A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex
Notice bibliographique
Résumé
Atypical multisensory integration is an understudied cognitive symptom in schizophrenia. Procedures to evaluate multisensory integration in rodent models are lacking. We developed a novel multisensory object oddity (MSO) task to assess multisensory integration in ketamine-treated rats, a well established model of schizophrenia. Ketamine-treated rats displayed a selective MSO task impairment with tactile–visual and olfactory–visual sensory combinations, whereas basic unisensory perception was unaffected. Orbitofrontal cortex (OFC) administration of nicotine or ABT-418, an α 4 β 2 nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABA A receptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of α 4 β 2 nAChRs. Furthermore, parvalbumin (PV) immunoreactivity was decreased in the OFC of ketamine-treated rats. Accordingly, silencing of PV interneurons in OFC of PV-Cre mice using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) selectively impaired MSO task performance and this was reversed by ABT-418. Likewise, clozapine- N -oxide-induced inhibition of PV interneurons in brain slices was reversed by activation of α 4 β 2 nAChRs. These findings strongly imply a role for prefrontal GABAergic transmission in the integration of multisensory object features, a cognitive process with relevance to schizophrenia. Accordingly, nAChR agonism, which improves various facets of cognition in schizophrenia, reversed the severe MSO task impairment in this study and appears to do so via a GABAergic mechanism. Interactions between GABAergic and nAChR receptor systems warrant further investigation for potential therapeutic applications. The novel behavioral procedure introduced in the current study is acutely sensitive to schizophrenia-relevant cognitive impairment and should prove highly valuable for such research. SIGNIFICANCE STATEMENT Adaptive behaviors are driven by integration of information from different sensory modalities. Multisensory integration is disrupted in patients with schizophrenia, but little is known about the neural basis of this cognitive symptom. Development and validation of multisensory integration tasks for animal models is essential given the strong link between functional outcome and cognitive impairment in schizophrenia. We present a novel multisensory object oddity procedure that detects selective multisensory integration deficits in a rat model of schizophrenia using various combinations of sensory modalities. Moreover, converging data are consistent with a nicotinic-GABAergic mechanism of multisensory integration in the prefrontal cortex, results with strong clinical relevance to the study of cognitive impairment and treatment in schizophrenia.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».