Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette’s syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic-like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype.

The hydrogen sulfide (H 2 S) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in trauma and are implicated in vascular protection and regulation of fluid homeostasis. Acute brain injury is associated with pressure-induced edema formation, blood brain barrier disruption, and neuro-inflammation. The similarities in brain anatomy: size, gyrencephalic organization, skull structure, may render the pig a highly relevant model for translational medicine. Cerebral biomarkers for pigs for pathophysiological changes and neuro-inflammation are limited. The current study aims to characterize the localization of OT/OTR and the endogenous H 2 S producing enzymes together with relevant neuro-inflammatory markers on available porcine brain tissue from an acute subdural hematoma (ASDH) model. In a recent pilot study, anesthetized pigs underwent ASDH by injection of 20 mL of autologous blood above the left parietal cortex and were resuscitated with neuro-intensive care measures. After 54 h of intensive care, the animals were sacrificed, the brain was removed and analyzed via immunohistochemistry. The endogenous H 2 S producing enzymes cystathionine-ɤ-lyase (CSE) and cystathionine-β-synthase (CBS), the OTR, and OT were localized in neurons, vasculature and parenchyma at the base of sulci, where pressure-induced injury leads to maximal stress in the gyrencephalic brain. The pathophysiological changes in response to brain injury in humans and pigs, we show here, are comparable. We additionally identified modulators of brain injury to further characterize the pathophysiology of ASDH and which may indicate future therapeutic approaches.

Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive compulsive disorder (OCD) are co-occurring neurodevelopmental diseases that share alterations of frontocortical neurometabolites. In this longitudinal study we investigated the behavioral and neurochemical effects of aripiprazole and riluzole treatment in juvenile spontaneously hypertensive rats (SHR), a model for ADHD. For neurochemical analysis we employed in vivo magnetic resonance spectroscopy (MRS). Spectra from voxels located at the central striatum and prefrontal cortex were acquired postnatally from day 35 to 50. In the SHR strain only, treatments reduced repetitive grooming and climbing behavior. The absolute quantification of cerebral metabolites in vivo using localized 1H-MRS at 11.7T showed significant alterations in SHR rats compared to controls (including glutamine, aspartate and total NAA). In addition, drug treatment reduced the majority of the detected metabolites (glutamate and glutamine) in the SHR brain. Our results indicate that the drug treatments might influence the hypothesized ‘hyperactive’ state of the cortico-striatal-thalamo-cortical circuitries of the SHR strain. Furthermore, we could show that behavioral changes correlate with brain region-specific alterations in neurometabolite levels in vivo. These findings should serve as reference for animal studies and for the analysis of neurometabolites in selected human brain regions to further define neurochemical alterations in neuropsychiatric diseases.

Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using in vivo proton magnetic resonance spectroscopy (1H-MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic-induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology.