Checking responses of goal- and sign-trackers are differentially affected by threat in a rodent analog of obsessive-compulsive disorder.

In obsessive-compulsive disorder (OCD), functional behaviors such as checking that a door is locked become dysfunctional, maladaptive, and debilitating. However, it is currently unknown how aversive and appetitive motivations interact to produce functional and dysfunctional behavior in OCD. Here we show a double dissociation in the effects of anxiogenic cues and sensitivity to rewarding stimuli on the propensity to develop functional and dysfunctional checking behavior in a rodent analog of OCD, the observing response task (ORT). While anxiogenic manipulations of perceived threat (presentation of threat-associated contextual cues) and actual threat (punishment of incorrect responding on the ORT) enhanced functional checking, dysfunctional checking was unaffected. In contrast, rats that had previously been identified as "sign-trackers" on an autoshaping task-and therefore were highly sensitive to the incentive salience of appetitive environmental cues-selectively showed elevated levels of dysfunctional checking under a range of conditions, but particularly so under conditions of uncertainty. These data indicate that functional and dysfunctional checking are dissociable and supported by aversive and appetitive motivational processes, respectively. While functional checking is modulated by perceived and actual threat, dysfunctional checking recruits appetitive motivational processes, possibly akin to the "incentive habits" that contribute to drug-seeking in addiction

Neuronal basis of temporal order judgement in rats

Le jugement d’ordre temporel est un processus permettant l’organisation chronologique des stimuli perçus en fonction de l’écoulement objectif ou subjectif du temps. Il permet de créer une représentation perceptuelle de l’environnement, essentielle à la mise en place de comportements adaptés. Plusieurs pathologies, telles que la schizophrénie ou les troubles du spectre autistique, montrent une perturbation de la sensibilité et de la précision à détecter un ordre temporel, pouvant conduire à des délires et hallucinations. La plupart des études recensées à ce jour ont été réalisées chez l’Homme. A notre connaissance, uniquement trois études ont exploré le jugement de l’ordre temporel chez le rongeur. Au cours de cette thèse, nous avons donc développé une tâche comportementale permettant l’étude du jugement d’ordre temporel de stimuli audiovisuels chez le rat. Les rats ont été entraînés à appuyer sur un levier spatialisé (droite ou gauche) suite à la présentation d’un ordre de stimuli audiovisuels (AV et VA). Afin de s’assurer d’un traitement du premier puis du deuxième stimulus, des essais non renforcés (AA et VV) ont été ajoutés. Dans ce cas, la détection du premier ou du deuxième stimulus de la paire n'est plus suffisante pour permettre la réalisation d’une réponse correcte dans la mesure où les rats doivent traiter les deux stimuli successifs pour distinguer les essais renforcés et non renforcés (par exemple, AV et AA). Nous avons montré que les rats entraînés à cette tâche présentent des signatures perceptuelles du traitement de l’ordre temporel comparables aux données chez l’Homme. Parmi ces signatures, nous retrouvons une grande variabilité interindividuelle et un effet séquentiel, c’est-à-dire un effet de l’essai précédent sur la réponse à l’ordre temporel présenté. Nous avons ensuite voulu déterminer si certaines structures cérébrales sont impliquées dans ce traitement d’ordre temporel. Grâce à l’utilisation d’un marqueur de l’activité neuronale, nous avons pu démontrer l’implication du cortex préfrontal dans le traitement de l’ordre temporel chez le rat.Temporal order judgment is a process allowing the chronological organization of the perceived stimuli according to the objective or subjective flow of time. The integration of stimuli order contributes to the perceptual representation of the environment in which individuals can evolve appropriately. Disruption of temporal order judgment is described in several pathologies, such as schizophrenia or autism spectrum disorders, in which the sensitivity and accuracy in the detection of the order are reduced, leading to delusions and hallucinations. To date, most of the studies have been carried out in humans. To our knowledge, only three studies have explored temporal order judgment in rodents. In this thesis, we have therefore developed a behavioural task allowing the study of temporal order judgment of audiovisual stimuli in rats. The rats were trained to press a spatialized lever (right or left) depending on the presentation of an audiovisual order (AV and VA). In order to ensure the processing of both the first and the second stimuli, non-reinforced trials (AA and VV) were added. Thus, the detection of the first or second stimulus of the pair was no longer sufficient to allow a correct response inasmuch as rats have to process the two successive stimuli to distinguish between reinforced and non-reinforced trials (e.g., AV and AA). We have shown that rats trained to this task displayed perceptual signatures comparable to the data reported in humans. Among these signatures, we found a large inter-individual variability and a sequential effect, in other words an effect of the previous trial on the ongoing trial. In addition, thanks to the use of a marker of neuronal activity, we were able to demonstrate the involvement of the prefrontal cortex in the temporal order judgment in rat

