Christiane Schreiweis

Symptom comorbidity is present amongst neuropsychiatric disorders with repetitive behaviours, complicating clinical diagnosis and impeding appropriate treatments. This is of particular importance for obsessive-compulsive disorder (OCD) and Tourette syndrome. Here, we meticulously analysed the behaviour of Sapap3 knockout mice, the recent rodent model predominantly used to study compulsive-like behaviours, and found that its behaviour is more complex than originally and persistently described. Indeed, we detected previously unreported elements of distinct pathologically repetitive behaviours, which do not form part of rodent syntactic cephalo-caudal self-grooming. These repetitive behaviours include sudden, rapid body and head/body twitches, resembling tic-like movements. We also observed that another type of repetitive behaviour, aberrant hindpaw scratching, might be responsible for the flagship-like skin lesions of this mouse model. In order to characterise the symptomatological nature of observed repetitive behaviours, we pharmacologically challenged these phenotypes by systemic aripiprazole administration, a first-line treatment for tic-like symptoms in Tourette syndrome and trichotillomania. A single treatment of aripiprazole significantly reduced the number of head/body twitches, scratching, and single-phase grooming, but not syntactic grooming events. These observations are in line with the high comorbidity of tic- and compulsive-like symptoms in Tourette, OCD and trichotillomania patients.

Decisions permeate every aspect of our lives (what to eat, where to live, etc) but decision-making policies seem to vary tremendously across time and across individuals. Rather than processing all decision-relevant information, we often rely on fast habitual and/or intuitive decision policies, which can lead to irrational biases and errors. Yet, we don’t always follow the fast and negligent lead of habits or intuitions. So what determines whether we engage cognitive control and override our default responses? A possibility is that engagement of cognitive control optimizes a cost-benefit trade-off. In this work, we rely on Markov Decision Processes to derive the optimal control allocation policy in standard decision-making tasks, under arbitrary default preferences. Our working hypothesis is that decision confidence serves as the benefit term of this allocation problem, hence the “metacognitive” nature of decision control. Importantly, we provide behavioural evidence that the ensuing model accurately predicts whether and how mice override their default policy in the context of a repeated perceptual decision-making task. This opens an alleyway for assessing the brain circuits that operate the arbitration between default and controlled decision processes, in rodent models of both healthy and neuropsychiatric conditions.

How learning reshapes the brain across temporal and spatial scales, from molecular to cellular levels, remains a fundamental question in neuroscience. In the striatum, ventromedial, dorsomedial and dorsolateral subregions are differentially recruited during early to late learning on a neurophysiological level. Here, we profile the transcriptome of these subregions across 396 biopsies from 66 mice to map molecular dynamics at three learning stages of a visual discrimination task. We find a strong transcriptional change during the early phase that diminishes towards later learning and is indistinguishable among subregions. The 818 genes altered during learning are enriched for neuronal processes, but also include circadian, vascular, and oligodendrocyte-related pathways. We provide a web application for this large learning-related expression dataset, enabling interactive exploration of genes, gene sets, and transcription factor activity, and suggest that this framework will be broadly useful for diverse neuroscience questions.

Difficult decisions typically involve mental effort, which scales with the deployment of cognitive (e.g., mnesic, attentional) resources engaged in processing decision-relevant information. But how does the brain regulate mental effort? A possibility is that the brain optimizes a resource allocation problem, whereby the amount of invested resources balances its expected cost (i.e. effort) and benefit. Our working assumption is that subjective decision confidence serves as the benefit term of the resource allocation problem, hence the “metacognitive” nature of decision control. Here, we present a computational model for the online metacognitive control of decisions or oMCD. Formally, oMCD is a Markov Decision Process that optimally solves the ensuing resource allocation problem under agnostic assumptions about the inner workings of the underlying decision system. We demonstrate how this makes oMCD a quasi-optimal control policy for a broad class of decision processes, including -but not limited to- progressive attribute integration . We disclose oMCD’s main properties (in terms of choice, confidence and response time), and show that they reproduce most established empirical results in the field of value-based decision making. Finally, we discuss the possible connections between oMCD and most prominent neurocognitive theories about decision control and mental effort regulation.

Pathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive–compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse; myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits.

