Neuronal morphology and synaptic plasticity in the hippocampus of vitamin A deficient rats.

Vitamin A (retinol) and related retinoids are micronutrients provided by food. Retinol derivatives are growth factors important for development, cell differentiation and tissue homeostasis, especially in the brain.Objective: The hippocampus is a pivotal brain structure for learning and memory and hippocampal-dependent memory is highly sensitive to retinoids action. However, the underlying mechanisms are still unclear. In this study, we characterized the impact of vitamin A deficiency on memory and neuronal plasticity, focusing on the CA1 region of the hippocampus in rats.Methods: Weaned male Wistar rats were fed a control (5 UI/g) or deficient vitamin A diet (0 UI/g) for 10 weeks. The effect of vitamin A supplementation (20 UI/g) for 3 weeks was also tested. Memory performances were assessed in the Y-maze (n = 24-30/group), retinoic acid levels were measured (LC-MS/MS) in the serum and in the hippocampus (n = 5/group), CA1 neuronal architecture was analyzed with Golgi staining (n = 17-20 neurons/group) and electrophysiological patch-clamp recordings were performed on hippocampal brain slices (n = 6-11/group).Results: Vitamin A deficiency from weaning significantly lowered hippocampal levels of retinoic acid, reduced dendritic length and branching of CA1 pyramidal neurons and decreased spontaneous glutamatergic synaptic events and synaptic plasticity. When replenishment with moderate dose of dietary vitamin A for 3 weeks was done, most of the synaptic and morphological alterations were absent.Conclusion: This study provides new mechanistic insight to understand the critical role of retinoic acid in hippocampal function.

Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of ß-amyloid peptides (Aß), and could thus contribute to the onset of AD. METHODS: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor ß (RARß) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aß40 and Aß42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aß load. However, the expression of Rxr-ß in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aß in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARß levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to ß-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.

Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations.

BACKGROUND: Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. METHODS: Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. RESULTS: As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. CONCLUSION: Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.

Retinoic acid increases glucocorticoid receptor phosphorylation via cyclin-dependent kinase 5.

Glucocorticoid receptor (GR) function is modulated by phosphorylation. As retinoic acid (RA) can activate some cytoplasmic kinases able to phosphorylate GR, we investigated whether RA could modulate GR phosphorylation in neuronal cells in a context of long-term glucocorticoid exposure. A 4-day treatment of dexamethasone (Dex) plus RA, showed that RA potentiated the (Dex)-induced phosphorylation on GR Serine 220 (pSer220GR) in the nucleus of a hippocampal HT22 cell line. This treatment increased the cytoplasmic ratio of p35/p25 proteins, which are major CDK5 cofactors. Roscovitine, a pharmacological CDK5 inhibitor, or a siRNA against CDK5 prevented RA potentiation of GR phosphorylation. Furthermore, roscovitine counter-acted the effect of RA on GR sensitive target proteins such as BDNF or tissue-transglutaminase. These data help understanding the interaction between RA- and glucocorticoid-signalling pathways, both of which have strong influences on the adult brain.

Stress and glucocorticoid regulation of NR4A genes in mice.

The NR4A nuclear receptors subgroup, comprising Nur77 (NR4A1), Nurr1 (NR4A2), and Nor1 (NR4A3), are orphan receptors induced by a variety of signals, including stress. These receptors are described as early response genes and in vitro studies have shown that they take part in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the major stress-responsive neuroendocrine system. This study analyzes further the interweaving of NR4A receptors with the HPA axis at rest and after a restraint stress in vivo in mice. We show that each NR4A member has a similar mRNA expression pattern and low levels of expression at rest except, in particular in hippocampus for Nurr1 and in adrenals for Nur77. After restraint stress, mRNA expression of each NR4A is markedly induced in adrenals and pituitary and significantly in hypothalamus. In higher cerebral regions, such as cortex, hippocampus, and amygdala, induction of NR4A mRNA elicited by stress was very moderate or undetected. The influence of glucocorticoids on NR4A mRNA expression was analyzed by comparing wild-type and Cbg k.o. mice used as a model of glucocorticoid hyposignaling. Nur77 mRNA and protein expression and a downstream Nur77 target gene were found to be affected in the hypothalamus and pituitary of the Cbg k.o. mice but not in hippocampus and cortex. These results further support a physiological role of NR4A orphan receptors in the glucocorticoid response to stress.