Bases neuronales du jugement d’ordre temporel chez le rat

Temporal order judgment is a process allowing the chronological organization of the perceived stimuli according to the objective or subjective flow of time. The integration of stimuli order contributes to the perceptual representation of the environment in which individuals can evolve appropriately. Disruption of temporal order judgment is described in several pathologies, such as schizophrenia or autism spectrum disorders, in which the sensitivity and accuracy in the detection of the order are reduced, leading to delusions and hallucinations. To date, most of the studies have been carried out in humans. To our knowledge, only three studies have explored temporal order judgment in rodents. In this thesis, we have therefore developed a behavioural task allowing the study of temporal order judgment of audiovisual stimuli in rats. The rats were trained to press a spatialized lever (right or left) depending on the presentation of an audiovisual order (AV and VA). In order to ensure the processing of both the first and the second stimuli, non-reinforced trials (AA and VV) were added. Thus, the detection of the first or second stimulus of the pair was no longer sufficient to allow a correct response inasmuch as rats have to process the two successive stimuli to distinguish between reinforced and non-reinforced trials (e.g., AV and AA). We have shown that rats trained to this task displayed perceptual signatures comparable to the data reported in humans. Among these signatures, we found a large inter-individual variability and a sequential effect, in other words an effect of the previous trial on the ongoing trial. In addition, thanks to the use of a marker of neuronal activity, we were able to demonstrate the involvement of the prefrontal cortex in the temporal order judgment in rat.Le jugement d’ordre temporel est un processus permettant l’organisation chronologique des stimuli perçus en fonction de l’écoulement objectif ou subjectif du temps. Il permet de créer une représentation perceptuelle de l’environnement, essentielle à la mise en place de comportements adaptés. Plusieurs pathologies, telles que la schizophrénie ou les troubles du spectre autistique, montrent une perturbation de la sensibilité et de la précision à détecter un ordre temporel, pouvant conduire à des délires et hallucinations. La plupart des études recensées à ce jour ont été réalisées chez l’Homme. A notre connaissance, uniquement trois études ont exploré le jugement de l’ordre temporel chez le rongeur. Au cours de cette thèse, nous avons donc développé une tâche comportementale permettant l’étude du jugement d’ordre temporel de stimuli audiovisuels chez le rat. Les rats ont été entraînés à appuyer sur un levier spatialisé (droite ou gauche) suite à la présentation d’un ordre de stimuli audiovisuels (AV et VA). Afin de s’assurer d’un traitement du premier puis du deuxième stimulus, des essais non renforcés (AA et VV) ont été ajoutés. Dans ce cas, la détection du premier ou du deuxième stimulus de la paire n'est plus suffisante pour permettre la réalisation d’une réponse correcte dans la mesure où les rats doivent traiter les deux stimuli successifs pour distinguer les essais renforcés et non renforcés (par exemple, AV et AA). Nous avons montré que les rats entraînés à cette tâche présentent des signatures perceptuelles du traitement de l’ordre temporel comparables aux données chez l’Homme. Parmi ces signatures, nous retrouvons une grande variabilité interindividuelle et un effet séquentiel, c’est-à-dire un effet de l’essai précédent sur la réponse à l’ordre temporel présenté. Nous avons ensuite voulu déterminer si certaines structures cérébrales sont impliquées dans ce traitement d’ordre temporel. Grâce à l’utilisation d’un marqueur de l’activité neuronale, nous avons pu démontrer l’implication du cortex préfrontal dans le traitement de l’ordre temporel chez le rat

Temporal order processing in rats depends on the training protocol.

The perception of temporal order can help infer the causal structure of the world. By investigating the perceptual signatures of audiovisual temporal order in rats, we demonstrate the importance of the protocol design for reliable order processing. Rats trained with both reinforced audiovisual trials and non-reinforced unisensory trials (two consecutive tones or flashes) learned the task surprisingly faster than rats trained with reinforced multisensory trials only. They also displayed signatures of temporal order perception, such as individual biases and sequential effects that are well described in humans, and impaired in clinical populations. We conclude that an experimental protocol requiring individuals to process all stimuli in a sequence is compulsory to ensure temporal order processing

Research data supporting "Checking responses of goal- and sign-trackers are differentially affected by threat in a rodent analogue of obsessive-compulsive disorder"

These files contain the behavioural data reported in Experiment 1 (B3.462 data for publication) and Experiment 2 (B3.470 data for publication) of Vousden et al. (2020). Rats were classified as sign-trackers or goal-trackers based on their performance on an autoshaping task. They were also trained on the Observing Response Task, which allows the measurement of OCD-like dysfunctional checking behaviour. In Experiment 1, the effects of manipulating the uncertainty of reinforcement and perceived threat on dysfunctional checking were assessed. In Experiment 2, the effects of actual threat (i.e. punishment) on dysfunctional checking were assessed. Also included is another Excel file which contains further information on how to interpret the spreadsheets and more detailed methodological information

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

International audienceOxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca 2+ influx, but is also dependent on Ca 2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca 2+ -dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca 2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior