Closed-loop recruitment of striatal interneurons prevents compulsive-like grooming behaviors.

Compulsive behaviors have been associated with striatal hyperactivity. Parvalbumin-positive striatal interneurons (PVIs) in the striatum play a crucial role in regulating striatal activity and suppressing prepotent inappropriate actions. To investigate the potential role of striatal PVIs in regulating compulsive behaviors, we assessed excessive self-grooming-a behavioral metric of compulsive-like behavior-in male Sapap3 knockout mice (Sapap3-KO). Continuous optogenetic activation of PVIs in striatal areas receiving input from the lateral orbitofrontal cortex reduced self-grooming events in Sapap3-KO mice to wild-type levels. Aiming to shorten the critical time window for PVI recruitment, we then provided real-time closed-loop optogenetic stimulation of striatal PVIs, using a transient power increase in the 1-4 Hz frequency band in the orbitofrontal cortex as a predictive biomarker of grooming onsets. Targeted closed-loop stimulation at grooming onsets was as effective as continuous stimulation in reducing grooming events but required 87% less stimulation time, paving the way for adaptive stimulation therapeutic protocols.

Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey.

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed.

The Sapap3-/- mouse reconsidered as a comorbid model expressing a spectrum of pathological 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/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.

Can we tackle climate change by behavioral hacking of the dopaminergic system?

Climate change is an undeniable fact that will certainly affect millions of people in the following decades. Despite this danger threatening our economies, wellbeing and our lives in general, there is a lack of immediate response at both the institutional and individual level. How can it be that the human brain cannot interpret this threat and act against it to avoid the immense negative consequences that may ensue? Here we argue that this paradox could be explained by the fact that some key brain mechanisms are potentially poorly tuned to take action against a threat that would take full effect only in the long-term. We present neuro-behavioral evidence in favor of this proposal and discuss the role of the dopaminergic (DA) system in learning accurate prediction of the value of an outcome, and its consequences regarding the climate issue. We discuss how this system discounts the value of delayed outcomes and, consequently, does not favor action against the climate crisis. Finally, according to this framework, we suggest that this view may be reconsidered and, on the contrary, that the DA reinforcement learning system could be a powerful ally if adapted to short-term incentives which promote climate-friendly behaviors. Additionally, the DA system interacts with multiple brain systems, in particular those related to higher cognitive functions, which can adjust its functions depending on psychological, social, or other complex contextual information. Thus, we propose several generic action plans that could help to hack these neuro-behavioral processes to promote climate-friendly actions.

Of pride and groom: The gains and limits of studying the neuroanatomy of rodent self-grooming in translational research.

In this issue of Neuron, Xie et al. characterize a cell-specific premotor circuit, generating rhythmic orofacial forelimb movements. The authors show that neurons of the caudal part of spinal trigeminal nucleus, expressing Cerebellin-2, are necessary and sufficient for triggering forelimb movements, which form a part of rodent self-grooming.

Reduced Axon Calibre in the Associative Striatum of the Sapap3 Knockout Mouse.

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.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

A cross-species assessment of behavioral flexibility in compulsive disorders.

Lack of behavioral flexibility has been proposed as one underlying cause of compulsions, defined as repetitive behaviors performed through rigid rituals. However, experimental evidence has proven inconsistent across human and animal models of compulsive-like behavior. In the present study, applying a similarly-designed reversal learning task in two different species, which share a common symptom of compulsivity (human OCD patients and Sapap3 KO mice), we found no consistent link between compulsive behaviors and lack of behavioral flexibility. However, we showed that a distinct subgroup of compulsive individuals of both species exhibit a behavioral flexibility deficit in reversal learning. This deficit was not due to perseverative, rigid behaviors as commonly hypothesized, but rather due to an increase in response lability. These cross-species results highlight the necessity to consider the heterogeneity of cognitive deficits in compulsive disorders and call for reconsidering the role of behavioral flexibility in the aetiology of compulsive behaviors.

Bio-inspired benchmark generator for extracellular multi-unit recordings.

The analysis of multi-unit extracellular recordings of brain activity has led to the development of numerous tools, ranging from signal processing algorithms to electronic devices and applications. Currently, the evaluation and optimisation of these tools are hampered by the lack of ground-truth databases of neural signals. These databases must be parameterisable, easy to generate and bio-inspired, i.e. containing features encountered in real electrophysiological recording sessions. Towards that end, this article introduces an original computational approach to create fully annotated and parameterised benchmark datasets, generated from the summation of three components: neural signals from compartmental models and recorded extracellular spikes, non-stationary slow oscillations, and a variety of different types of artefacts. We present three application examples. (1) We reproduced in-vivo extracellular hippocampal multi-unit recordings from either tetrode or polytrode designs. (2) We simulated recordings in two different experimental conditions: anaesthetised and awake subjects. (3) Last, we also conducted a series of simulations to study the impact of different level of artefacts on extracellular recordings and their influence in the frequency domain. Beyond the results presented here, such a benchmark dataset generator has many applications such as calibration, evaluation and development of both hardware and software architectures.

