to the basal ganglia is potentiated through transgenic expression of a cholera toxin subunit in cortical neurons under the control of the D1 dopamine receptor promoter; this leads to chronic activation of G-αs signaling and consequent hyperex-citability in these cells. The animals show a variety of behavioral phenotypes, including generalized hyper-activity, perseveration, altered patterns of grooming, “repetitive leaping” (Campbell et al., 1999a), altered response to psychostimulants (Campbell et al., 1999b), a reduced seizure threshold (Campbell et al., 2000), and repetitive twitching (Nordstrom and Burton, 2002).

47.1.4.1 Validity as a TS ModelThe D1CT-7 mice represent an intriguing attempt to

construct an animal model with construct validity by recapitulating known circuit-level abnormalities from patients with TS (Campbell et al., 1999a; Nordstrom and Burton, 2002), and they provided early evidence sup-porting the involvement of the cortico-basal ganglia circuitry in an array of behaviors of relevance to both TS and a variety of other neuropsychiatric conditions. However, alterations in this circuitry in TS are unlikely to be as simple as the broad potentiation of corticostria-tal afferents produced in this transgenic mouse. In par-ticular, activity in the corticostriatal circuitry appears to be decreased at rest in individuals with TS; increases in activity emerge during tic emission, suppression, or cog-nitive challenge (Rickards, 2009). Such subtleties are not captured by the D1CT-7 transgenic model.

The face validity of model is mixed. Repetitive twitch-ing movements have been interpreted as resembling tics and possessing a temporal structure similar to that seen in TS (Nordstrom and Burton, 2002). However, other aspects of the phenotype, such as generalized hyperac-tivity and an altered seizure threshold, are not typical

of TS. Predictive validity in this model has been exten-sively investigated. The α2 adrenergic agonist clonidine, which is a first-line pharmacotherapy for TS, has been reported to mitigate tic-like behaviors in these animals (Nordstrom and Burton, 2002). The effect of D2 antago-nists, which are more potent anti-TS agents, has not been reported. Glutamatergic agents, which have been inves-tigated in both TS and OCD, also modulate the pheno-type (McGrath et al., 2000). However, in the absence of clearer construct validity, such pharmacological effects are difficult to interpret.

47.1.5 Knockout Models

The genetics of TS is complex, and major risk alleles and causative mutations have proven elusive (State, 2011). This has made the production of genetic models with clear construct validity a slow process. A few poten-tially informative models have recently been described.

The idea that TS is characterized by dysregulated DA tone has led to interest in hyperdopaminergic mice as a potential model. Mice with a 90% reduction of the dopa-mine transporter (DAT-KD mice) have constitutively elevated DA levels in the striatum (Zhuang et al., 2001). Careful analysis in these animals documented increased grooming, increased rigidity in the patterns of groom-ing, and increased resistance to interruption of this pat-tern. These effects have been described as potentiation of a “super-stereotypy” and as potentially modeling repetitive complex behaviors and behavioral rigidity in TS and OCD (Berridge et al., 2005). However, the fact that DA dysregulation in TS is likely to be more subtle than is seen in these mice weakens the construct validity of this model, as does the fact that DAT mutations have not been associated with TS in reports to date.

Putatively pathogenic sequence variants that disrupt SLITRK1 have been associated with TS. Both truncating mutations that are likely to completely abrogate func-tion and more subtle mutations of regulatory regions have been described (Abelson et al., 2005). Slitrk1 is a transmembrane protein that is broadly expressed dur-ing development but is downregulated in the adult; it is thought to have a role in axon guidance and den-dritic elaboration, though its precise role in these pro-cesses remains to be elucidated (Stillman et al., 2009; Kajiwara et al., 2009). A constitutive knockout of Slitrk1 produced elevated anxiety and a depression-like phe-notype in a behavioral model, the forced swim test, but no reported tic-like movements or stereotypies; anxiety was attenuated by clonidine (Katayama et al., 2010). The knockout also exhibited an increase in norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol (Katayama et al., 2010). This knockout mouse has clear construct validity, at least as a model of those rare cases of TS that have been associated with SLITRK1 mutations,

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but its limited face validity, at least in the reports that have appeared to date, renders it difficult to interpret. A deeper understanding of the normal physiological func-tion of Slitrk1 would do much to better elucidate rele-vant pathophysiological processes.

More recently, the gene encoding histidine decarbox-ylase (HDC) has been identified as a rare candidate cause of TS in a unique family with an exceptionally high inci-dence of the disorder (Ercan-Sencicek et al., 2010). This suggests for the first time that dysregulation of histamin-ergic neurotransmission may be a rare cause of TS (Bloch et al., 2011; Haas et al., 2008). Emergence of genes related to histaminergic signaling in a subsequent analysis of copy number variants in TS lends further support to the idea that dysregulation in this system can contribute to TS, beyond the unique family described in the original report (Fernandez et al., 2012). Hdc knockout mice have been reported to have abnormalities in DA tone and a potentiated response to amphetamine, as well as abnor-malities in various forms of learning (Dere et al., 2010). More recently, tic-like stereotypies after amphetamine challenge and a deficit in PPI have been described. The stereotypies are mitigated by pretreatment with the D2 antagonist haloperidol. A similar PPI disruption is seen in patients carrying the HDC mutation. In addi-tion, Hdc−/− and Hdc+/− mice and TS patients harboring an HDC mutation show dysregulation of DA receptors within the basal ganglia (Castellan Baldan et al., 2014). This suggests that Hdc knockout mice may possess con-struct, face, and predictive validity as a model of TS and may shed new light on downstream processes. Further investigations in these Hdc knockout mice, and of the brain’s histaminergic system more generally, may shed important new light on the pathophysiology of TS.

