DS0407 -

Role of the Striatal Inhibitory Networks in Repetitive Behaviors – SINREP

Submission summary

Several neuropsychiatric pathologies are characterized by movement disorders, especially repetitive behaviors (RB) such as compulsions, tics, stereotypies or mannerisms. Their distinction by the clinician is not always trivial, in particular when they are defined by their association with other cognitive or behavioral abnormalities (Edwards et al., 2012). This is particularly relevant in two neuropsychiatric disorders that are often comorbid, Tourette syndrome (TS) and obsessive compulsive disorder (OCD), characterized by tics and compulsions respectively. The exact nature of the pathological RB in these patients is not always easy to distinguish, and can be the source of misdiagnosis and inappropriate treatment (Worbe et al., 2010). However, RB in these two diseases can be controlled by acting on distinct parts of the basal ganglia (Welter 2008, Mallet 2008). Additionally, the recent emergence of animal models of neuropsychiatric disorders characterized by RB could help to better characterize the particularity of symptoms observed with regards to the underlying pathophysiology (Greer and Capecchi, 2002; Welch et al., 2007). In this project, we propose to use a translational approach with patients (OCD and Tourette patients) and mice models expressing repetitive behaviors (including the SAPAP3-KO model) to study phenomenologically, functionally and physiologically the different and/or common mechanisms within the cortico-striatal circuitry underlying the emergence of repetitive behaviors.
The circuitry hypothesized to mediate the expression of repetitive behaviors points to abnormalities in cortico-striatal loops as central to their pathophysiology. The emergence of RB could result from a loss of control of isolated motor bout execution (tics) and/or overexpression of habitual complex behavioral sequences (compulsions), functions that have been shown to be supported by cortico-striatal circuits (Graybiel, 2008). The view that striatal circuits dysfunction is central in the etiology of RB has also been strengthened by neuroimaging and postmortem findings in humans, and functional studies in animal models of these disorders. In this project we will take advantage of one of these animal models, the SAPAP3-KO mouse, which express pathological repetitive behaviors (Burguiere et al., 2013; Welch et al., 2007). We will focus our studies on different striatal regions, and particularly on their inhibitory microcircuitry that has been recently highlighted in RB (Burguière et al., 2015; Kalanithi et al., 2005).
To better understand the pathophysiology of RB we first need to refine the behavioral characterization of animal models of RB regarding the symptoms observed in patients, especially in OCD and TS (Aim 1).
According to the diverse type of RB observed (e.g. tics and compulsions), one could hypothesize that the underlying dysfunctional neural substrate must differ. On the cellular level, recent studies, have raised interest in the possible implication of the striatal inhibitory networks in RB, such as acetylcholine (ACh) and parvalbumin (PV) interneurons, (Burguière et al., 2013; Kataoka et al., 2010). Since the striatum is functionally segregated, we will investigate if the intrinsic nature of an RB (tics or compulsions) could lie in the anatomo-functional specificity of the striatal areas affected (Aim 2). As mentioned before, we will particularly focus on the distribution and local wiring of the inhibitory interneurons of the striatum.
Last, we will use the advantage of optogenetics to specifically modulate different types of interneurons and areas of the striatum and study the functional consequences of the striatal inhibitory networks optogenetic stimulation on the expression of RB (Aim3).

Project coordination

Eric BURGUIERE (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM UMR_S1127 Institut National de la Santé et de la Recherche Médicale

Help of the ANR 240,226 euros
Beginning and duration of the scientific project: December 2016 - 42 Months

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