Cognitive Dysfunction in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a mental disorder featuring obsessions (intrusive thoughts) and compulsions (repetitive behaviors performed in the context of rigid rituals). There is strong evidence for a neurobiological basis of this disorder, involving limbic cortical regions and related basal ganglion areas. However, more research is needed to lift the veil on the precise nature of that involvement and the way it drives the clinical expression of OCD. Altered cognitive functions may underlie the symptoms and thus draw a link between the clinical expression of the disorder and its neurobiological etiology. Our extensive review demonstrates that OCD patients do present a broad range of neuropsychological dysfunctions across all cognitive domains (memory, attention, flexibility, inhibition, verbal fluency, planning, decision-making), but some methodological issues temper this observation. Thus, future research should have a more integrative approach to cognitive functioning, gathering contributions of both experimental psychology and more fundamental neurosciences.

Striatal circuits, habits, and implications for obsessive-compulsive disorder.

Increasing evidence implicates abnormalities in corticostriatal circuits in the pathophysiology of obsessive-compulsive disorder (OCD) and OC-spectrum disorders. Parallels between the emergence of repetitive, compulsive behaviors and the acquisition of automated behaviors suggest that the expression of compulsions could in part involve loss of control of such habitual behaviors. The view that striatal circuit dysfunction is involved in OC-spectrum disorders is strengthened by imaging and other evidence in humans, by discovery of genes related to OCD syndromes, and by functional studies in animal models of these disorders. We highlight this growing concordance of work in genetics and neurobiology suggesting that frontostriatal circuits, and their links with basal ganglia, thalamus and brainstem, are promising candidates for therapeutic intervention in OCD.

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.

Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors.

Dysfunctions in frontostriatal brain circuits have been implicated in neuropsychiatric disorders, including those characterized by the presence of repetitive behaviors. We developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene, Sapap3, results in excessive grooming. With a delay-conditioning task, we identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective down-regulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective down-regulation, and compensated for impaired fast-spiking neuron striatal microcircuits. These findings raise promising potential for the design of targeted therapy for disorders involving excessive repetitive behavior.

A Navigation Analysis Tool (NAT) to assess spatial behavior in open-field and structured mazes.

Spatial navigation calls upon mnemonic capabilities (e.g. remembering the location of a rewarding site) as well as adaptive motor control (e.g. fine tuning of the trajectory according to the ongoing sensory context). To study this complex process by means of behavioral measurements it is necessary to quantify a large set of meaningful parameters on multiple time scales (from milliseconds to several minutes), and to compare them across different paradigms. Moreover, the issue of automating the behavioral analysis is critical to cope with the consequent computational load and the sophistication of the measurements. We developed a general purpose Navigation Analysis Tool (NAT) that provides an integrated architecture consisting of a data management system (implemented in MySQL), a core analysis toolbox (in MATLAB), and a graphical user interface (in JAVA). Its extensive characterization of trajectories over time, from exploratory behavior to goal-oriented navigation with decision points using a wide range of parameters, makes NAT a powerful analysis tool. In particular, NAT supplies a new set of specific measurements assessing performances in multiple intersection mazes and allowing navigation strategies to be discriminated (e.g. in the starmaze). Its user interface enables easy use while its modular organization provides many opportunities of extension and customization. Importantly, the portability of NAT to any type of maze and environment extends its exploitation far beyond the field of spatial navigation.

Role of the cerebellar cortex in conditioned goal-directed behavior.

Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulus-response association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response. We therefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses.

Spatial navigation impairment in mice lacking cerebellar LTD: a motor adaptation deficit?

L7-PKCI transgenic mice, which lack parallel fiber-Purkinje cell long-term depression (LTD), were tested with two different mazes to dissociate the relative importance of declarative and procedural components of spatial navigation. We show that L7-PKCI mice are deficient in acquisition of an adapted goal-oriented behavior, part of the procedural component of the task. This supports the hypothesis that cerebellar LTD may subserve a general sensorimotor adaptation process shared by motor and spatial learning functions.

Is the cerebellum ready for navigation?

Spatial navigation required the acquisition of at least two complementary processes: the organization of the spatial representation of the environment (declarative learning) and the acquisition of a motor behaviour adapted to the specific context (procedural learning). The potential role of the cerebellum in spatial navigation is part of the debate concerning its role in cognitive function. Experiments ranging from cerebellar patients to animal models have indicated that cerebellar damage affects the processing of spatial information. The main unresolved issue concern the interpretation of these deficits. Is the cerebellum involved in both declarative and procedural components of navigation? Could all deficits in navigation paradigms be interpreted by a deficit in a motor-dependant process? The purpose of this review is to examine different results coming from anatomical data, experimental paradigms and models in order to give a critical answer to this question.