47.1.6 Interneuronal Manipulations

Postmortem investigations of a small number of patients with severe, treatment-refractory, adult TS have revealed intriguing abnormalities in the number and distribution of striatal interneurons. Reductions in cholinergic and parvalbumin-expressing GABAergic interneurons have been reported (Kalanithi et al., 2005; Kataoka et al., 2010). Manipulations of these interneu-ronal populations may shed light on their contribution to the pathophysiology of TS and form the basis of an animal model with construct validity.

Indeed, a spontaneous mutation in the Syrian ham-ster, termed the dtsz hamster, has been described as having just such an abnormality: a reduced density of parvalbumin-expressing interneurons in the striatum (Gernert et al., 2000). Furthermore, both the interneuro-nal abnormality and the corresponding pattern behav-iors improve with age, paralleling the natural history of TS (Hamann et al., 2007). These animals exhibit dystonic

movements and corresponding abnormalities in fir-ing within the basal ganglia (Gernert et al., 2000). Their phenotype resembles dystonia more than it does a tic disorder. The cooccurrence of an interneuronal deficit with a movement disorder serves to validate the poten-tial pathophysiological importance of this abnormal-ity. However, the fact that the resultant behaviors do not recapitulate tics—that is, inadequately specific face validity—suggests that other, cooccurring abnormali-ties may contribute to the specific symptoms in patients with TS. A recent pharmacological study corroborates this conclusion: intrastriatal treatment with a glutama-tergic antagonist that is argued to preferentially inhibit PV-expressing interneurons led, again, to dystonia-like movements (Gittis et al., 2011).

47.1.7 Targeted Inhibition within the Striatum in a Primate Model

The association of a deficit in inhibitory interneurons with TS, both in postmortem studies and in the model systems described, suggests that impaired inhibition may contribute importantly to pathophysiology. Indeed, a focal deficit in striatal inhibition has been invoked in theoretical models. Mink proposed that a focal deficit in inhibition within the striatum during action selection would lead to impaired inhibition of “off-target” actions, resulting in their inappropriate emission in the form of tics (Mink, 2001a,b).

This hypothesis has been directly tested in a series of studies in nonhuman primates. Focal infusion of the GABA-A antagonist bicuculline into the striatum of pri-mates produces discrete contralateral movements that are remarkably reminiscent of tics: they are nonrhythmic, stereotyped but waxing and waning, and independent of the actions being performed (McCairn et al., 2009). A series of electrophysiological studies in this model have revealed tic-associated patterns of neuronal activ-ity throughout the basal ganglia and thalamus, in the motor cortex, and—perhaps most intriguingly—in the cerebellum (McCairn et al., 2009, 2013b; Bronfeld et al., 2011). These movements can be modulated by deep brain stimulation (McCairn et al., 2013a), which has been employed as a treatment for tics in refractory, debilitat-ing cases (McNaught and Mink, 2011).

47.1.7.1 Validity as a Model of TSThis focal-disinhibition model draws construct

validity from the hypothesis proposed by Mink that local dysregulation of intrastriatal inhibition is key to the production of tics (Mink, 2001a). The hypothesis, in its original form, is challenged by the fact that electro-physiological abnormalities in the globus pallidus are widespread, not focal (McCairn et al., 2009); but this is perhaps seen as illustrating the utility of the model to

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refine existing hypotheses, rather than as challenging its validity. Much work remains to be done in this area. The face validity of this model also seems good; the fine-scale characteristics of the movements produced are a good match for many aspects of simple motor tics. Predictive validity has yet to be tested in this model system.

47.1.8 Autoimmune Models of TS

As noted, immune dysregulation has been observed in conjunction with both TS and OCD in some cases, and an autoimmune etiology has been hypothesized ( Conelea et al., 2011; Selling, 1929; Swedo et al., 1998). This remains a controversial area (Singer et al., 2012). Nevertheless, a number of investigators have sought to model tics by way of immune manipulations, chiefly in rodents (Hornig and Lipkin, 2013).

A full recapitulation of this literature is beyond our scope here and can be found in recent reviews (Hornig and Lipkin, 2013). In general, two approaches have been taken. In the first, infusion of antibodies or other mate-rial from patients with tics or OCD of presumed auto-immune etiology is introduced into the brain, either intracerebroventricularly or into the striatum. A total of five studies have taken this approach using serum from patients with TS; four of these have reported tic-like or stereotypical movements as a result (Hornig and Lipkin, 2013). The mechanism of this effect, however, has not been clearly elucidated. It is generally presumed that particular antibodies in the patient serum interact with specific neuronal elements in the basal ganglia circuitry, leading to alterations in information processing. Anti-bodies against dopamine receptors have been identi-fied in the serum of some patients with pediatric-onset TS/OCD symptoms of presumed autoimmune etiology (Brimberg et al., 2012); this represents a plausible link between autoimmunity and disruption of basal ganglia functioning. However, pathogenicity has not been con-firmed for any antibody.