Erythrocyte DHA level as a biomarker of DHA status in specific brain regions of n-3 long-chain PUFA-supplemented aged rats.

n-3 Long-chain PUFA (n-3 LC-PUFA), particularly EPA and DHA, play a key role in the maintenance of brain functions such as learning and memory that are impaired during ageing. Ageing is also associated with changes in the DHA content of brain membranes that could contribute to memory impairment. Limited studies have investigated the effects of ageing and n-3 LC-PUFA supplementation on both blood and brain fatty acid compositions. Therefore, we assessed the relationship between fatty acid contents in plasma and erythrocyte membranes and those in the hippocampus, striatum and cerebral cortex during ageing, and after a 5-month period of EPA/DHA supplementation in rats. In the blood, ageing was associated with an increase in plasma DHA content, whereas the DHA content remained stable in erythrocyte membranes. In the brain, ageing was associated with a decrease in DHA content, which was both region-specific and phospholipid class-specific. In EPA/DHA-supplemented aged rats, DHA contents were increased both in the blood and brain compared with the control rats. The present results demonstrated that n-3 LC-PUFA level in the plasma was not an accurate biomarker of brain DHA status during ageing. Moreover, we highlighted a positive relationship between the DHA levels in erythrocyte phosphatidylethanolamine (PE) and those in the hippocampus and prefrontal cortex in EPA/DHA-supplemented aged rats. Within the framework of preventive dietary supplementation to delay brain ageing, these results suggest the possibility of using erythrocyte PE DHA content as a reliable biomarker of DHA status in specific brain regions.

Retinoids and glucocorticoids target common genes in hippocampal HT22 cells.

Vitamin A metabolite retinoic acid (RA) plays a major role in the aging adult brain plasticity. Conversely, chronic excess of glucocorticoids (GC) elicits some deleterious effects in the hippocampus. We questioned here the involvement of RA and GC in the expression of target proteins in hippocampal neurons. We investigated proteins involved either in the signaling pathways [RA receptor ß (RARß) and glucocorticoid receptor (GR)] or in neuron differentiation and plasticity [tissue transglutaminase 2 (tTG) and brain-derived neurotrophic factor (BDNF)] in a hippocampal cell line, HT22. We applied RA and/or dexamethasone (Dex) as activators of the pathways and investigated mRNA and protein expression of their receptors and of tTG and BDNF as well as tTG activity and BDNF secretion. Our results confirm the involvement of RA- and GC-dependent pathways and their interaction in our neuronal cell model. First, both pathways regulate the transcription and expression of own and reciprocal receptors: RA and Dex increased RARß and decreased GR expressions. Second, Dex reduces the expression of tTG when associated with RA despite stimulating its expression when used alone. Importantly, when they are combined, RA counteracts the deleterious effect of glucocorticoids on BDNF regulation and thus may improve neuronal plasticity under stress conditions. In conclusion, GC and RA both interact through regulations of the two receptors, RARß and GR. Furthermore, they both act, synergistically or oppositely, on other target proteins critical for neuronal plasticity, tTG and BDNF.

Intrinsic expression of transcortin in neural cells of the mouse brain: a histochemical and molecular study.

