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

Dysfunction of Orbitofrontal GABAergic Interneurons Leads to Impaired Reversal Learning in a Mouse Model of Obsessive-Compulsive Disorder

2020 ◽  
Author(s):  
Zicheng Yang ◽  
Geming Wu ◽  
Min Liu ◽  
Xiaohong Sun ◽  
Qunyuan Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Reversal Learning ◽  
Gabaergic Interneurons ◽  
Obsessive Compulsive ◽  
Compulsive Disorder

Spotlight on a mouse model of obsessive-compulsive disorder

2013 ◽  
Vol 28 (S2) ◽  
pp. 17-17
Author(s):  
E. Burguière
Keyword(s):  
Basal Ganglia ◽  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Response Inhibition ◽  
Mutant Mouse ◽  
Repetitive Behavior ◽  
Inhibitory Neurons ◽  
Obsessive Compulsive ◽  
Repetitive Behaviour ◽  
Compulsive Disorder

It has been shown these last years that optogenetic tool, that uses a combination of optics and genetics technics to control neuronal activity with light on behaving animals, allows to establish causal relationship between brain activity and normal or pathological behaviors [3]. In combination with animal model of neuropsychiatric disorder, optogenetic could help to identify deficient circuitry in numerous pathologies by exploring functional connectivity, with a specificity never reached before, while observing behavioral and/or physiological correlates. To illustrate the promising potential of these tools for the understanding of psychiatric diseases, we will present our recent study where we used optogenetic to block abnormal repetitive behavior in a mutant mouse model of obsessive-compulsive disorder [1]. Using a delay-conditioning task we showed that these mutant mouse model had a deficit in response inhibition that lead to repetitive behaviour. With optogenetic, we could stimulate a specific circuitry in the brain that connect the orbitofrontal cortex with the basal ganglia; a circuitry that has been shown to be dysfunctional in compulsive behaviors. We observed that these optogenetic stimulations, through their effect on inhibitory neurons of the basal ganglia, could restore the behavioral response inhibition and alleviate the compulsive behavior. These findings raise promising potential for the design of targeted deep brain stimulation therapy for disorders involving excessive repetitive behavior and/or for the optimization of already existing stimulation protocol [2].

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 Postpartum Lactation-Mediated Behavioral Outcomes and Drug Responses in a Spontaneous Mouse Model of Obsessive–Compulsive Disorder

2017 ◽  
Vol 8 (12) ◽  
pp. 2683-2697 ◽  
Author(s):  
Swarup Mitra ◽  
McKenzie Mucha ◽  
Savanah Owen ◽  
Abel Bult-Ito
Keyword(s):  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Behavioral Outcomes ◽  
Obsessive Compulsive ◽  
Drug Responses ◽  
Compulsive Disorder

scholarly journals Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [11C]UCB-J PET study in a model of obsessive–compulsive disorder-like behaviour

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dorien Glorie ◽  
Jeroen Verhaeghe ◽  
Alan Miranda ◽  
Stef De Lombaerde ◽  
Sigrid Stroobants ◽  
...  
Keyword(s):  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Ex Vivo ◽  
Obsessive Compulsive ◽  
Synaptic Density ◽  
Compulsive Disorder ◽  
In Vitro Autoradiography ◽  
Ex Vivo Autoradiography ◽  
The Brain

