title: D2 dopamine receptor regulation of learning, sleep and plasticity.
abstract: Dopamine and sleep have been independently linked with hippocampus-dependent learning. Since D2 dopaminergic transmission is required for the occurrence of rapid-eye-movement (REM) sleep, it is possible that dopamine affects learning by way of changes in post-acquisition REM sleep. To investigate this hypothesis, we first assessed whether D2 dopaminergic modulation in mice affects novel object preference, a hippocampus-dependent task. Animals trained in the dark period, when sleep is reduced, did not improve significantly in performance when tested 24h after training. In contrast, animals trained in the sleep-rich light period showed significant learning after 24h. When injected with the D2 inverse agonist haloperidol immediately after the exploration of novel objects, animals trained in the light period showed reduced novelty preference upon retesting 24h later. Next we investigated whether haloperidol affected the protein levels of plasticity factors shown to be up-regulated in an experience-dependent manner during REM sleep. Haloperidol decreased post-exploration hippocampal protein levels at 3h, 6h and 12h for phosphorylated Ca(2+)/calmodulin-dependent protein kinase II, at 6h for Zif-268; and at 12h for the brain-derived neurotrophic factor. Electrophysiological and kinematic recordings showed a significant decrease in the amount of REM sleep following haloperidol injection, while slow-wave sleep remained unaltered. Importantly, REM sleep decrease across animals was strongly correlated with deficits in novelty preference (Rho=0.56, p=0.012). Altogether, the results suggest that the dopaminergic regulation of REM sleep affects learning by modulating post-training levels of calcium-dependent plasticity factors.
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte (UFRN), 59056-450 Natal, RN, Brazil.
authors.forename: A S C
authors.initials: AS
authors.lastname: França
authors.affiliation: Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte (UFRN), Brazil. Electronic address: brunolobaosoares@gmail.com.
authors.forename: B
authors.initials: B
authors.lastname: Lobão-Soares
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte (UFRN), 59056-450 Natal, RN, Brazil; Department of Biochemistry, Federal University of Rio Grande do Norte (UFRN), Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Muratori
authors.affiliation: Department of Biomedical Engineering, Federal University of Rio Grande do Norte (UFRN), Brazil; Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Nascimento
authors.affiliation: Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Winne
authors.affiliation: Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: C M
authors.initials: CM
authors.lastname: Pereira
authors.affiliation: Department of Biochemistry, Federal University of Rio Grande do Norte (UFRN), Brazil.
authors.forename: S M B
authors.initials: SM
authors.lastname: Jeronimo
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte (UFRN), 59056-450 Natal, RN, Brazil. Electronic address: sidartaribeiro@neuro.ufrn.br.
authors.forename: S
authors.initials: S
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003623:Dark Adaptation / Q000187:drug effects / Q000502:physiology; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D065127:Dopamine D2 Receptor Antagonists; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017448:Receptors, Dopamine D2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006220:Haloperidol
keywords: BDNF; CaMKII; Haloperidol; Object recognition; REM sleep; Zif-268