Corticosteroid binding globulin (CBG, transcortin) has been shown to be expressed in the brain of rat and human species. In this study, we examined the CBG brain expression and cDNA structure in mice, comparing wild-type (Cbg(+/+)) and Cbg knockout mice (Cbg(-/-), obtained by genetic disruption of the SerpinA6 alias Cbg gene). We used double immunofluorescence labeling with specific neuronal and glial markers to analyze the cellular localization of CBG in various regions of the mouse brain. In wild-type (Cbg(+/+)) mice, we found CBG immunoreactivity in neuronal perikarya of the magnocellular hypothalamic nuclei, amygdala, hippocampus, cerebral cortex, cerebellum and pituitary. A portion of glial cells (astrocytes, oligodendrocytes) contained CBG immunoreactivity, including some of the ependymal cells and choroid plexus cells. No CBG immunoreactivity was detected in Cbg(-/-) brain tissues. Using RT-PCR, we showed that the full-length Cbg mRNA is present in those regions, indicating an intrinsic expression of the steroid-binding globulin. Furthermore, sequencing analysis showed that Cbg cDNA obtained from the mouse hypothalamus was homologous to Cbg cDNA obtained from the liver. Finally, we have evaluated the relative levels of CBG expression in various brain regions and in the liver by quantitative PCR. We found that brain levels of Cbg mRNA are low compared with the liver but significantly higher than in CBG-deficient mice. Although derived from the same gene as liver CBG, brain CBG protein may play a specific or complementary role that requires the production and analysis of brain-specific Cbg knockout models.

Effects of a polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study.

Background: Polyphenols are naturally occurring organic compounds found in plants. Research suggests that their intake reduces the risk of cognitive decline and related dementias. Grapes and blueberries are polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Purpose: Examine the effects of supplementation with a standardized and patented polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Methods: One hundred and forty-three volunteers aged 60 to 80 years with mild cognitive impairment were supplemented with either 150 mg of Memophenol™, twice daily or a placebo. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function (BRIEF-A), the Cognitive Failures Questionnaire, and the CASP-19. Results: Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing (p = 0.020), visuospatial learning (p = 0.012), and the BRIEF-A global score (p = 0.046). However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires. Memophenol™ supplementation was well-tolerated with no reports of significant adverse reactions. Conclusion: The promising results from this trial suggest that 6-months of supplementation with Memophenol™ may improve aspects of cognitive function in adults with mild cognitive impairment. Further research will be important to expand on the current findings and identify the potential mechanisms of action associated with the intake of this polyphenol-rich extract.

Dietary Marine Hydrolysate Improves Memory Performance and Social Behavior through Gut Microbiota Remodeling during Aging.

Aging is characterized by a decline in social behavior and cognitive functions leading to a decrease in life quality. In a previous study, we show that a fish hydrolysate supplementation prevents age-related decline in spatial short-term memory and long-term memory and anxiety-like behavior and improves the stress response in aged mice. The aim of this study was to determine the effects of a fish hydrolysate enriched with EPA/DHA or not on the cognitive ability and social interaction during aging and the biological mechanisms involved. We showed for the first time that a fish hydrolysate enriched with EPA/DHA or not improved memory performance and preference for social novelty that were diminished by aging. These changes were associated with the modulation of the gut microbiota, normalization of corticosterone, and modulation of the expression of genes involved in the mitochondrial respiratory chain, circadian clock, neuroprotection, and antioxidant activity. Thus, these changes may contribute to the observed improvements in social behavior and memory and reinforced the innovative character of fish hydrolysate in the prevention of age-related impairments.

Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation.

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1ß (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation.

Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging.

Brain aging is characterized by a chronic low-grade inflammation, which significantly impairs cognitive function. Microglial cells, the immunocompetent cells of the brain, present a different phenotype, switching from a homeostatic signature (M0) to a more reactive phenotype called "MGnD" (microglial neurodegenerative phenotype), leading to a high production of pro-inflammatory cytokines. Furthermore, microglial cells can be activated by age-induced gut dysbiosis through the vagus nerve or the modulation of the peripheral immune system. Nutrients, in particular n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides, display powerful immunomodulatory properties, and can thus prevent age-related cognitive decline. The objective of this study was to investigate the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine by-product-derived hydrolysate on microglial phenotypes and intestinal permeability and their consequences on cognition in mice. We demonstrated that the hydrolysate supplementation for 8 weeks prevented short- and long-term memory decline during aging. These observations were linked to the modulation of microglial signature. Indeed, the hydrolysate supplementation promoted homeostatic microglial phenotype by increasing TGF-ß1 expression and stimulated phagocytosis by increasing Clec7a expression. Moreover, the hydrolysate supplementation promoted anti-inflammatory intestinal pathway and tended to prevent intestinal permeability alteration occurring during aging. Therefore, the fish hydrolysate appears as an interesting candidate to prevent cognitive decline during aging.

