Biology subjects

Schreiweis, C.

Publications and source records attributed to Schreiweis, C..

7 recordsLinked to original sources

bioRxiv2023

The metacognitive control of decisions predicts whether and how mice override their default policy

Decisions permeate every aspect of our lives but decision-making policies seem to vary tremendously across time and individuals. Rather than processing all decision-relevant information, we sometimes rely on habitual and/or intuitive responses, which can lead to irrational biases and errors. This raises the twofold issue of whether a single normative principle can (i) determine when cognitive control is engaged, and (ii) account for the diverse behavioral signature of cognitive control regulation. In line with recent theoretical proposals, our working hypothesis is that cognitive control is flexibly deployed to optimize a cost-benefit trade-off. Using Markov Decision Processes, we derive the optimal online control allocation policy in standard decision-making tasks, under arbitrary default biases. This bridges the gap between motivational theories of cognitive control regulation and accumulation-to-bound models of decision making. Under the model, response times, default response rates, decision accuracy and interference effects are not independent behavioral phenomena, but distinct manifestations of the same underlying arbitration process. We then test the distinct behavioral predictions of the model using a customized pseudo-ecological set-up, whereby mice engage with a self-administered perceptual decision-making task over several weeks. In this context, processing decision-relevant cues engages cognitive control, whereas default responses are determined by learned, cue-independent, action-outcome associations. The model accurately predicts both performance and response time interference effects, their interactions, as well as their modulation by reward and task demands. This work provides novel computational means for assessing the brain circuits that operate the arbitration between default and controlled decision processes, in rodent models of both healthy and neuropsychiatric conditions.

animal behavior and cognition↗

bioRxiv2023

Expression profiling of the learning striatum

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.

neuroscience↗

bioRxiv2023

The online metacognitive control of decisions

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 oMCDs 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.

animal behavior and cognition↗

bioRxiv2022

Closed-loop recruitment of striatal parvalbumin interneurons prevents the onset of compulsive behaviors

A prominent electrophysiological feature of compulsive behaviours is striatal hyperactivity, yet, its underlying regulatory processes still need to be characterised. Within the striatum, parvalbumin-positive interneurons (PVI) exert a powerful feed-forward inhibition essential for the regulation of striatal activity and are implied in the suppression of prepotent inappropriate actions. To investigate the potential role of striatal PVI in regulating striatal activity and compulsive behaviours, we used the Sapap3 knockout mice (Sapap3-KO), which exhibit compulsive-like self-grooming. We first showed that the number of compulsive-like events in Sapap3-KO mice was reduced to normal levels by continuous optogenetic activation of striatal PVI in the centromedial striatum. To narrow down the critical time window of striatal PVI recruitment for regulating compulsive-like grooming, we then developed a novel closed-loop optogenetic stimulation pipeline. Upon a predictive biomarker of grooming onsets, characterised by a transient power increase of 1-4 Hz frequency band in the orbitofrontal cortex, we provided real-time closed-loop stimulation of striatal PVI. This targeted closed-loop optogenetics approach reduced grooming events as efficiently as continuous recruitment of striatal PVI with a reduction of stimulation time of 87%. Together, these results demonstrated that recruitment of striatal PVI at the initiation of the compulsive events is sufficient to drastically reduce compulsive-like behaviours and pave the way for targeted closed-loop therapeutic protocols.

neuroscience↗

bioRxiv2021

Reduced axon caliber in the associative striatum of the Sapap3 knockout mouse

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.

neuroscience↗

bioRxiv2020

The Sapap3-knockout mouse model manifests a spectrum of repetitive behaviours

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 twitches, resembling tic-like movements. We also observed that another type of repetitive behaviours, aberrant hindpaw scratching, is responsible for the flagship-like skin lesions of this mouse model, rather than originally suspected self-grooming. In order to characterize 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 tic-like movements 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 as well as with the hypothesis of shared neurobiological mechanisms.

neuroscience↗

bioRxiv2019

Mice carrying a humanized Foxp2 knock-in allele show region-specific shifts of striatal Foxp2 expression levels

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 (Foxp2hum/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 Foxp2hum/hum mice. Consistent with prior reports in wildtype mice, we find that striatal neurons in Foxp2hum/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 Foxp2hum/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 Foxp2hum/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.

neuroscience↗