A second category of model based on the hypoth-esis of an autoimmune etiology consists of systemic immune challenge or dysregulation that produces specific TS-like behaviors. Immunization of mice ( Hoffman et al., 2004; Yaddanapudi et al., 2010) and rats (Brimberg et al., 2012) with Streptococcus antigens leads to repetitive behaviors that have been interpreted as resembling the symptoms of TS or of Sydenham chorea; transfer of antibodies from an immunized to an unimmunized mouse can produce similar effects, supporting the existence of a specific pathogenic humoral factor (Yaddanapudi et al., 2010). Immune challenge with lipopolysaccharide or with dIdC has also been reported to lead to abnormal movements in rats (Hornig and Lipkin, 2013).

47.1.8.1 Validity as a Model of TSThe various reports of immune dysregulation lead-

ing to tic-like movements or other movement abnormali-ties support the general idea that regionally specific or generalized inflammatory processes can contribute to movement disorder symptoms. They draw limited con-struct/etiological validity from the proposed causal role of immune dysregulation in the pathophysiology of TS. However, the link between immune dysregulation and TS remains controversial, and its specificity to TS, as opposed to other neurological conditions, is not well established (Singer et al., 2012). The pathogenic process being mod-eled has also not been well specified. In particular, a particular pathogenic antibody or other humoral factor has not been identified. In addition, the manipulations vary substantially among the different studies reported, making generalized conclusions difficult to draw. These various challenges to the etiological validity of these auto-immune models will need to be resolved for them to be of more general utility in dissecting pathophysiology.

The face validity of these models varies between studies. In the absence of a more clearly specified patho-physiology, this is a potentially critical point, because the existence of an abnormal movement does not pro-vide clear confirmation that the model system is recapit-ulating core features of TS. Predictive validity has only occasionally been addressed in these models, although D2 antagonists were shown to attenuate abnormal movements in one recent study of rats immunized with Streptococcus antigens (Brimberg et al., 2012).

47.2 OCD MODELS

OCD is frequently comorbid with TS, occurring in 30–60% of individuals (Freeman et al., 2000; Scharf et al., 2012), and involves pathological abnormalities in similar circuitry. The details of these abnormalities differ, how-ever. In particular, OCD is characterized by increased metabolic activity in the orbitofrontal cortex (OFC) and the striatum, both at rest and on symptom provocation (Menzies et al., 2008). The disorders have similar herita-bility and are thought to share genetic risk factors, with a genetic correlation of 0.41 (Davis et al., 2013).

There has been great interest in recent years in several putative animal models of OCD. Because of the genetic relationship between TS and OCD and the overlap-ping phenomenology of the disorders, both clinically and (even more so) in the evaluation of animal models, we describe some of these here. Space does not permit an exhaustive review and assessment of these models; several recent review articles provide comprehensive overviews (Albelda and Joel, 2012a,b; Eilam et al., 2012; Fineberg et al., 2011). We focus on some of the more influential and conceptually important recent work.

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47.2.1 Assessing OCD-Relevant Behaviors in Animal Models

The assessment of relevant behaviors in animals—that is, the establishment of face validity of models—is, if anything, more vexing in the case of OCD than it is in TS (Pittenger, 2011). Clinically, the core symptoms of OCD are ineluctably subjective. Obsessions are repetitive thoughts that are experienced as being unpleasant and difficult to control; this is not assessable in the absence of subjective, linguistic report. Compulsions are not merely repetitive actions; they are, clinically, repetitive actions that are driven by a need to reduce the subjective discomfort associated with obsessions. This, too, is dif-ficult or impossible to directly assess in animals. Not all repetitive behaviors are compulsions: repetitive, appar-ently purposeless, or excessive actions are also seen in tic disorders, autism, grooming disorders such as trichotil-lomania, and so forth. Assessment of animal models of OCD focused on a few specific repetitive behaviors that are straightforward to measure. This makes the problem more tractable but begs the question of how isomorphic those behavioral assays are for the symptoms they seek to model.

47.2.1.1 AnxietyAnxiety is a prominent symptom of OCD—much

more so than of TS—and is readily assessed in rodents. Its drawback as a measure of face validity is its lack of specificity: anxiety is present in most psychiatric condi-tions and is sufficiently prominent as to be part of the definition in many. Nevertheless, it has been an impor-tant component of a number of recent models of OCD. The presence of anxiety in a putative animal model of OCD is not sufficient to establish its face validity, but it does provide valuable corroboration.

Anxiety is most commonly measured in rodents using any of a variety of opponent tests, in which a natural tendency (to explore, to eat or drink) competes with anxiety to control behavior. For example, in the elevated plus maze, two arms of an elevated arena are enclosed, while two are open; an anxious animal will spend almost all of its time in the enclosed arms, while a less anxious one will explore the whole apparatus. A similar dynamic regulates exploratory behavior in such tests as the zero maze, the light–dark box, and the open field.

47.2.1.2 GroomingMuch attention has been focused recently on animal

models characterized by excessive grooming (Welch et al., 2007; Shmelkov et al., 2010; Chen et al., 2010; Greer and Capecchi, 2002). Strain-specific increases in groom-ing are seen in normal rodents exposed to crowding and to restricted housing environments (Reinhardt, 2005). It has been described in putative animal models of TS and

autism, as well as of OCD; it therefore cannot be consid-ered an OCD-specific phenotype.

Both normal and pathological grooming in rodents can be characterized in a variety of ways. Normal rodent grooming occurs in bouts throughout both dark (active) and light (inactive) circadian phases. Both the number of grooming bouts per unit time and the total time spent grooming can be quantified and compared between groups. This is usually done by observation and manual scoring (either live or on a videotape), but automated systems have been developed and validated for this purpose (Kyzar et al., 2011; Chen et al., 2010). Conse-quences of grooming—typically bald patches or skin lesions—can also be observed and quantified (Greer and Capecchi, 2002; Shmelkov et al., 2010; Welch et al., 2007). In all cases, it is important to distinguish between central and peripheral sources of alterations in grooming behav-ior. Clearly, skin pathology can lead to elevated normal grooming or to altered patterns of grooming driven by sensory stimulation.

Qualitative patterns of grooming can also be assayed. Normal grooming progresses through a series of discrete phases, typically progressing in a rostral-caudal direc-tion, in what has been described as a syntactic chain (Berridge, 1990). An increase in grooming can corre-spond either to an increase in complete syntactic chains (Berridge et al., 2005) or to perseverative repetition of truncated, syntactically abnormal patterns (Greer et al., 2002). Both patterns have been described in putative OCD models.

Because of the prominence of grooming phenotypes in recent literature, especially in genetically modified mice, it is worth reemphasizing that the correspondence between increased grooming and the symptoms of OCD remains tenuous—that is, “compulsive” grooming has a degree of face validity for the compulsions seen in OC, but it is less clear-cut than are behavioral models of most movement disorders, or psychiatric symptoms such as anxiety. In individual cases it should be an empirical question of whether a grooming phenotype may rea-sonably be considered isomorphic to the symptoms of OCD. The strongest case for such a correspondence, in the case of grooming or of any other behavioral model of a psychiatric symptom, derives from a convergence of multiple behaviors with a degree of face validity in a model with defensible construct validity and is bolstered by pharmacological tests that help establish predictive validity. Such a convergence is a high bar that has been approached by only a few models.

47.2.1.3 Prepulse InhibitionPPI has been reviewed in this chapter in the con-

text of TS. It is also deficient in OCD (Kohl et al., 2013). Like grooming and anxiety, this behavioral biomarker is clearly not specific to OCD; while the presence of a

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PPI deficit may support the composite face validity of an animal model, it is not by itself sufficient to establish a model as valid for OCD.

47.2.1.4 Perseverative BehaviorsA variety of perseverative behaviors have been inter-

preted as indicating “compulsivity” in animal models. In the marble-burying task, for example, animals are placed in a cage with deep bedding and a number of glass marbles; both anxious and “compulsive” animals spend an increased percentage of their time fruitlessly attempting to bury these marbles (Terlecki et al., 1979). Analysis across multiple lines of mice suggest that this behavior correlates better with other measures of com-pulsivity than it does with anxiety (Thomas et al., 2009).

Perseveration in locomotor behavior has also been described in multiple rodent models. Different persever-ative patterns have been described. A thigmotaxic pat-tern of locomotion is defined as one in which the animals repeatedly follow the same path, rather than exploring more broadly (Paulus and Geyer, 1993). This is distinct (though not mutually exclusive) from the behavior of anxious animals, who avoid the central area of the arena but do not repeatedly follow the same path. Another abnormal locomotor pattern, seen in the quinpirole rat model (see below), entails repeated visits to a few loca-tions restricted to a small subset of a large arena. This has been described, somewhat anthropomorphically, as “compulsive checking.”

Perseverative behavior has also been examined in the context of delayed alternation; performance in delayed alternation tasks is impaired in subjects with OCD and appears to depend on the function of the OFC ( Abbruzzese et al., 1995, 1997). To test this in rodent models, animals are placed in a T-shaped apparatus, such that they have a single left-or-right choice to make. Alternation is reinforced by providing food on alter-nating sides on successive trials with no delay. During subsequent trials a delay is introduced; perseveration is defined as repeated choice of the same arm (i.e., errors) (Zahrt et al., 1997). Perseverative choices can also be measured in more complex environments, such as an eight-arm radial maze.

47.2.1.5 Predictive ValidityThe selective serotonin reuptake inhibitor (SSRI) anti-

depressants, and the older serotonin reuptake inhibitor clomipramine, are the mainstay of the pharmacologi-cal treatment of OCD and are of benefit in 50–60% of patients (American Psychiatric Association, 2007). Chronic treatment is typically required; acute treatment is ineffective. The response to chronic SRI treatment is therefore the core of establishing predictive validity in any animal model of OCD. However, these medications are not specific to OCD; they are also used in depression,

generalized anxiety disorder, bulimia, autism, posttrau-matic stress disorder, and numerous other conditions. Additional predictive validity can be established in an animal model by showing a lack of response to other medications that are generally ineffective in the treat-ment of OCD, such as the noradrenergic antidepressant desipramine, D2 antagonists such as haloperidol, and benzodiazepine anxiolytics such as diazepam. This com-bination of response to chronic SRI treatment and non-response to other agents has been established in several models (Albelda and Joel, 2012a).

47.2.2 Spontaneous OCD-like Behaviors in Animals

A variety of spontaneously occurring OCD-like behaviors have been described in rodents, dogs, horses, and other species. For example, deer mice spontane-ously develop a variety of repetitive, apparently pur-poseless behaviors, such as jumping backwards and somersaulting. These are seen in both genders and are modulated by housing conditions (Powell et al., 1999). They are reduced by chronic SSRI treatment but not by the noradrenergic antidepressant desipramine, mirror-ing the response pattern seen in OCD (Korff et al., 2008).

“Canine compulsive disorder” (CCD), common in some breeds of dogs, has been described as an analogue of OCD; a similar condition is seen in cats (Overall and Dunham, 2002; Shuster and Dodman, 1998). Specific behaviors include excessive grooming (“acral lick der-matitis”), tail chasing, eating or sucking, and persevera-tive locomotor patterns. Interestingly, these disorders are often responsive to pharmacological treatment with serotonin reuptake inhibitors such as the SSRIs or clo-mipramine (Rapoport et al., 1992).

Recently, genetics and neuroimaging have been brought to bear to try to elucidate the underlying neuro-biology of CCD. In Doberman Pinschers, a locus on Chr. 7 has been associated with susceptibility to the develop-ment of compulsive disorders; the neuronal cadherin gene CDH2 lies within this locus and may be a candi-date OCD risk gene (Dodman et al., 2010). A first brain imaging study in these dogs has suggested structural abnormalities in the anterior cingulate cortex and ante-rior insula, regions that have been implicated in OCD (although no abnormalities were seen in the basal gan-glia or in the OFC) (Ogata et al., 2013). Studies of this sort attempt to take advantage of these spontaneous OCD-like disorders as a window onto the pathophysiology of the human condition.

47.2.2.1 Validity as a Model of OCDThe validity of these spontaneous behavioral mod-

els rests primarily on their resemblance to human symptoms—that is, on their face validity. This is bolstered

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in some cases by a specific responsivity to serotonergic antidepressants—that is, by predictive validity. Con-struct validity of these models is more problematic. The fact that they occur spontaneously in certain organ-isms and in certain contexts has been interpreted as a strength; since OCD occurs spontaneously, not after a genetic manipulation or pharmacological challenge, in the human population, spontaneously occurring behav-ioral disorders in animals may prove to be the best model for it. This supposition has motivated investigations into the genetics and neurobiology of such conditions as CCD. However, our understanding of the neurobiology of these conditions remains rudimentary, and studies to date have provided only limited evidence of conver-gence with what is known about the substrates of OCD. Much more work is needed in this area to establish the construct validity of these spontaneous animal models (Ogata et al., 2013).

47.2.3 Behaviorally Induced OCD-Like Behaviors in Rodents

Several putative OCD models have been described in which perseverative behaviors are induced by particu-lar behavioral protocols; these have been interpreted as modeling the symptoms of OCD. The fact that these behavioral models are produced in wild-type mice (or rats) is both an advantage and a potential weakness. These models are biologically agnostic—they make no assumptions about the biological abnormalities that may accompany the observed behaviors. This may make them a fruitful context in which to investigate aspects of pathophysiology that are not predicted a priori. However, it is clear that OCD has significant biological underpinnings, including a heritability of approximately 40% (Davis et al., 2013); it is possible that particular experiences or behavioral manipula-tions can induce OCD in humans in the absence of a biological predisposition, but there is as yet no clinical evidence to support this thesis.

47.2.3.1 The Signal Attenuation ModelOne psychological hypothesis of the etiology of OCD

is that it derives from deficiency in the normal feed-back associated with the successful completion of a task or goal-directed response (Otto, 1992; Joel, 2006). In the absence of this signal, it is hypothesized, patients experience a feeling of incompleteness and feel an urge to repeat an action until it finally feels “done”; many patients endorse such a subjective. Joel and colleagues have developed and extensively investigated a behav-ioral model that seeks to induce such a deficit in a feed-back signal of task completion in wild-type rats (Joel and Avisar, 2001). The behavioral manipulations behind this “signal attenuation model” are rather involved, and

beyond our scope to fully recapitulate here; they have been recently reviewed elsewhere (Joel, 2006). Briefly, rats are trained to lever-press for food. The delivery of food is accompanied by a particular auditory stimulus. After extensive training on this association, the signal-ing properties of the auditory stimulus are attenuated by presenting it in the absence of both lever-presses and food. Animals are then tested for lever-pressing that results in presentation of the stimulus but not of food delivery. Compulsive behaviors are defined as lever-presses for the tone that are not followed by attempts to retrieve food. Lesion and pharmacological studies in this model have implicated the OFC, corticostriatal sys-tems more generally, and the DA, serotonergic, and glu-tamatergic neurotransmitter systems (Albelda and Joel, 2012a; Joel, 2006).

47.2.3.1.1 VALIDITY AS A MODEL OF OCD

As noted, both a strength and a weakness of this model is that it derives from a behavioral manipu-lation in normal rats; biological abnormalities that emerge in the model are independent of any particu-lar etiological hypothesis. The construct validity of the signal attenuation model rests on its recapitulation of a psychological process that has been hypothesized to underlie OCD: the impoverishment of a feedback sig-nal associated with task completion. Its face validity rests on the interpretation of repeated lever-presses for the tone, and not for food, as “excessive” and “com-pulsive.” Predictive validity has been investigated in several studies. Compulsive lever-presses are reduced by chronic treatment with SSRIs but not by the norad-renergic antidepressant desipramine, the D2 antago-nist haloperidol, or the benzodiazepine diazepam (Joel et al., 2004), paralleling the pattern of response seen in clinical OCD (American Psychiatric Association, 2007). Lever-pressing is also modulated by deep brain stimulation (DBS) within the corticostriatal circuitry (Klavir et al., 2009, 2011); DBS is increasingly used as a treatment of last resort in severe, refractory OCD (Greenberg et al., 2010a).