A high-fat diet induces lower expression of retinoid receptors and their target genes GAP-43/neuromodulin and RC3/neurogranin in the rat brain.

Numerous studies have reported an association between cognitive impairment in old age and nutritional factors, including dietary fat. Retinoic acid (RA) plays a central role in the maintenance of cognitive processes via its nuclear receptors (NR), retinoic acid receptor (RAR) and retinoid X receptor (RXR), and the control of target genes, e.g. the synaptic plasticity markers GAP-43/neuromodulin and RC3/neurogranin. Given the relationship between RA and the fatty acid signalling pathways mediated by their respective NR (RAR/RXR and PPAR), we investigated the effect of a high-fat diet (HFD) on (1) PUFA status in the plasma and brain, and (2) the expression of RA and fatty acid NR (RARbeta, RXRbetagamma and PPARdelta), and synaptic plasticity genes (GAP-43 and RC3), in young male Wistar rats. In the striatum of rats given a HFD for 8 weeks, real-time PCR (RT-PCR) revealed a decrease in mRNA levels of RARbeta ( - 14 %) and PPARdelta ( - 13 %) along with an increase in RXRbetagamma (+52 %). Concomitantly, RT-PCR and Western blot analysis revealed (1) a clear reduction in striatal mRNA and protein levels of RC3 ( - 24 and - 26 %, respectively) and GAP-43 ( - 10 and - 42 %, respectively), which was confirmed by in situ hybridisation, and (2) decreased hippocampal RC3 and GAP-43 protein levels (approximately 25 %). Additionally, HFD rats exhibited a significant decrease in plasma ( - 59 %) and brain ( - 6 %) n-3 PUFA content, mainly due to the loss of DHA. These results suggest that dietary fat induces neurobiological alterations by modulating the brain RA signalling pathway and n-3 PUFA content, which have been previously correlated with cognitive impairment.

Plasma retinol and association with socio-demographic and dietary characteristics of free-living older persons: the Bordeaux sample of the three-city study.

The objective was to describe retinol plasma concentration and its association with socio-demographic characteristics and dietary habits in French older persons. The study population consisted of 1664 subjects aged 65 + from Bordeaux (France), included in the Three-City cohort. Retinol plasma concentration was determined in fasting blood samples. Dietary assessment was performed by a food frequency questionnaire allowing estimation of weekly intake of dietary sources of vitamin A or provitamin A. The weekly number of glasses of alcohol was also recorded. Age, sex, marital status, educational and income levels, body-mass index (BMI), and smoking were registered. Cross-sectional analysis of the association between plasma retinol and socio-demographic characteristics and dietary habits was performed by multilinear regression. Mean plasma retinol was close to the homeostatically regulated concentration of 2.0 micromol/L but ranged from 0.35 to 6.77 micromol/L. It was higher in women and divorced or separated individuals, and increased with income but not with age or educational level. Plasma retinol was positively and independently associated with the frequency of offal consumption and to the number of glasses of alcohol consumed per week. These results allow targeting older individuals who are at risk of either excessive or deficient vitamin A status and who should benefit from dietary counseling.

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging.

: Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.

Chronic Supplementation with a Mix of Salvia officinalis and Salvia lavandulaefolia Improves Morris Water Maze Learning in Normal Adult C57Bl/6J Mice.

