Long-term intake of Lactobacillus helveticus enhances bioavailability of omega-3 fatty acids in the mouse retina.

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), are required for the structure and function of the retina. Several observational studies indicate that consumption of a diet with relatively high levels of n-3 PUFAs, such as those provided by fish oils, has a protective effect against the development of age-related macular degeneration. Given the accumulating evidence showing the role of gut microbiota in regulating retinal physiology and host lipid metabolism, we evaluated the potential of long-term dietary supplementation with the Gram-positive bacterium Lactobacillus helveticus strain VEL12193 to modulate the retinal n-3 PUFA content. A set of complementary approaches was used to study the impact of such a supplementation on the gut microbiota and host lipid/fatty acid (FA) metabolism. L. helveticus-supplementation was associated with a decrease in retinal saturated FAs (SFAs) and monounsaturated FAs (MUFAs) as well as an increase in retinal n-3 and omega-6 (n-6) PUFAs. Interestingly, supplementation with L. helveticus enriched the retina in C22:5n-3 (docosapentaenoic acid, DPA), C22:6n-3 (DHA), C18:2n-6 (linoleic acid, LA) and C20:3n-6 (dihomo gamma-linolenic acid, DGLA). Long-term consumption of L. helveticus also modulated gut microbiota composition and some changes in OTUs abundance correlated with the retinal FA content. This study provides a proof of concept that targeting the gut microbiota could be an effective strategy to modulate the retinal FA content, including that of protective n-3 PUFAs, thus opening paths for the design of novel preventive and/or therapeutical strategies for retinopathies.

Study protocol of OmegaROP-2 prospective study: expression of placental fatty acid receptors in preterm newborns with retinopathy of prematurity.

BACKGROUND: Incomplete vascularization of the retina in preterm infants carries a risk of retinopathy of prematurity (ROP). Progress in neonatal resuscitation in developing countries has led to the survival of an increasing number of premature infants, resulting in an increased rate of ROP and consequently in visual disability. Strategies to reduce ROP involve optimizing oxygen saturation, nutrition, and normalizing factors such as insulin-like growth factor 1 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA). Our previous study, OmegaROP, showed that there is an accumulation or retention of docosahexaenoic acid (DHA) in mothers of infants developing ROP, suggesting abnormalities in the LC-PUFA placental transfer via fatty acid transporting proteins. The present study aims to better understand the LC-PUFA transport dysfunction in the fetoplacental unit during pregnancy and to find a novel target for the prevention of ROP development. METHODS: The study protocol is designed to evaluate the correlation between the expression level of placental fatty acid receptors and ROP occurrence. This ongoing study will include 100 mother-infant dyads: mother-infant dyads born before 29 weeks of gestational age (GA) and mother-infant dyads with full-term pregnancies. Recruitment is planned over a period of 46 months. Maternal and cord blood samples as well as placental tissue samples will be taken following delivery. ROP screening will be performed using wide-field camera imaging according to the International Classification of ROP consensus statement. DISCUSSION: The results of this study will have a tangible impact on public health. Indeed, if we show a correlation between the expression level of placental omega-3 receptors and the occurrence of ROP, it would be an essential step in discovering novel pathophysiological mechanisms involved in this retinopathy. TRIAL REGISTRATION: NCT04819893.

Impact of dietary n-3 polyunsaturated fatty acid intake during the perinatal and post-weaning periods on the phospholipid and ganglioside composition of olfactory tissues.