47.2.3.2 Schedule-Induced PolydipsiaThis model entails restricting rats’ access to food,

for which they must lever-press, but giving them free access to water. After extensive training, rats begin to drink excessively; this has been interpreted as compul-sive because it appears excessive and purposeless. Con-struct validity for this model is limited; but predictive validity is supported by the finding that SSRIs attenu-ate the excessive drinking, while haloperidol, desipra-mine, and diazepam do not (Woods et al., 1993). Deep brain stimulation within the corticostriatal circuitry has also been shown to modulate polydipsic behavior (van Kuyck et al., 2008).

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47.2.4 Pharmacological Models of OCD-Like Behavior

A number of models have been described in which perseverative behavior is induced by pharmacologi-cal manipulation of the DA or serotonergic systems in rodents. Such models derive their construct validity from the targeting of specific neurotransmitter systems that are implicated in OCD. However, since these same systems are also implicated in innumerable other neu-ropsychiatric conditions, including TS and many others discussed throughout this volume, additional evidence is necessary to confirm their validity.

47.2.4.1 Quinpirole-Induced CheckingRats injected repeatedly with the D2/D3 agonist

quinpirole and then allowed to explore a large environ-ment develop a pattern of repeatedly visiting specific objects or locations, to the exclusion of the rest of the environment; this has been interpreted as analogous to the compulsive checking seen in many patients with OCD (Szechtman et al., 1998). The microstructure of this checking behavior in rats resembles that seen in patients (Szechtman et al., 2001). The validity of this model rests largely on this face validity. Construct validity is some-what limited; it is unclear why D2 agonist treatment over time would lead to OCD-like abnormalities. Checking behaviors are partially ameliorated by clomipramine, a serotonergic reuptake inhibitor (Szechtman et al., 1998), and by DBS (Mundt et al., 2009; Winter et al., 2008), giv-ing the model a degree of predictive validity.

47.2.4.2 Neonatal Clomipramine ExposureRats exposed to clomipramine early in postnatal

life (days 9–16) express a variety of behaviors during adulthood that have been interpreted as recapitulat-ing aspects of OCD (Andersen et al., 2010). They show elevated anxiety, increased marble-burying, reduced spontaneous alternation in a T-maze, and increased accumulation of food pellets, which has been inter-preted as potentially recapitulating hoarding behavior (Andersen et al., 2010). This is an attractive model in that it explicitly seeks to model the neurodevelopmen-tal nature of OCD and that behavior is assayed in the absence of drug, ensuring that the observed behavioral effects derive from developmental brain abnormalities rather than acute actions of the drug. The construct validity of this model derives from the perturbation of the serotonergic system, which is associated with OCD because of the efficacy of SSRI antidepressants. The authors hypothesize that the normal ontogeny of the serotonergic modulatory system is disrupted in OCD in a way that is recapitulated by this treatment. However, there is no clinical evidence associating in utero or neonatal exposure to clomipramine or SSRIs

with the later development of OCD. Predictive valid-ity has not been tested in this model.

47.2.4.3 5-HT1b Agonist TreatmentA handful of clinical studies suggest that administra-

tion of an agonist of the 5-HT1b receptor, such as the triptan antimigraine medications, can acutely worsen symptoms in patients with OCD (Gross-Isseroff et al., 2004; Koran et al., 2001; Zohar et al., 2004). This obser-vation has motivated examination of the acute effects of 5-HT1b in mice. The 5-HT1b agonist R024969 induces deficits in PPI (Sipes and Geyer, 1994), perseverative patterns of locomotion (Cheetham and Heal, 1993; Shanahan et al., 2009), and perseveration in a delayed alternation task (Woehrle et al., 2013); these effects have some face validity for OCD. These behavioral effects are mitigated by chronic pretreatment with clomipramine or fluoxetine, but not with desipramine, and by genetic reduction in serotonin transporter function (Shanahan et al., 2009; Woehrle et al., 2013), giving them some pre-dictive validity as an OCD model. Furthermore, ana-tomically targeted pharmacological manipulations have shown the 5-HT1b effect to depend specifically on the OFC, recapitulating a core feature of the functional neu-roanatomy of OCD (Shanahan et al., 2011). Together, these findings validate acute 5-HT1b agonist treatment as an intriguing and potentially important new model.

47.2.5 Genetic Models

OCD has substantial heritability (Davis et al., 2013), but no specific genetic abnormalities have been defini-tively identified as candidate causes or major risk factors. A recent genomewide association study (GWAS) failed to identify any loci that reached statistical criteria for genomewide statistical significance as OCD-associated alleles, though several came close (Stewart et al., 2013b). Despite this fact, there has been substantial interest in recent years in several knockout mice that recapitulate aspects of the phenomenology of OCD and show abnor-malities in some of the underlying circuitry.

