scholarly journals A cross-species assessment of behavioral flexibility in compulsive disorders

2019 ◽  
Author(s):  
Nabil Benzina ◽  
Karim N’Diaye ◽  
Antoine Pelissolo ◽  
Luc Mallet ◽  
Eric Burguière
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Common Symptom ◽  
Obsessive Compulsive ◽  
Homogeneous Groups ◽  
Impaired Performance ◽  
Compulsive Disorder ◽  
Compulsive Behaviors

ABSTRACTBackgroundCompulsive behaviors, one of the core symptoms of Obsessive-Compulsive Disorder (OCD), are defined as repetitive behaviors performed through rigid rituals. The lack of behavioral flexibility has been as being one of the primary causes of compulsions, but studies exploring this dimension have shown inconsistencies in different tasks performed in human and animal models of compulsive behavior. The aim of this study was so to assess the involvement of behavioral flexibility in compulsion, with a similar approach across different species sharing a common symptom of compulsivity.Methods40 OCD patients, 40 healthy individually matched control subjects, 26 C57BL/6J Sapap3 KO mice and 26 matched wildtype littermates were included in this study. A similar reversal learning task was designed to assess behavioral flexibility in parallel in these two species.ResultsWhen considered as homogeneous groups, OCD patients and KO mice expressing compulsive behaviors did not significantly differ from their controls regarding behavioral flexibility. When clinical subtypes were considered, only patients exhibiting checking compulsions were impaired with more trials needed to reach the reversal criterion. In KO mice, a similarly impaired subgroup was identified. For both species, this impairment did not result in a greater perseveration after reversal, but in a greater lability in their responses in the reversal condition. Moreover, this impairment did not correlate with the severity of compulsive behaviors.ConclusionsIn our cross-species study, we found no consistent link between compulsive behaviors and a lack of behavioral flexibility. However, we showed in both species that the compulsive group was heterogeneous in term of performance in our reversal learning task. Among the compulsive subjects, we identified a subgroup with impaired performance not due to perseverative and rigid behaviors as commonly hypothesized, but rather to an increase in response lability.

Compulsivity and probabilistic reversal learning in OCD and cocaine addiction

2015 ◽  
Vol 30 (S2) ◽  
pp. S110-S111 ◽  
Author(s):  
P. Smith ◽  
N. Benzina ◽  
F. Vorspan ◽  
L. Mallet ◽  
K. N’Diaye
Keyword(s):  
Reversal Learning ◽  
A Priori ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Cocaine Addiction ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Cocaine Users ◽  
Probabilistic Reversal Learning

Compulsive behavior is a core symptom of both obsessive compulsive disorder (OCD) and cocaine addiction (CA). Across both pathologies, one can identify a priori goal-directed actions (purportedly anxiolytic checking or washing in OCD and pleasure-seeking drug use in addiction) that turn into rigid, ritualized and repetitive behaviors over which the patient loose control. One possible psychopathological mechanism underlying compulsivity is behavioral inflexibility, namely a deficit in the aptitude to dynamically adapt to novel contexts and changing reward rules. The probabilistic reversal learning paradigm allows to objectively assess behavioral flexibility by challenging participants with a task where they have to learn through trials-and-errors which of two stimuli is the most-often rewarded one, while adjusting to sudden inconspicuous contingency reversals. We therefore hypothesized that both OCD and CA would be associated with impaired cognitive flexibility, as measured through perseverative response rate following contingency reversals in this task. Interestingly, impulsivity may also be assessed within this task via the tendency of participants to switch from one stimulus to the other following probabilistic errors. To investigate cognitive inflexibility in relation to CA and OCD respectively, we first compared the performance in a probabilistic reversal learning task of cocaine users, ex cocaine users (abstinent for 2 months or more), and controls, as well as that of participants from the general population whose obsessive-compulsive traits were assessed using the OCI-R, a well-validated self-questionnaire. Our task yielded results similar to those found in the literature: cocaine addicts changed their responses more often, and learned less effectively. Ex-cocaine addicts performed better than addicts but worse than controls, suggesting that addicts’ poor results may be in part explained by reversible cognitive consequences of addiction. Addicts with less cognitive impairments may also be less likely to relapse. Regarding the relationship of flexibility to subclinical OCD traits, we found no link between OCI-R score and perseveration, or between impulsiveness and excessive switching.