The olfactory mucosa (OM) and olfactory bulb (OB) are neuronal tissues that contribute to the early processing of olfactory information. They contain significant amounts of n-3 and n-6 polyunsaturated fatty acids (PUFAs), which are crucial for neuronal tissue development. In this study, we evaluated the impact of feeding mice diets that are either deficient in α-linolenic acid (ALA) or supplemented with n-3 long-chain PUFAs from gestation to adolescence on the phospholipid and ganglioside composition of these tissues. Both diets modified the levels of some phospholipid classes, notably the phosphatidylserine and phosphatidylethanolamine levels. In addition, the low-ALA diet enriched n-6 PUFAs in the main phospholipid classes of both tissues, while the diet supplemented with n-3 PUFAs enhanced the n-3 PUFA-containing phospholipid species level, mainly in OM. The diets also modulated the levels and profiles of several ganglioside classes in OM and OB. These modifications may have repercussions on the olfactory sensitivity.

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.

Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of ß-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.

Dietary n-3 polyunsaturated fatty acid deficiency alters olfactory mucosa sensitivity in young mice but has no impact on olfactory behavior.

BACKGROUND AND OBJECTIVE: We recently showed that perinatal exposure to diets with unbalanced n-6:n-3 polyunsaturated fatty acid (PUFA) ratios affects the olfactory mucosa (OM) fatty acid composition. To assess the repercussions of these modifications, we investigated the impact of diets unbalanced in n-3 PUFAs on the molecular composition and functionality of the OM in young mice. METHODS: After mating, female mice were fed diets either deficient in α-linolenic acid (LOW diet) or supplemented with n-3 long-chain PUFAs (HIGH diet) during the perinatal period. Weaned male offspring were then fed ad libitum with the same experimental diets for 5 weeks. At 8 weeks of age, olfactory behavior tests were performed in young mice. The fatty acid composition of OM and olfactory cilia, as well as the expression of genes involved in different cellular pathways, were analyzed. The electroolfactograms induced by odorant stimuli were recorded to assess the impact of diets on OM functionality. RESULTS AND CONCLUSION: Both diets significantly modified the fatty acid profiles of OM and olfactory cilia in young mice. They also induced changes in the expression of genes involved in olfactory signaling and in olfactory neuron maturation. The electroolfactogram amplitudes were reduced in mice fed the LOW diet. Nevertheless, the LOW diet and the HIGH diet did not affect mouse olfactory behavior. Our study demonstrated that consumption of diets deficient in or supplemented with n-3 PUFAs during the perinatal and postweaning periods caused significant changes in young mouse OM. However, these modifications did not impair their olfactory capacities.

Effects of topical docosahexaenoic acid on postoperative fibrosis in an animal model of glaucoma filtration surgery.

PURPOSE: The aim of this study was to evaluate docosahexaenoic acid (DHA) as a potential antifibrotic agent after glaucoma filtration surgery (GFS) in rats. METHODS: A total of 36 10-week-old Brown Norway rats underwent GFS. Animals were equally divided into three groups: a control group, a DHA group and a mitomycin C (MMC) group. Intraocular pressure (IOP) was measured using a dynamic rebound tonometer, and a photograph of the surgical site was taken on days 1, 3, 7, 10, 14 and 17. The incorporation of DHA into fibroblasts was evaluated by gas chromatography. The expression of alfa-smooth muscle actin (α-SMA) and Smad proteins was assessed by Western blotting. RESULTS: IOP decreased after surgery in animals from the three groups on day 1 after surgery. Over time, IOP remained lower in the DHA and MMC groups than in the control group (median [interquartile range] 8.0 [7.0-8.0] and 8.0 [7.3-8.0] mmHg vs. 9.0 [8.0-9.0] mmHg, respectively; p < 0.001). Bleb area in the DHA and MMC groups remained larger than that of the control group from day 7 to day 14 (3.9 [2.9-5.2] and 3.5 [2.3-4.4] mm2 vs. 2.3 [2.0-2.8] mm2 , respectively; p = 0.0021). We did not observe any change in DHA concentrations in the fibroblasts of the DHA group compared with the other groups. CONCLUSION: The impact of DHA on IOP and bleb area was similar to that of MMC. The mechanisms of action of DHA in rat eye fibroblasts deserve further investigation.