47.2.5.1 Slc1a1 Knockout MiceDysregulated glutamate may contribute to the patho-

physiology of OCD (Pittenger et al., 2011). Slc1a1 is the primary neuronal glutamate transporter; it also trans-ports cysteine, which is rate-limiting for the biosynthesis of glutathione and thus is critical for normal antioxidant balance in neurons (Aoyama et al., 2006). Several link-age and candidate–gene association studies have impli-cated a number of alleles in Slc1a1 in OCD (Stewart et al., 2013a; Dickel et al., 2006; Arnold et al., 2006). Although heterogeneity in the implicated alleles attenuated the sta-tistical significance of this locus in a recent meta-analysis (Stewart et al., 2013a) and Slc1a1 did not emerge as one

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of the primary implicated loci in a recent GWAS (Stewart et al., 2013b), it remains the most replicated genetic find-ing in OCD and a focus of significant interest. While the functional effects of the various OCD-associated Slc1a1 alleles are not fully clear (Wendland et al., 2009), the Slc1a1 knockout mouse therefore represents a potential OCD model with inherent construct validity.

It is therefore disappointing that the Slc1a1 knock-out mouse has not emerged as a valid model of OCD symptomatology. The most prominent phenotype of this knockout mouse is an acceleration of aging-like changes in the brain (Aoyama et al., 2006) and a reduction in resistance to ischemia-induced brain damage (Li and Zuo, 2011). These phenotypes have been interpreted as resulting from increased oxidative damage. Extensive behavioral phenotyping has not been reported in these mice, and there have been no studies investigating the effects of OCD-related medications.

47.2.5.2 HoxB8 Knockout MiceHoxB8 is a homeobox transcription factor expressed

prominently in the immune system. It was something of a surprise when HoxB8 knockout mice were found to exhibit excessive grooming behavior, to the extent that they develop prominent skin lesions (Greer and Capecchi, 2002). Still more startling is the more recent suggestion that this phenotype relates to dysfunction of microglia, the primary immune cells in the brain (Chen et al., 2010). Such an association is unexpected, given that the primary phenotype described in these knockout animals is behavioral, but may be related to evidence implicating dysregulated immune function in both OCD and TS (as described in the context of TS).

Provocative though these findings are, their relevance to OCD (or TS) remains to be clearly established. The validity of these mice as an animal model rests on the face validity of the excessive grooming phenotype; as reviewed, this is not a straightforward isomorphism. Other investigators have suggested that the grooming phenotype relates to abnormalities in peripheral sensa-tion, rather than to central mechanisms (Holstege et al., 2008). Predictive validity has not been tested in this model.

47.2.5.3 Dlgap3 Knockout MiceKnockout of Dlgap3 (alias Sapap3) was similarly

observed to produce an unexpected but marked increase in grooming; in this case, convergent evidence further bolsters the validity of the model (Welch et al., 2007). The SAP90/PSD-95 associated proteins, or SAPAPs, are key constituents of the postsynaptic density, a large protein complex that organizes glutamate receptors and other constituents of the postsynaptic machinery at glu-tamatergic synapses. There are four of them; SAPAP3 is the only one prominently expressed in the striatum

(Welch et al., 2004). In addition to excessive grooming, Dlgap3 knockout mice exhibit increased anxiety; both phenotypes are ameliorated by chronic, but not acute, treatment with the SSRI fluoxetine, and by virus- mediated expression of the Dlgap3 in the striatum (Welch et al., 2007). Both the initial description of these animals and a series of more recent follow-up studies have revealed intriguing electrophysiological abnormal-ities in the corticostriatal circuitry (Wan et al., 2011, 2013; Chen et al., 2011; Welch et al., 2007). We do not review the details of this evolving literature here, but it serves to highlight the potential of an animal model to generate new circuit-level hypotheses for the pathophysiology of neuropsychiatric disease.

Face validity in this model derives from two pheno-types, excessive grooming and increased anxiety; nei-ther is specific to OCD or perfectly recapitulates the core symptomatology of the clinical condition, but parallel-ism between the two bolsters the claim to validity. Pre-dictive validity is supported by the response of these phenotypes to chronic, but not acute, fluoxetine; other medication treatments have not been reported as of yet. The claim to construct validity is more complicated. A handful of mutations in DLGAP3 have been reported in patients with OCD and grooming disorders, but such mutations are also found in the normal population, and a statistically compelling demonstration of their associa-tion with OCD has yet to emerge (Zuchner et al., 2009; Bienvenu et al., 2009). In the context of the growing lit-erature implicating glutamate dysregulation in OCD (Pittenger et al., 2011), morphological and electrophysi-ological abnormalities in striatal glutamatergic synapses in these animals are supportive of construct validity. Ultimately a stronger tie-in to the human condition is essential to definitively establish the validity of this mouse model, but it has already had a valuable stimula-tory effect on the field.

47.2.5.4 Slitrk5 Knockout MiceA similar model, described more recently, is the Slitrk5

knockout mouse (Shmelkov et al., 2010). As noted, the SLITRK proteins are single-transmembrane signaling molecules whose function has yet to be clearly eluci-dated; SLITRK1 has been implicated by genetic studies as a rare cause of TS (Abelson et al., 2005; O’Roak et al., 2010). Mice with a knockout of Slitrk5 were observed to groom excessively. As in the case of the SAPAP3 mice, this is accompanied by increased anxiety; both pheno-types are ameliorated by chronic, but not acute, SSRI treatment. The SliTrk5 knockout mouse exhibits elec-trophysiological abnormalities in the corticostriatal cir-cuitry, including the OFC (Shmelkov et al., 2010).

