Animal models of tic disorders: A translational perspective
Abstract
Tics are insistent, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive precursory urges. The most austere tic disorder, Tourette syndrome ( TS ), is a childhood-onset condition featuring multiple drive and at least one phonetic tic for a duration longer than 1 year. The pharmacological treatment of TS is chiefly based on major tranquilizer agents ; while these drugs are frequently effective in reducing tic severity and frequency, their remedy conformity is limited by dangerous motor and cognitive side effects. The identification of novel remedy targets and growth of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove highly utilitarian to test hypotheses on the etiology and neurobiological bases of TS and associate conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater concenter on endophenotypes and quantitative indices, preferably than qualitative descriptors. Given the building complex and multifactorial nature of TS and other tic disorders, the survival of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on familial mutations, environmental interventions a well as pharmacological manipulations. furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant advance in the identification of novel curative targets for tic disorders.
Keywords:
Tourette syndrome, Tic disorders, Animal models, Dopamine
2. Animal models of tic disorders: validity criteria and endophenotypes
alike to other neuropsychiatric disorders, animal models provide a potent creature to test hypotheses on the biological substrates of TS and other tic disorders in a control experimental set. Given the high complexity of tics and related behavioral phenomenon, animal model of these circumstance is by and large based on mammalian species, and, in particular, rodents, given their high cost-effectiveness and acceptable degree of neurobiological similarity with humans. As in the case of other illnesses, the validation of an animal model of TS is basically based on three major criteria ( Willner, 1986 ) :
- Face robustness, which refers to the doctrine of analogy between the behavioral performance of the animal models and the signs and symptoms in tic disorders ;
- Construct robustness ( encompassing besides etiological validity ), which evaluates the congruity between the etiological and pathophysiological processes in tic disorders and the neurobiological basis of the behavioral manifestations in the animal models ;
- predictive robustness, which qualifies the responsiveness of the animal model to treatments validated for tic disorders ( such as major tranquilizer agents and clonidine ) .
The application of each of these criteria to animal models of tic disorders poses a number of challenges. For example, testing an animal model for face robustness implies the presentation of tic-like behaviors ; however, given that the behavioral repertoire of rodents is distinctly different from that of humans, and tics reproduce purposeful behaviors in a repetitive and maladaptive fashion, it is to be expected that tic-like behaviors in these species may markedly diverge from those observed in TS patients. For exercise, it is difficult to predict whether these manifestations should involve vocalizations, in consideration of the unlike development of laryngeal motor apparatus in humans, as compared to rats and mouse. thus, it is authorize that the validation of a likely model of TS based on face robustness bears meaning risks of anthropomorphic bias, and can lead to numerous confounds. In relation to this exit, Swerdlow and Sutherland ( 2006 ) indicated several instances of animal models ( such as the stargazer rats and mouse ) in which spontaneous motive jerks in animals have been sometimes framed as “ tic-like ” manifestations, even though their neurobiological underpinnings are strikingly different from the substrates of TS. These examples show that, while confront validity remains a key criterion in the analysis of animal models of tic disorders, a superficial appraisal based uniquely on this parameter has identical limit translational value and should not be deemed sufficient for drug development studies. The humble dependability of confront cogency in the evaluation of tic-like manifestations is further underline by late studies, showing mark variations in the expression of tic-like behaviors induced pharmacologically across different murine strains ( Proietti Onori et al., 2014 ). finally, the nature of tic-like behaviors can not be in full validated ascribable to the impossibility to ascertain the universe of precursory urges or inner experiences in animals.
While predictive cogency can be an effective complement to face validity, excessive reliance upon this standard should besides be avoided, in consideration of the fact that respective TS patients do not respond to any of the available treatments. furthermore, the excessive refining of animal models and behavioral prototype aimed at enhancing their responsiveness to well-validated therapies can constrain their translational electric potential, by reduce their ability to capture the effects of fresh treatments based on divergent mechanisms of military action. The most baffling expression of the confirmation of manufacture validity in animal models of tic disorders lies in our limited cognition of the pathophysiological bases of these conditions. This problem is compounded by the limitations of our current diagnostic classification of tic disorders, which are based on diagnostic parameters, but not on quantitative, measurable indices. indeed, the diagnostic guidelines of the DSM-5 ( APA, 2013 ) differentiate subtypes of tic disorders based on the austereness and pervasiveness of tics, but not on their neurobiological bases. This classification is likely to mix in the lapp class a count of potentially heterogeneous conditions that share alike diagnostic aspects, but depend on different pathophysiological mechanism and besides respond to different therapies. This reliance on signs and symptoms as central diagnostic criteria may besides be applied to several other types of neuropsychiatric conditions. In order to overcome these limitations, researchers have begun dissecting complex neuropsychiatric conditions, such as TS into more elementary “ build blocks ”. In this respect, a very important invention in our conceptual framework for animal models of tic disorders is a raw focus on average phenotypes ( Leboyer et al., 1998 ) which are defined as measurable indices posited to reflect a more elementary place of neuroanatomic, functional or psychological deficits, than the wholly array of deficits associated with TS. The best-known model of intercede phenotypes is afforded by endophenotypes, defined as inheritable features corresponding to elements of vulnerability to a given perturb ( Gottesman and Shields, 1973 ). Endophenotypes may encompass behavioral, neuroanatomic, biochemical, neurophysiological, neuropsychological, or cognitive traits related to specific genic factors ( Gould and Gottesman, 2006 ; Arts et al., 2008 ; Viswanath, 2009 ). Endophenotypes are not inherently pathological, but should be regarded as vulnerability elements, which can facilitate the development of a disorder in the presence of other critical abnormalities ( derived from other familial factors or environmental variables ). It is worth noting that the “ atomistic ” approach afforded by intercede phenotypes is more amenable to the implementation of effective translational strategies, particularly when referring to cross-species parameters ( which can be faithfully measured in both humans and animal models ) ( Rutter, 2008 ; Bearden et al., 2009 ; Markou et al., 2009 ). This background highlights that research on animal models of tic disorders and TS refers to two main objectives : ( 1 ) the development of animal models based on either familial mutations or environmental interventions aimed at replicating the samara factors associated with the etiology of these disorders ; and ( 2 ) the confirmation of endophenotypes in TS models across the criteria of face, reconstruct and predictive robustness .
8. Concluding remarks
In summary, the pathogenesis of TS is underpinned by the interaction between genic risk factors and environmental insults ; however, the neurobiological mechanism that underlie this disorderliness are hush ill-defined. several key questions still remain unanswered, including : the neurobiological bases of sex differences in TS ; the mechanisms that contribute to the developmental trajectory of tic disorders ; and the designation of likely biomarkers and premorbid signs. This scenario highlights the need for animal models that can capture specific symptomatic traits. careful consideration into animal model choice based on key criteria will be essential to further our agreement of TS pathogenesis and identify translational leads for the development of future therapies .
- Animal models of Tourette syndrome and other tic disorders ( TD ) are reviewed .
- TD models are based on genic mutations and environmental interventions .
- TD models are validated across criteria of confront, manufacture and predictive validity.
- Endophenotype test is essential to enhance the translational value of TD models .
- TD models may assist in the identification of new therapeutic targets .
Acknowledgments
This shape was supported by grants from the National Institute of Mental Health ( NIH R01 MH104603 ) National Institute of General Medical Sciences ( NIH P20 GM103638 ) and Tourette Syndrome Association. The authors are indebted to the EU COST Action CM1103 “ Structure-based drug design for diagnosis and treatment of neurological diseases : dissect and regulate complex function in the monoaminergic systems of the mind ” for supporting their external collaboration. none of the institutions had any far role in the decision to submit the paper for issue .
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