scholarly journals A cross-species assessment of behavioral flexibility in compulsive disorders

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nabil Benzina ◽  
Karim N’Diaye ◽  
Antoine Pelissolo ◽  
Luc Mallet ◽  
Eric Burguière
Keyword(s):  
Reversal Learning ◽  
Cognitive Deficits ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Common Symptom ◽  
Distinct Subgroup ◽  
Compulsive Behaviors ◽  
Compulsive Disorders

AbstractLack 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.

Translational approach to study flexibility as an endophenotype of obsessive compulsive disorders

2014 ◽  
Vol 29 (S3) ◽  
pp. 546-546
Author(s):  
N. Benzina ◽  
S.L. Mondragon ◽  
N. Ouarti ◽  
L. Mallet ◽  
E. Burguiere
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Repetitive Behaviors ◽  
Reward Contingency ◽  
Neural Basis ◽  
Obsessive Compulsive ◽  
Compulsive Behaviors ◽  
Translational Approach ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Behavioral flexibility is the ability of a subject to change its behavior according to contextual cues. In humans, Obsessive Compulsive Disorders (OCD) is characterized by repetitive behavior, performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients may have diminished behavioral flexibility. To address this question we developed innovative translational approaches across multiple species, including human patients suffering from obsessive-compulsive disorders, and rodent genetic models of OCD to provide original data in the perspective of enlightening the neurocognitive bases of compulsive behaviors. Behavioral flexibility may be challenged in experimental tasks such as reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. After this first association has been learned, reward contingency are inverted, so that the previously neutral stimulus is now rewarded, while the previously rewarded stimulus is not. Performance in reversal learning is indexed by the number of perseverative errors committed when participants maintain their response towards previously reinforced stimulus in spite of negative reward. Unsurprisingly, this behavioral task has been adapted to mice using various response modalities (T-maze, lever press, nose-poke). Using animal models of compulsive behaviors give much more possibilities to study the deficient functions and their underlying neural basis that could lead to pathological repetitive behaviors. Here we present new behavioral set-ups that we developed in parallel in human (i.e. healthy subjects and OCD patients) and mice (i.e. controls and SAPAP3-KO mice) to study the role of the behavioral flexibility as a possible endophenotype of OCD. We observed that the subjects suffering of compulsive behaviors showed perseverative maladaptive behaviors in these tasks. By comparing the results of a similar task-design in humans and mouse models we will discuss the pertinence of such translational approach to further study the neurocognitive basis of compulsive behaviors.

scholarly journals Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants

2019 ◽  
Vol 18 (4) ◽  
pp. e12557 ◽  
Author(s):  
Bastijn J.G. van den Boom ◽  
Adriana H. Mooij ◽  
Ieva Misevičiūtė ◽  
Damiaan Denys ◽  
Ingo Willuhn
Keyword(s):  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Obsessive Compulsive ◽  
Compulsive Disorder

scholarly journals Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

2016 ◽  
Vol 113 (27) ◽  
pp. 7644-7649 ◽  
Author(s):  
Tao Dong ◽  
Jing He ◽  
Shiqing Wang ◽  
Lianzhang Wang ◽  
Yuqi Cheng ◽  
...  
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Loss Of Function ◽  
Risk Genes ◽  
Risk Gene ◽  
Alternative Approach ◽  
Similar Phenotype ◽  
Autistic Symptoms

The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.

scholarly journals Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

2019 ◽  
Author(s):  
Daniel Lustberg ◽  
Alexa Iannitelli ◽  
Rachel P. Tillage ◽  
Molly Pruitt ◽  
L. Cameron Liles ◽  
...  
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Symptomatic Relief ◽  
Repetitive Behavior ◽  
Repetitive Behaviors ◽  
Anterior Cingulate ◽  
Obsessive Compulsive ◽  
General Anxiety ◽  
Compulsive Disorder ◽  
Adrenergic Drugs ◽  
Compulsive Behaviors

AbstractRationaleObsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated.ObjectiveTo determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS) in two animal models of OCD.MethodsWe assessed NE-deficient (Dbh -/-) mice and NE-competent (Dbh +/-) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh -/- mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh -/- and control mice following both tasks.ResultsDbh -/- mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh -/- mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh -/- mice after MB and NS.ConclusionThese findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.

scholarly journals Independent and distinct patterns of abnormal lateral orbitofrontal cortex activity during compulsive grooming and reversal learning normalize after fluoxetine

2021 ◽  
Author(s):  
Elizabeth E Manning ◽  
Matthew A Geramita ◽  
Sean C Piantadosi ◽  
Susanne E Ahmari
Keyword(s):  
Reversal Learning ◽  
Neural Activity ◽  
Orbitofrontal Cortex ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Fluoxetine Treatment ◽  
Compulsive Behaviors ◽  
Before And After ◽  
Neural Underpinnings

AbstractBackgroundPatients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment.MethodsSapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks).ResultsBaseline compulsive grooming and reversal learning impairments in KOs improve after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, encoding of reversal learning and compulsive behavior are independent, as reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance).ConclusionsIn OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct and independent roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

scholarly journals Reduced Orbitofrontal-Striatal Activity on a Reversal Learning Task in Obsessive-Compulsive Disorder

2006 ◽  
Vol 63 (11) ◽  
pp. 1225 ◽  
Author(s):  
Peter L. Remijnse ◽  
Marjan M. A. Nielen ◽  
Anton J. L. M. van Balkom ◽  
Daniëlle C. Cath ◽  
Patricia van Oppen ◽  
...  
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Reversal Learning ◽  
Learning Task ◽  
Obsessive Compulsive ◽  
Compulsive Disorder

Why Can’t I Stop Thinking About It?

2015 ◽  
Vol 74 (2) ◽  
pp. 75-82 ◽  
Author(s):  
Monique C. Pfaltz ◽  
Beatrice Mörstedt ◽  
Andrea H. Meyer ◽  
Frank H. Wilhelm ◽  
Joe Kossowsky ◽  
...  
Keyword(s):  
Thought Suppression ◽  
Positive Association ◽  
Repetitive Behaviors ◽  
Thought Processes ◽  
Obsessive Compulsive ◽  
Vulnerability Factor ◽  
Compulsive Disorder ◽  
Order Factor ◽  
Maladaptive Thought ◽  
Severe Anxiety

Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by frequent obsessive thoughts and repetitive behaviors. Neuroticism is a vulnerability factor for OCD, yet the mechanisms by which this general vulnerability factor affects the development of OCD-related symptoms are unknown. The present study assessed a hierarchical model of the development of obsessive thoughts that includes neuroticism as a general, higher-order factor, and specific, potentially maladaptive thought processes (thought suppression, worry, and brooding) as second-order factors manifesting in the tendency toward obsessing. A total of 238 participants completed questionnaires assessing the examined constructs. The results of mediator analyses demonstrated the hypothesized relationships: A positive association between neuroticism and obsessing was mediated by thought suppression, worry, and brooding. Independent of the participant’s sex, all three mediators contributed equally and substantially to the association between neuroticism and obsessing. These findings extend earlier research on hierarchical models of anxiety and provide a basis for further refinement of models of the development of obsessive thoughts.

scholarly journals Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Science ◽  
2013 ◽  
Vol 340 (6137) ◽  
pp. 1234-1239 ◽  
Author(s):  
Susanne E. Ahmari ◽  
Timothy Spellman ◽  
Neria L. Douglass ◽  
Mazen A. Kheirbek ◽  
H. Blair Simpson ◽  
...  
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Orbitofrontal Cortex ◽  
Progressive Increase ◽  
Repetitive Behaviors ◽  
Mouse Behavior ◽  
First Line ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Chronic Fluoxetine

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)–ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

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