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

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 ...

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Bar-Ilan University

Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole.

Pathophysiology of tic disorders.

Experimental findings and theoretical models have associated Tourette syndrome with abnormal striatal inhibition. The expression of tics, the hallmark symptom of this disorder, has been transiently induced in non-human primates and rodents by the injection of GABA antagonists into the striatum, leading to temporary disinhibition.

Prolonged striatal disinhibition as a chronic animal model of tic disorders.

Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are two neurodevelopmental hyper-behavioral disorders that are highly comorbid. The source of this comorbidity and the neuronal mechanisms underlying these disorders are still unclear. We examined the neuronal activity of freely behaving rats before and after striatal disinhibition, to reveal the similar and distinct neuronal components underlying the mechanisms of TS-like and ADHD-like symptom expression. Focal disinhibition induced motor tics, locomotor hyperactivity or a comorbid effect depending on the location of the injection within the different functional domains of the striatum. While injections within the motor domain induced motor tics, injections into the limbic domain induced mainly locomotor hyperactivity. Disinhibition, regardless of its striatal location, led to qualitatively similar macro-scale and micro-scale neuronal changes. These changes were localized to the domain of the manipulation and remained partly segregated, indicating that hyperactivity is induced as a result of changes in the limbic domain without directly activating the motor domain. Despite the general similarity of induced neuronal changes, these changes were associated with different behavioral effects and were more stereotypic and pronounced following motor-domain disinhibition in comparison to limbic-domain disinhibition. Our recordings revealed a disparity in the neuronal input-output transformation of the two models of the disorders. The results suggest that tic expression and hyperactivity states share similar local neuronal activity changes which manifest in different neuronal and behavioral outcomes. These results expose an intriguing link between tics and their comorbid symptoms and hint at striatal disinhibition, resulting from GABAergic alterations, as a potential common mechanism underlying distinct symptoms expressed by hyper-behavioral patients.

Esther Vinner

The Leslie & Susan Goldschmied (Gonda) Multidisciplinary Brain Research Center

Libraries and Information System of Bar-Ilan University

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