Pathological repetitive behaviors are a common feature of different neuropsychiatric disorders such as obsessive-compulsive disorder or Gilles de la Tourette syndrome. The Sapap3 knockout mouse ( Sapap3 -KO) is the current reference model used in translational psychiatry to study co-morbid repetitive behaviors, presenting both compulsive-like as well as tic-like behaviors. Consistent with clinical and fundamental research literature relating compulsive-like symptoms to associative cortico-striatal dysfunctions and tic-like symptoms to sensorimotor cortico-striatal dysfunctions, abnormalities comprising both circuits have been described in this mouse model. Findings reported on these mice point towards not only macro-, but also micro-circuitry deficits, both of which can be affected by neuronal structural changes. As such, in the present study, we aimed to investigate structural changes in associative and sensorimotor striatal areas that could affect information conduction. We used AxonDeepSeg, an open-source software to automatically segment and measure myelin thickness and axon caliber, and found that axon caliber, the main contributor for changes in conduction speed, is specifically reduced in the associative but not the sensorimotor striatum of the Sapap3 -KO mouse. This smaller axon caliber in Sapap3 -KO mice is not a general neuronal feature of this region, but specific to a subpopulation of axons with large caliber. These results point to a primary structural deficit in the associative striatum, affecting signal conduction and consequent connectivity.

Symptom comorbidity is present amongst neuropsychiatric disorders with repetitive behaviors, complicating clinical diagnosis and impeding appropriate subsequent treatments. This is of particular importance for Obsessive-Compulsive Disorder, Tourette Syndrome and trichotillomania. Here, we analysed in detail the behaviour of the Sapap3^-/- mouse model, the currently predominant mouse model for compulsive-like behaviours. We confirm previously reported aberrantly elevated grooming behaviour, which is essentially composed of a pathologically increased number of short grooming bouts. We furthermore detected other elements of repetitive behaviour in Sapap3^-/- mice, which do not form part of the classic cephalo-caudal rodent self-grooming sequence. These elements include the sudden, rapid execution of single, isolated movements such as body twitches or head jerks as well as hindpaw scratching episodes. We provide evidence that it is sufficient to avoid hindpaw scratching-induced effects in order to alleviate skin lesions. In order to characterize the symptomatological nature of the previously unreported repetitive behaviours, we pharmacologically challenged these phenotypes by systemic aripiprazole administration, a first-line treatment for tic-like symptoms in Tourette Syndrome and trichotillomania. A single treatment of aripiprazole significantly reduced the number of short but not long grooming events and sudden head-body twitches. The situation was less clear for hindpaw scratching. These findings suggest that the phenotype of the Sapap3^-/- mouse model consists of several pathologically repetitive behaviours of different nature. The observation of the presence of different types of repetitive behaviours in the Sapap3^-/- mouse model is in line with the high comorbidity of tic-like and compulsive-like symptoms in human TS, OCD or trichotillomania patients as well as with the hypothesis of a shared neurobiological mechanism behind different types of repetitive behaviours, which are present across different neuropsychiatric disorders.

Genetic and clinical studies of speech and language disorders are providing starting points to unravel underlying neurobiological mechanisms. The gene encoding the transcription factor FOXP2 has been the first example of a gene involved in the development and evolution of this human-specific trait. A number of autosomal-dominant FOXP2 mutations are associated with developmental speech and language deficits indicating that gene dosage plays an important role in the disorder. Comparative genomics studies suggest that two human-specific amino acid substitutions in FOXP2 might have been positively selected during human evolution. A knock-in mouse model carrying these two amino acid changes in the endogenous mouse Foxp2 gene (Foxp2 ^hum/hum ) shows profound changes in striatum-dependent behaviour and neurophysiology, supporting a functional role for these changes. However, how this affects Foxp2 expression patterns in different striatal regions and compartments has not been assessed. Here, we characterized Foxp2 protein expression patterns in adult striatal tissue in Foxp2 ^hum/hum mice. Consistent with prior reports in wildtype mice, we find that striatal neurons in Foxp2 ^hum/hum mice and wildtype littermates express Foxp2 in a range from low to high levels. However, we observe a shift towards more cells with higher Foxp2 expression levels in Foxp2 ^hum/hum mice, significantly depending on the striatal region and the compartment. As potential behavioural readout of these shifts in Foxp2 levels across striatal neurons, we employed a morphine sensitization assay. While we did not detect differences in morphine-induced hyperlocomotion during acute treatment, there was an attenuated hyperlocomotion plateau during sensitization in Foxp2 ^hum/hum mice. Taken together, these results suggest that the humanized Foxp2 allele in a mouse background is associated with a shift in striatal Foxp2 protein expression pattern.