Synaptic mechanisms for associative learning in the cerebellar nuclei.

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.

GluA4 facilitates cerebellar expansion coding and enables associative memory formation.

AMPA receptors (AMPARs) mediate excitatory neurotransmission in the central nervous system (CNS) and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1-GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here, we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

Cannabinoids modulate associative cerebellar learning via alterations in behavioral state.

Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.

Locomotor activity modulates associative learning in mouse cerebellum.

Changes in behavioral state can profoundly influence brain function. Here we show that behavioral state modulates performance in delay eyeblink conditioning, a cerebellum-dependent form of associative learning. Increased locomotor speed in head-fixed mice drove earlier onset of learning and trial-by-trial enhancement of learned responses that were dissociable from changes in arousal and independent of sensory modality. Eyelid responses evoked by optogenetic stimulation of mossy fiber inputs to the cerebellum, but not at sites downstream, were positively modulated by ongoing locomotion. Substituting prolonged, low-intensity optogenetic mossy fiber stimulation for locomotion was sufficient to enhance conditioned responses. Our results suggest that locomotor activity modulates delay eyeblink conditioning through increased activation of the mossy fiber pathway within the cerebellum. Taken together, these results provide evidence for a novel role for behavioral state modulation in associative learning and suggest a potential mechanism through which engaging in movement can improve an individual's ability to learn.

Plasma levels of eight different mediators and their potential as biomarkers of various clinical malaria conditions in African children.

BACKGROUND: Plasmodium falciparum infection can lead to several clinical manifestations ranging from asymptomatic infections (AM) and uncomplicated malaria (UM) to potentially fatal severe malaria (SM), including cerebral malaria (CM). Factors implicated in the progression towards severe disease are not fully understood. METHODS: In the present study, an enzyme-linked immunosorbent assay (ELISA) method was used to investigate the plasma content of several biomarkers of the immune response, namely Neopterin, sCD163, suPAR, Pentraxin 3 (PTX3), sCD14, Fractalkine (CX3CL1), sTREM-1 and MIG (CXCL9), in patients with distinct clinical manifestations of malaria. The goal of this study was to determine the relative involvement of these inflammatory mediators in the pathogenesis of malaria and test their relevance as biomarkers of disease severity. RESULTS: ROC curve analysis show that children with AM were characterized by high levels of Fractalkine and sCD163 whereas children with UM were distinguishable by the presence of PTX3 in their plasma. Furthermore, principal component analysis indicated that the combination of Fractalkine, MIG, and Neopterin was the best predictor of AM condition, while suPAR, PTX3 and sTREM-1 combination was the best indicator of UM when compared to AM. The association of Neopterin, suPAR and Fractalkine was strongly predictive of SM or CM compared to UM. CONCLUSIONS: The results indicate that the simultaneous evaluation of these bioactive molecules as quantifiable blood parameters may be helpful to get a better insight into the clinical syndromes in children with malaria.

All Purkinje cells are not created equal.

Although the wiring of the cerebellar cortex appears to be uniform, the neurons in this region of the brain behave more differently from each other than previously thought.

Adenosine receptors interacting proteins (ARIPs): Behind the biology of adenosine signaling.

Adenosine is a well known neuromodulator in the central nervous system. As a consequence, adenosine can be beneficial in certain disorders and adenosine receptors will be potential targets for therapy in a variety of diseases. Adenosine receptors are G protein-coupled receptors, and are also expressed in a large variety of cells and tissues. Using these receptors as a paradigm of G protein-coupled receptors, the present review focus on how protein-protein interactions might contribute to neurotransmitter/neuromodulator regulation, based on the fact that accessory proteins impinge on the receptor/G protein interaction and therefore modulate receptor functioning. Besides affecting receptor signaling, these accessory components also play a key role in receptor trafficking, internalization and desensitization, as it will be reviewed here. In conclusion, the finding of an increasing number of adenosine receptors interacting proteins, and specially the molecular and functional integration of these accessory proteins into receptorsomes, will open new perspectives in the understanding of particular disorders where these receptors have been proved to be involved.

The association of metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function.

Metabotropic glutamate (mGlu) receptors mediate in part the CNS effects of glutamate. These receptors interact with a large array of intracellular proteins in which the final role is to regulate receptor function. Here, using co-immunoprecipitation and pull-down experiments we showed a close and specific interaction between mGlu(5) receptor and NECAB2 in both transfected human embryonic kidney cells and rat hippocampus. Interestingly, in pull-down experiments increasing concentrations of calcium drastically reduced the ability of these two proteins to interact, suggesting that NECAB2 binds to mGlu(5) receptor in a calcium-regulated manner. Immunoelectron microscopy detection of NECAB2 and mGlu(5) receptor in the rat hippocampal formation indicated that both proteins are codistributed in the same subcellular compartment of pyramidal cells. In addition, the NECAB2/mGlu(5) receptor interaction regulated mGlu(5b)-mediated activation of both inositol phosphate accumulation and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Overall, these findings indicate that NECAB2 by its physical interaction with mGlu(5b) receptor modulates receptor function.