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Predictive learning exerts a powerful influence over choice between instrumental actions. Nevertheless, how this learning is encoded in a sufficiently stable manner to influence choices that can occur much later in time is unclear. Here, we report that the basolateral amygdala (BLA) encodes predictive learning and establishes the memory necessary for future choices by driving the accumulation of delta-opioid receptors (DOPRs) on the somatic membrane of cholinergic interneurons in the nucleus accumbens shell (NAc-S). We found that the BLA controls DOPR accumulation via its influence on substance P release in the NAc-S, and that although DOPR accumulation is not necessary for predictive learning per se, it is necessary for the influence of this learning on later choice between actions. This study uncovers, therefore, a novel GPCR-based form of memory that is established by predictive learning and is necessary for such learning to guide the selection and execution of specific actions.

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Sphingosine-1-phosphate (S1P) is a potent bioactive lipid mediator that acts as a natural ligand upon binding to five different receptors that are located in astrocytes, oligodendrocytes, microglial and neuronal cells. Recently, global activation of these receptors by FTY720 (fingolimod) has been suggested to provide neuroprotection in animal model of Parkinson's disease (PD). Among S1P receptors, the subtype 1 (S1P1R) has been linked to features of neuroprotection and, using the selective agonist SEW2871, the present investigation assessed potential benefits (and mechanisms) of this receptor subtype in an established animal model of PD. We demonstrated that oral treatments with SEW2871 are able to provide protection to the same levels as FTY720 against loss of dopaminergic neurons and motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg, i.p., 5 days) mouse model of PD. At the molecular level, we observed that the beneficial effects of both S1PR agonists were not associated with alterations in ERK and Akt levels, two markers of molecular adaptations in the striatum neurons. However, these compounds have the capacity to prevent signs of neuroinflammation such as the activation of astrocytes and glial cells, as well as MPTP-induced reduction of BDNF levels in key regions of the brain implicated in motor functions. These findings suggest that selective S1P1R modulation has the ability to provide neuroprotection in response to MPTP neurotoxicity. Targeting S1P1R in PD therapy may represent a prominent candidate for treatment of this neurodegenerative conditions.

RESUMEN

Akt protein family (Akt1, Akt2 and Akt3) of serine/threonine kinases, also known as protein kinase B, are enzymes implicated in many physiological and pathological processes in the central nervous system. A striking feature of these enzymes is their ability to interact with several molecular targets such as the glycogen synthase kinase 3 (GSK-3). Among Akt isoforms, the Akt3 is significantly more expressed in the brain and the present investigation was designed to determine whether the Akt3/GSK-3 pathway plays a role in the learning of a complex motor skill. Using the accelerating rotarod task, known to reproduce different motor learning phases, we demonstrated in mouse models that genetic deletion of GSK-3α or GSK-3ß had no effect on rotarod performances. However, Akt3 deletion robustly compromised rotarod learning when compared with wild-type animals. Biochemical analysis in the striatum revealed modifications in the levels of both phosphorylated GSK-3 and tau in Akt3-deficient mice, which are reminiscent of enhanced GSK-3 activity. In this line, we observed that both biochemical and motor learning impairments were prevented in Akt3-deficent mice by chronic treatments with lithium, a well-known GSK-3 inhibitor. Altogether, our findings raised the interesting possibility that interconnection between Akt3 and GSK-3 kinases is required in the learning of new complex motor tasks. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

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Sphingosine-1-phosphate (S1P) is a ceramide derivative serving not only as a regulator of immune properties but also as a modulator of brain functions. To better understand the mechanism underlying the effects of S1P on brain functions, we investigated the potential impact of S1P receptor (S1PR) activation on NMDA receptor subunits. We used acute rat hippocampal slices as a model system, and determined the effects of the active phosphorylated S1P analog, fingolimod (FTY720P) on various NMDA receptors. Treatment with FTY720P significantly increased phosphorylation of GluN2B-containing NMDA receptors at Tyr1472. This effect appears rather specific, as treatment with FTY720P did not modify GluN2B-Tyr1336, GluN2B-Ser1480, GluN2A-Tyr1325 or GluN1-Ser897 phosphorylation. Pre-treatment of hippocampal slices with the compounds W146 and PP1 indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 epitopes was dependent on activation of S1PR subunit 1 (S1PR1) and Src/Fyn kinase, respectively. Cell surface biotinylation experiments indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 was also associated with increased levels of GluN1 and GluN2B subunits on membrane surface, whereas no change was observed for GluN2A subunits. We finally demonstrate that FTY720P is inclined to favor Tau and Fyn accumulation on plasma membranes. These results suggest that activation of S1PR1 by FTY720P enhances GluN2B receptor phosphorylation in rat hippocampal slices, resulting in increased levels of GluN1 and GluN2B receptor subunits in neuronal membranes through a mechanism probably involving Fyn and Tau.

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