Abstract Background Currently, the evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging. The newly established positron emission tomography (PET) ligand ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([11C]UCB-J) provides the opportunity to visualize synaptic density changes in vivo, by targeting the synaptic vesicle protein 2A (SV2A). Here, we aim to evaluate such alterations in the brain of the SAP90/PSD-95-associated protein 3 (Sapap3) knockout (ko) mouse model, showing an abnormal corticostriatal neurotransmission resulting in OCD-like behaviour. Methods Longitudinal [11C]UCB-J µPET/CT scans were acquired in Sapap3 ko and wildtype (wt) control mice (n = 9/group) to study SV2A availability. Based on the Logan reference method, we calculated the volume of distribution (VT(IDIF)) for [11C]UCB-J. Both cross-sectional (wt vs. ko) and longitudinal (3 vs. 9 months) volume-of-interest-based statistical analysis and voxel-based statistical parametric mapping were performed. Both [11C]UCB-J ex vivo autoradiography and [3H]UCB-J in vitro autoradiography were used for the validation of the µPET data. Results At the age of 3 months, Sapap3 ko mice are already characterized by a significantly lower SV2A availability compared to wt littermates (i.a. cortex − 12.69%, p < 0.01; striatum − 14.12%, p < 0.001, thalamus − 13.11%, p < 0.001, and hippocampus − 12.99%, p < 0.001). Healthy ageing in control mice was associated with a diffuse and significant (p < 0.001) decline throughout the brain, whereas in Sapap3 ko mice this decline was more confined to the corticostriatal level. A strong linear relationship (p < 0.0001) was established between the outcome parameters of [11C]UCB-J µPET and [11C]UCB-J ex vivo autoradiography, while such relationship was absent for [3H]UCB-J in vitro autoradiography. Conclusions [11C]UCB-J PET is a potential marker for synaptic density deficits in the Sapap3 ko mouse model for OCD, parallel to disease progression. Our data suggest that [11C]UCB-J ex vivo autoradiography is a suitable proxy for [11C]UCB-J PET data in mice.

scholarly journals Differential frontal–striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive–compulsive disorder

2009 ◽  
Vol 39 (9) ◽  
pp. 1503-1518 ◽  
Author(s):  
P. L. Remijnse ◽  
M. M. A. Nielen ◽  
A. J. L. M. van Balkom ◽  
G.-J. Hendriks ◽  
W. J. Hoogendijk ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Obsessive Compulsive Disorder ◽  
Reversal Learning ◽  
Anterior Insula ◽  
Healthy Controls ◽  
Obsessive Compulsive ◽  
Major Depressive ◽  
Compulsive Disorder ◽  
Imaging Results

BackgroundSeveral lines of research suggest a disturbance of reversal learning (reward and punishment processing, and affective switching) in patients with major depressive disorder (MDD). Obsessive–compulsive disorder (OCD) is also characterized by abnormal reversal learning, and is often co-morbid with MDD. However, neurobiological distinctions between the disorders are unclear. Functional neuroimaging (activation) studies comparing MDD and OCD directly are lacking.MethodTwenty non-medicated OCD-free patients with MDD, 20 non-medicated MDD-free patients with OCD, and 27 healthy controls performed a self-paced reversal learning task in an event-related design during functional magnetic resonance imaging (fMRI).ResultsCompared with healthy controls, both MDD and OCD patients displayed prolonged mean reaction times (RTs) but normal accuracy. In MDD subjects, mean RTs were correlated with disease severity. Imaging results showed MDD-specific hyperactivity in the anterior insula during punishment processing and in the putamen during reward processing. Moreover, blood oxygen level-dependent (BOLD) responses in the dorsolateral prefrontal cortex (DLPFC) and the anterior PFC during affective switching showed a linear decrease across controls, MDD and OCD. Finally, the OCD group showed blunted responsiveness of the orbitofrontal (OFC)–striatal loop during reward, and in the OFC and anterior insula during affective switching.ConclusionsThis study shows frontal–striatal and (para)limbic functional abnormalities during reversal learning in MDD, in the context of generic psychomotor slowing. These data converge with currently influential models on the neuropathophysiology of MDD. Moreover, this study reports differential neural patterns in frontal–striatal and paralimbic structures on this task between MDD and OCD, confirming previous findings regarding the neural correlates of deficient reversal learning in OCD.

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

2008 ◽  
Vol 20 (2) ◽  
pp. 210-218 ◽  
Author(s):  
Gabriele Valerius ◽  
Anne Lumpp ◽  
Anne-Katrin Kuelz ◽  
Tobias Freyer ◽  
Ulrich Voderholzer
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Reversal Learning ◽  
Behavioral Study ◽  
Obsessive Compulsive ◽  
Compulsive Disorder
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