Modification of erythrocyte membrane phospholipid composition in preterm newborns with retinopathy of prematurity: The omegaROP study.

N-3 polyunsaturated fatty acids (PUFAs) may prevent retinal vascular abnormalities observed in oxygen-induced retinopathy, a model of retinopathy of prematurity (ROP). In the OmegaROP prospective cohort study, we showed that preterm infants who will develop ROP accumulate the n-6 PUFA arachidonic acid (ARA) at the expense of the n-3 PUFA docosahexaenoic acid (DHA) in erythrocytes with advancing gestational age (GA). As mice lacking plasmalogens -That are specific phospholipids considered as reservoirs of n-6 and n-3 PUFAs- Display a ROP-like phenotype, the aim of this study was to determine whether plasmalogens are responsible for the changes observed in subjects from the OmegaROP study. Accordingly, preterm infants aged less than 29 weeks GA were recruited at birth in the Neonatal Intensive Care Unit of University Hospital Dijon, France. Blood was sampled very early after birth to avoid any nutritional influence on its lipid composition. The lipid composition of erythrocytes and the structure of phospholipids including plasmalogens were determined by global lipidomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). LC-HRMS data confirmed our previous observations by showing a negative association between the erythrocyte content in phospholipid esterified to n-6 PUFAs and GA in infants without ROP (rho = -0.485, p = 0.013 and rho = -0.477, p = 0.015 for ethanolamine and choline total phospholipids, respectively). Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) species with ARA, namely PtdCho16:0/20:4 (rho = -0.511, p < 0.01) and PtdEtn18:1/20:4 (rho = -0.479, p = 0.015), were the major contributors to the relationship observed. On the contrary, preterm infants developing ROP displayed negative association between PtdEtn species with n-3 PUFAs and GA (rho = -0.380, p = 0.034). They were also characterized by a positive association between GA and the ratio of ethanolamine plasmalogens (PlsEtn) with n-6 PUFA to PlsEtn with n-3 PUFAs (rho = 0.420, p = 0.029), as well as the ratio of PlsEtn with ARA to PlsEtn with DHA (rho = 0.843, p = 0.011). Altogether, these data confirm the potential accumulation of n-6 PUFAs with advancing GA in erythrocytes of infants developing ROP. These changes may be partly due to plasmalogens.

Dietary Inulin Supplementation Affects Specific Plasmalogen Species in the Brain.

Plasmalogens (Pls) are glycerophospholipids that play critical roles in the brain. Evidence supports the role of diet and that of the gut microbiota in regulating brain lipids. We investigated the impact of dietary intake of inulin-a soluble fiber used as prebiotic-on the Pl content of the cortex in mice. No global modification in the Pl amounts was observed when evaluated by gas chromatographic analysis of dimethyl acetals (DMAs). However, the analysis of individual molecular species of Pls by liquid chromatography revealed a reduced abundance of major species of ethanolamine Pls (PlsEtn)-PE(P-18:0/22:6) and PE(P-34:1)-in the cortex of mice fed a diet supplemented with inulin. DMA and expression levels of genes (Far-1, Gnpat, Agps, Pla2g6 and Tmem86b) encoding key enzymes of Pl biosynthesis or degradation were not altered in the liver and in the cortex of mice exposed to inulin. In addition, the fatty acid profile and the amount of lyso forms derived from PlsEtn were not modified in the cortex by inulin consumption. To conclude, inulin affects the brain levels of major PlsEtn and further investigation is needed to determine the exact molecular mechanisms involved.

Intrinsic differences in rod and cone membrane composition: implications for cone degeneration.

PURPOSE: In many retinal pathological conditions, rod and cone degeneration differs. For example, the early-onset maculopathy Stargardts disease type 1 (STGD1) is typified by loss of cones while rods are often less affected. We wanted to examine whether there exist intrinsic membrane differences between rods and cones that might explain such features. METHODS: Abca4 mRNA and protein levels were quantified in rod- and cone-enriched samples from wild-type and Nrl-/- mice retinas; rod- and cone-enriched outer segments (ROS and COS respectively) were prepared from pig retinas, and total lipids were analyzed by flame ionization, chromatography, and tandem mass spectrometry. Immunohistochemical staining of cone-rich rodent Arvicanthis ansorgei retinas was conducted, and ultra-high performance liquid chromatography of lipid species in porcine ROS and COS was performed. RESULTS: Abca4 mRNA and Abca4 protein content was significantly higher (50-300%) in cone compared to rod-enriched samples. ROS and COS displayed dramatic differences in several lipids, including very long chain poly-unsaturated fatty acids (VLC-PUFAs), especially docosahexaenoic acid (DHA, 22:6n-3): ROS 20.6% DHA, COS 3.3% (p < 0.001). VLC-PUFAs (> 50 total carbons) were virtually absent from COS. COS were impoverished (> 6× less) in phosphatidylethanolamine compared to ROS. ELOVL4 ("ELOngation of Very Long chain fatty acids 4") antibody labelled Arvicanthis cones only very weakly compared to rods. Finally, there were large amounts (905 a.u.) of the bisretinoid A2PE in ROS, whereas it was much lower (121 a.u., ~ 7.5-fold less) in COS fractions. In contrast, COS contained fivefold higher amounts of all-trans-retinal dimer (115 a.u. compared to 22 a.u. in rods). CONCLUSIONS: Compared to rods, cones expressed higher levels of Abca4 mRNA and Abca4 protein, were highly impoverished in PUFA (especially DHA) and phosphatidylethanolamine, and contained significant amounts of all-trans-retinal dimer. Based on these and other data, we propose that in contrast to rods, cones are preferentially vulnerable to stress and may die through direct cellular toxicity in pathologies such as STGD1.

Plasmalogens Regulate Retinal Connexin 43 Expression and Müller Glial Cells Gap Junction Intercellular Communication and Migration.

Plasmalogens are a specific glycerophospholipid subtype characterized by a vinyl-ether bound at their sn-1 moiety. Their biosynthesis is initiated in the peroxisome by dihydroxyacetone phosphate-acyltransferase (DHAPAT), which is encoded by the DAPAT gene. Previous studies have shown that plasmalogen-deficient mice exhibit major physiological dysfunctions including several eye defects, among which abnormal vascular development of the retina and a reactive activation of macroglial Müller cells. Interestingly, plasmalogen deficiency in mice is also associated with a reduced expression of brain connexin 43 (Cx43). Cx43 is the main connexin subtype of retinal glial cells and is involved in several cellular mechanisms such as calcium-based gap junction intercellular communication (GJIC) or cell migration. Thus, the aim of our work was 1) to confirm the alteration of Cx43 expression in the retina of plasmalogen-deficient DAPAT-/- mice and 2) to investigate whether plasmalogens are involved in crucial functions of Müller cells such as GJIC and cell migration. First, we found that plasmalogen deficiency was associated with a significant reduction of Cx43 expression in the retina of DAPAT-/- mice in vivo. Secondly, using a siRNA targeting DHAPAT in vitro, we found that a 50%-reduction of Müller cells content in plasmalogens was sufficient to significantly downregulate Cx43 expression, while increasing its phosphorylation. Furthermore, plasmalogen-depleted Müller cells exhibited several alterations in ATP-induced GJIC, such as calcium waves of higher amplitude that propagated slower to neighboring cells, including astrocytes. Finally, in vitro plasmalogen depletion was also associated with a significant downregulation of Müller cells migration. Taken together, these data confirm that plasmalogens are critical for the regulation of Cx43 expression and for characteristics of retinal Müller glial cells such as GJIC and cell migration.

N-3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development.

Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.

Lipidomic profile of human nasal mucosa and associations with circulating fatty acids and olfactory deficiency.

The nasal mucosa (NM) contains olfactory mucosa which contributes to the detection of odorant molecules and the transmission of olfactory information to the brain. To date, the lipid composition of the human NM has not been adequately characterized. Using gas chromatography, liquid chromatography coupled to mass spectrometry and thin layer chromatography, we analyzed the fatty acids and the phospholipid and ceramide molecular species in adult human nasal and blood biopsies. Saturated and polyunsaturated fatty acids (PUFAs) accounted for 45% and 29% of the nasal total fatty acids, respectively. Fatty acids of the n-6 family were predominant in the PUFA subgroup. Linoleic acid and arachidonic acid (AA) were incorporated in the main nasal phospholipid classes. Correlation analysis revealed that the nasal AA level might be positively associated with olfactory deficiency. In addition, a strong positive association between the AA levels in the NM and in plasma cholesteryl esters suggested that this blood fraction might be used as an indicator of the nasal AA level. The most abundant species of ceramides and their glycosylated derivatives detected in NM contained palmitic acid and long-chain fatty acids. Overall, this study provides new insight into lipid species that potentially contribute to the maintenance of NM homeostasis and demonstrates that circulating biomarkers might be used to predict nasal fatty acid content.

Soluble Fiber Inulin Consumption Limits Alterations of the Gut Microbiota and Hepatic Fatty Acid Metabolism Caused by High-Fat Diet.

Diet shapes the gut microbiota which impacts hepatic lipid metabolism. Modifications in liver fat content are associated with metabolic disorders. We investigated the extent of dietary fat and fiber-induced alterations in the composition of gut microbiota and hepatic fatty acids (FAs). Mice were fed a purified low-fat diet (LFD) or high-fat diet (HFD) containing non-soluble fiber cellulose or soluble fiber inulin. HFD induced hepatic decreases in the amounts of C14:0, C16:1n-7, C18:1n-7 and increases in the amounts of C17:0, C20:0, C16:1n-9, C22:5n-3, C20:2n-6, C20:3n-6, and C22:4n-6. When incorporated in a LFD, inulin poorly affected the profile of FAs. However, when incorporated in a HFD, it (i) specifically led to an increase in the amounts of hepatic C18:0, C22:0, total polyunsaturated FAs (PUFAs), total n-6 PUFAs, C18:3n-3, and C18:2n-6, (ii) exacerbated the HFD-induced increase in the amount of C17:0, and (iii) prevented the HFD-induced increases in C16:1n-9 and C20:3n-6. Importantly, the expression/activity of some elongases and desaturases, as well as the gut microbiota composition, were impacted by the dietary fat and fiber content. To conclude, inulin modulated gut microbiota and hepatic fatty acid composition, and further investigations will determine whether a causal relationship exists between these two parameters.

Bioavailability and spatial distribution of fatty acids in the rat retina after dietary omega-3 supplementation.

Spatial changes of FAs in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids (PLs), EPA-containing TGs, DHA-containing PLs, or DHA-containing TGs. Qualitative changes in FA composition of plasma, erythrocytes, and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of PC and PE species in retina were determined by LC coupled to MS/MS and MALDI coupled to MS imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that PLs as well as TGs are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain PUFAs (more than 28 carbons) following PL-EPA and TG-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of FAs in the rat retina.

Perinatal exposure to diets with different n-6:n-3 fatty acid ratios affects olfactory tissue fatty acid composition.

The olfactory mucosa (OM) and the olfactory bulb (OB) are responsible for the detection and processing of olfactory signals. Like the brain and retina, they contain high levels of n-3 and n-6 polyunsaturated fatty acids (PUFAs), which are essential for the structure and function of neuronal and non-neuronal cells. Since the influence of the maternal diet on olfactory lipid profiles of the offspring has been poorly explored, we examined the effects of feeding mice during the perinatal period with diets containing an adequate linoleic acid level but either deficient in α-linolenic acid (ALA) or supplemented in n-3 long-chain PUFAs on the lipid composition of dams and weaning offspring olfactory tissues. In both the OM and OB, the low n-3 ALA diet led to a marked reduction in n-3 PUFAs with a concomitant increase in n-6 PUFAs, whereas consumption of the high n-3 PUFA diet reduced n-6 PUFAs and increased n-3 PUFAs. Structural analysis showed that the molecular species profiles of the main phospholipid classes of olfactory tissues from weaning pups were markedly affected by the maternal diets. This study demonstrates that the PUFA status of olfactory tissues is sensitive to diet composition from the early stages of development.

Impact of a high-fat diet on the fatty acid composition of the retina.

Structure and function of the retina mainly rely on its fatty acid (FA) composition. Evidence from epidemiological studies and from animal experiments indicates that FA composition of the retina is influenced by the diet. Mice under chronic high-fat diet (HFD) develop metabolic syndrome, a risk factor for diabetes that is associated with structural and functional alterations of the retina. Here, we studied the impact of chronic exposure of mice to HFD on retinal FA composition. C57BL/6 J male mice were fed either a chow diet or a HFD for 11 weeks. As expected, HFD induced weight gain, adiposity, hyperglycemia and dyslipidemia. The retinal FA composition was determined by gas chromatography coupled to flame ionization detection. No significant change in the relative abundance of total saturated FAs (SFAs), total monounsaturated FAs (MUFAs) or total polyunsaturated FAs (PUFAs) was observed. However, retinas of HFD-fed mice displayed decreased amounts of C24:0 (p = 0.0231), C16:1n-7 (p < 0.0001), C18:1n-7 (p < 0.0001), C20:3n-9 (p = 0.0425) and C20:3n-6 (p = 0.0008), and an increased amount of C20:2n-6 (p < 0.0001). In addition, the ratio of linoleic acid (C18:2n-6) to alpha-linolenic acid (C18:3n-3) was increased in the retinas of HFD-fed mice (15.0 ± 0.8 versus 11.8 ± 0.6 in HFD and CD, respectively, p = 0.0045). No modification in the contents of arachidonic acid (C20:4n-6, AA) and docosahexaenoic acid (C22:6n-3, DHA) were observed. Analysis of dimethylacetals (DMA), which are residues of plasmalogens (Pls), revealed that the amount of Pls containing octadecanal-aldehydes (DMA C18:0) was significantly increased in HFD-fed mice (p = 0.0447). This increase was, at least in part, balanced by a decrease in Pls containing 7-octadecanal-aldehydes (DMA C18:1n-7) (p = 0.0007). In conclusion, HFD had an impact on the relative proportion of essential dietary fatty acids linoleic acid and alpha-linolenic acid that are incorporated in the retina. However, this imbalance in PUFA precursors did not alter the content of the two major retinal long-chain PUFAs, AA and DHA. HFD consumption also led to alterations in the retinal SFAs, MUFAs and Pls profiles.

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits.

Reward-processing impairment is a common symptomatic dimension of several psychiatric disorders. However, whether the underlying pathological mechanisms are common is unknown. Herein, we asked if the decrease in the n-3 polyunsaturated fatty acid (PUFA) lipid species, consistently described in these pathologies, could underlie reward-processing deficits. We show that reduced n-3 PUFA biostatus in mice leads to selective motivational impairments. Electrophysiological recordings revealed increased collateral inhibition of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) onto dopamine D1 receptor-expressing MSNs in the nucleus accumbens, a main brain region for the modulation of motivation. Strikingly, transgenically preventing n-3 PUFA deficiency selectively in D2-expressing neurons normalizes MSN collateral inhibition and enhances motivation. These results constitute the first demonstration of a causal link between a behavioral deficit and n-3 PUFA decrease in a discrete neuronal population and suggest that lower n-3 PUFA biostatus in psychopathologies could participate in the etiology of reward-related symptoms.