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Omega-3 fatty acids (FA) are essential long-chain polyunsaturated FA, amongst others, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The main food source of omega-3 is the oily fish which is found in salmon, anchovy or tuna. A diet enriched with omega-3 is known to favour healthy states by promoting molecular and functional changes during brain damage recovery, membranes fluidity, energy metabolism regulation, release of signalling molecules or gene expression. Likewise, the activation of signalling pathways by omega-3 improves neural transmission and plasticity and decreases oxidative stress and inflammation in cells, particularly in neurons. Therefore, omega-3 supplements have been used to prevent or treat many human disorders. This review is intended to provide the stateof- the art of omega-3 as a natural component with beneficial therapeutic properties in cardiovascular and neurodegenerative diseases (Alzheimer and Parkinson), cancer, alcoholism and overweight. Lastly, some insights into the potential benefits of omega-3 supplementation to dodge or treat some other diseases in the future are also considered.; Kate luzeko omega-3 mantenugaiak, azido α-linolenikoa (ALA), azido eikosapentaenoikoa (EPA) eta azido dokosahexaenoikoa (DHA), dietaren bitartez bereganatzen diren gantz-azido (GA) poliasegabeak dira. Propietate antioxidatzaileak barne hartzen dituzten hiru osagai horien elikagai-iturri nagusia arrain koipetsua (izokina, antxoa, hegalaburra…) eta horretatik eratorritako arrain-olioa dira batez ere. Omega-3 GA osagarriaz aberastutako dietak aldaketa molekular zein funtzional mesedegarriak eragiten ditu garunaren garapen prozesuan, zenbait garun lesioren berreskurapenean parte hartzen. Gehigarri horrek mintz zelularraren fluidotasuna areagotzen du, eta metabolismoaren erregulazioan parte hartzen du, seinaleztapen molekulen askapena sustatuz eta gene espresioan eraginez. Bi ekintza horien bidez seinaleztapen bideak aktibatzen dira, eta ondorioz garun plastikotasuna eta transmisio sinaptikoa suspertu. Areago, omega-3 GAk zeluletan oro har, eta neuronetan bereziki, oxidazio-estresak eta hanturak eragindako kalteak murriztu ditzake. Horregatik guztiagatik, omega-3 osagarria hainbat patologietan prebentzioan edo tratamenduan erabili da. Berrikuspen honek laburbiltzen ditu kate luzeko omega-3 GAetan aberastutako tratamenduak bihotz hodietako gaixotasunetan, minbizian, neuroendekapenezko gaixotasunetan (Alzheimer eta Parkinson), alkoholismoan eta gainpisuan, oinarrizko ikerkuntzan eta ikerketa klinikoan frogatu eta egiaztatu diren aurrerapen terapeutiko berriak; eta etorkizunera begira beste hainbat gaixotasuni aurrea hartzeko edo haiek tratatzeko potentzialtasun handiko eta albo ondoriorik gabeko osagarri ez-inbaditzaile aproposa izan daitekeela iradokitzen du.

Summary The nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptor medium spiny neurons (MSNs) of the NAc and the endogenous cannabinoid (eCB) system have been implicated in reward seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSNs (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain-stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses., Graphical Abstract, Highlights • mGluR5-D1-CB1-induced eCB-LTD mediates drugs of abuse and natural reward seeking • eCB-LTD in D2-MSNs plays no important role in processing of reward-seeking responses • Loss of eCB-LTD is a consequence of higher MAGL activity and lower CB1R expression • Acute drug administration stops craving for alternative rewards on following days, Neuroscience; Behavioral Neuroscience; Molecular Neuroscience

The transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel that plays an important role in pain perception and modulates neurotransmitter release and synaptic plasticity in the brain. TRPV1 function must lay on its anatomical distribution in the peripheral and central nervous system regions involved in the physiological roles of the channel. However, the anatomical localization of TRPV1 is well established in the periphery, but in the brain it is a matter of debate. While some studies support the presence of TRPV1 in several brain regions, recent evidences suggest a restricted distribution of the channel in the central nervous system. To investigate to what extent central TRPV1 function stands on a precise brain distribution of the channel, we examined the mouse hippocampal dentate molecular layer (ML) where TRPV1 mediates long-term synaptic plasticity. Using pre-embedding immunocytochemistry for high resolution electron microscopy, we show that TRPV1 immunoparticles are highly concentrated in postsynaptic dendritic spines to asymmetric perforant path synapses in the outer 2/3 of the ML. However, TRPV1 is poorly expressed at the excitatory hilar mossy cell synapses in the inner 1/3 of this layer. Importantly, the TRPV1 pattern distribution disappeared in the ML of TRPV1-knockout mice. Taken together, these findings support the notion of the presence of TRPV1 in a brain region where the channel has been shown to have a functional role, such as the perforant path synapses in the hippocampal dentate ML.

The hypothalamus and the endocannabinoid system are important players in the regulation of energy homeostasis. In a previous study, we described the ultrastructural distribution of CB1 receptors in GABAergic and glutamatergic synaptic terminals of the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH). However, the specific localization of the enzymes responsible for the synthesis of the two main endocannabinoids in the hypothalamus is not known. The objective of this study was to investigate the precise subcellular distribution of N-arachidonoylphospatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase α (DAGL-α) in the dorsomedial VMH of wild-type mice by a high resolution immunogold electron microscopy technique. Knock-out mice for each enzyme were used to validate the specificity of the antibodies. NAPE-PLD was localized presynaptically and postsynaptically but showed a preferential distribution in dendrites. DAGL-α was mostly postsynaptic in dendrites and dendritic spines. These anatomical results contribute to a better understanding of the endocannabinoid modulation in the VMH nucleus. Furthermore, they support the idea that the dorsomedial VMH displays the necessary machinery for the endocannabinoid-mediated modulation of synaptic transmission of brain circuitries that regulate important hypothalamic functions such as feeding behaviors.

We have recently shown that the transient receptor potential vanilloid type 1 (TRPV1), a non-selective cation channel in the peripheral and central nervous system, is localized at postsynaptic sites of the excitatory perforant path synapses in the hippocampal dentate molecular layer (ML). In the present work, we have studied the distribution of TRPV1 at inhibitory synapses in the ML. With this aim, a preembedding immunogold method for high resolution electron microscopy was applied to mouse hippocampus. About 30% of the inhibitory synapses in the ML are TRPV1 immunopositive, which is mostly localized perisynaptically (similar to 60% of total immunoparticles) at postsynaptic dendritic membranes receiving symmetric synapses in the inner 1/3 of the layer. This TRPV1 pattern distribution is not observed in the ML of TRPV1 knock-out mice. These findings extend the knowledge of the subcellular localization of TRPV1 to inhibitory synapses of the dentate molecular layer where the channel, in addition to excitatory synapses, is present. P. Grandes' laboratory is provided by Ministerio de Economia y Competitividad (BFU2012-33334); Basque Government grant IT764-13; University of the Basque Country (UFI11/41) and by Red de Trastornos Adictivos, RETICS, Instituto de Salud Carlos III, grant number: RD07/0001/2001, RD12/0028/0004.

To what extent the intrinsic glutamatergic system of the cerebellum is able to keep normal features in the absence of mossy and climbing fibres, is at present not known. To answer this question, immunocytochemistry for light and high resolution electron microscopy was used to reveal the cellular and subcellular distribution of glutamate receptors in isolated cerebellar cultures. The localization of the ionotropic glutamate receptor subunits GluA2/3 and the metabotropic glutamate (mGlu) 1a and mGlu2/3 receptor subtypes was carried out in 0 to 9-day-old rat parasagittal slices developed in vitro for 20–40 days. The typical localization of GluA2/3, mGlu1a and mGlu2/3 observed in Purkinje cells, granule cells, Golgi cells and unipolar brush cells was maintained in the organotypic cultures. Furthermore, the subcellular distribution of mGlu1a showed the characteristic in vivo perisynaptic position in Purkinje cell dendritic spines receiving parallel fibre synapses. We conclude that the cellular and subcellular localization of the studied ionotropic and metabotropic glutamate receptors is not affected by the removal of the two extrinsic cerebellar glutamatergic inputs, the mossy and climbing fibres.