As in the case of the Dlgap3 knockout mice, the claim to construct validity of the Slitrk5 knockout mouse is complex. As of yet, no mutations in human SLITRK5

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have been associated with OCD, TS, or related disorders; the gene has not emerged as a candidate in recent GWAS studies (Stewart et al., 2013b). However, convergent evidence of relevant abnormalities in the corticostriatal circuitry is consistent with what is known about the cir-cuit abnormalities in OCD (and TS). Improved under-standing of the normal function of the SLITRK5 in brain development and corticostriatal function will be essen-tial to the further evaluation of the validity of this mouse model and the extent to which it can shed new light on the pathophysiology of OCD.

47.2.6 Targeted Manipulations of the Corticostriatal Circuitry

As reviewed, hyperactivity in the corticostriatal cir-cuitry has been repeatedly associated with OCD. Tar-geting of this circuitry, either to recapitulate OCD-like phenomenology or to ameliorate it in the context of another animal model, provides an opportunity to caus-ally test this association.

The D1CT-7 transgenic mouse represents an early effort in this direction; it has been described as a model of comorbid TS and OCD (Nordstrom and Burton, 2002). While the lack of specificity of both the neuronal manip-ulation and the resulting behavioral phenotypes limits the value of this model, it provided an early demonstra-tion of how targeting this circuitry can produce poten-tially relevant behavioral effects.

More recently, Ahmari and colleagues have used optogenetics to specifically target excitatory projections from the OFC to the ventromedial striatum (Ahmari et al., 2013). Acute effects were limited; but after repeated stimulation, mice developed increased grooming that persisted for days after stimulation was stopped. This effect was accompanied by changes in electrophysi-ological coupling within the corticostriatal circuitry and was ameliorated by fluoxetine treatment. This impor-tant finding demonstrates that experimentally induced hyperactivity in the OCD-related circuitry is sufficient to produce OCD-relevant behavior, providing perhaps the strongest evidence to date for the causality of this rela-tionship. In so doing, it enhances confidence in the valid-ity of enhanced grooming as a valid behavioral homolog of symptoms of OCD.

The converse strategy is to seek to mitigate putative OCD-like behaviors in other models through targeted brain stimulation. This approach seeks to recapitulate the intriguing clinical evidence for the efficacy of DBS of the corticostriatal circuitry in patients with profound refractory disease (Greenberg et al., 2010b). As noted, electrical DBS has been shown to modulate behav-ioral abnormalities in the quinpirole-induced checking model (Mundt et al., 2009; Winter et al., 2008), the sig-nal attenuation model (Klavir et al., 2009, 2011), and the

schedule-induced polydipsia model (van Kuyck et al., 2008), as well as in the primate local-disinhibition model of TS (McCairn et al., 2012).

Recently, more precise neuronal stimulation using optogenetics has been applied. Burguiere and col-leagues applied optogenetic DBS of glutamatergic projections from the lateral OFC to the dorsolateral stri-atum in the SAPAP3 knockout mouse model of OCD and found that it mitigated excessive grooming and defective inhibitory microcircuits within the striatum (Burguiere et al., 2013).

47.3 CONCLUSIONS

Numerous animal models of TS, OCD, and related disorders have been described over the decades, at an accelerating pace in recent years. Many of these models exhibit intriguing phenomenology, and some of them will surely shed important new light on the pathophysi-ology and treatment of these disorders. To date, however, no model is fully satisfying: no single model exhibits compelling construct, face, and predictive validity; and no model has proven itself by revealing new details of the disorders or contributing to the development of new treatments.

There are several reasons for this situation (Pittenger, 2011). The modeling of complex neuropsychiatric dis-orders in which core phenomenology extends beyond readily observable behaviors is inherently challenging. It is not possible to assess premonitory urges or obses-sions in an animal; surrogate measures must be used. The manifest behaviors that are invoked as support for face validity – repetitive or stereotypic movements, anxi-ety, grooming – are not specific to TS or OCD.

Predictive validity is also difficult to definitively establish, due to the relatively primitive state of phar-macological treatment for these disorders. Dopamine D2 antagonists are the most efficacious treatment for tic disorders, but they have only a small effect size and are ineffective in many severe cases (Bloch, 2008). Similarly, the SSRIs are the mainstay of the pharmacological treat-ment of OCD, but they are only efficacious in 50–60% of cases (American Psychiatric Association, 2007). In nei-ther case is the medication specific: both D2 antagonists and SSRIs are used broadly for many neuropsychiatric disorders. In this context, response to the medication does not ensure validity of a model, and lack of response does not definitively refute it.

The surest basis for a plausible animal model is thus construct or etiological validity. Here, however, we are constrained by our limited understanding of the patho-physiology of these conditions. Both have substantial heritability, but in neither have major genetic contributors been unequivocally established. Immune dysregulation

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may contribute to both, but the details remain to be established. Corticostriatal abnormalities are thought to contribute to both; but they also contribute to innumer-able other conditions, including many other movement disorders, and thus better specification of the particular abnormalities in TS and OCD is critical to the evaluation of construct validity in an animal model.

Despite these difficulties, there has been clear prog-ress in recent years, and a number of intriguing mod-els have been developed. In particular, models based on rare alleles of high penetrance (Castellan Baldan et al., 2014), on specific hypotheses of basal ganglia dysregu-lation (McCairn et al., 2009; Mink, 2001a; Ahmari et al., 2013), or on convergent evidence of basal ganglia dys-regulation in the context of an intriguing behavioral phe-notype (Shmelkov et al., 2010; Welch et al., 2007) hold great promise.

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