Background: Two different species of sage, Salvia officinalis and Salvia lavandulaefolia, have demonstrated activities in cognitive function during preclinical and clinical studies related to impaired health situations or single administration. Different memory processes have been described to be significantly and positively impacted. Objective: Our objective is to explore the potential of these Salvia, and their additional activities, in healthy situations, and during prolonged administration, on memory and subsequent mechanisms of action related to putative effects. Design: This mouse study has implicated four investigational arms dedicated to control, Salvia officinalis aqueous extract, Salvia lavandulaefolia-encapsulated essential oil and a mix thereof (Cognivia™) for 2 weeks of administration. Cognitive functions have been assessed throughout Y-maze and Morris water maze models. The impact of supplementation on lipid peroxidation, oxidative stress, neurogenesis, neuronal activity, neurotrophins, neurotrophin receptors, CaM kinase II and glucocorticoid receptors has been assessed via post-interventional tissue collection. Results: All Salvia groups had a significant effect on Y-maze markers on day 1 of administration. Only the mix of two Salvia species demonstrated significant improvements in Morris water maze markers at the end of administration. Considering all biological and histological markers, we did not observe any significant effect of S. officinalis, S. lavandulaefolia and a mix of Salvia supplementation on lipid peroxidation, oxidative stress and neuronal plasticity (neurogenesis, neuronal activity, neurotrophins). Interestingly, CaM kinase II protein expression is significantly increased in animals supplemented with Salvia. Conclusion: The activities of Salvia alone after one intake have been confirmed; however, a particular combination of different types of Salvia have been shown to improve memory and present specific synergistic effects after chronic administration in healthy mice.

Normalization of hippocampal retinoic acid level corrects age-related memory deficits in rats.

Dietary micronutrients constitute a major environmental factor influencing aging processes. Vitamin A (vit. A) is the precursor of retinoic acid, a bioactive molecule that controls the expression of several genes involved in brain function. Evidence suggests a reduction of vit. A bioavailability with aging, but its impact on neuronal network is poorly understood. We investigated the mechanisms linking memory impairments with specific alterations of retinoic acid metabolism in the hippocampus. We compared young (10 weeks) and aged (16 months) rats, supplemented or not with dietary vit. A (20 IU retinol/g) for 4 weeks. Our study reveals that aging induced dysregulation of gene expression involved in vit. A and retinoic acid metabolism in the liver. Furthermore, vit. A supplementation restored the integrity of the hippocampal neuronal morphology altered by aging. Importantly, we found a high correlation between hippocampal levels of retinoic acid and memory performance. The present work establishes the link between collapse of retinoid metabolism and age-related cognitive decline, highlighting the role of vit. A in maintaining memory through aging.

Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice.

An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoid-mediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like short-term RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor beta and retinoid X receptor gamma, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.

Vitamin A deficiency in rats induces anatomic and metabolic changes comparable with those of neurodegenerative disorders.

Anatomic and metabolic changes in central nervous system induced by 14 wk of vitamin A deprivation (VAD) were monitored and quantified in rats. In vivo brain magnetic resonance imaging (4.7T) was performed at 5, 7, 9, 11, and 14 wk of each diet after weaning in the following: 1) VAD group; 2) control pair-fed group; and 3) control group that consumed the diet ad libitum (1.15 microg retinol/g diet). After 14 wk, high-resolution magic angle spinning proton NMR spectroscopy (11.7T) was performed on small samples of cortex, hippocampus, and striatum. Serum retinol concentrations remained stable and cerebral volume (CV) increased as a linear function of body weight in the ad libitum group (R(2) = 0.78; P = 0.047) and pair-fed controls (R(2) = 0.78; P = 0.046). In VAD rats, retinol decreased from the onset of deprivation (2.2 +/- 0.14 micromol/L) to reach 0.3 +/- 0.13 micromol/L at wk 5, followed by a stopping of body weight gain from wk 7. In VAD rats, the CV decreased from wk 5 and reached a value 11% lower than that of the control group (P < 0.001) at wk 14 and was correlated with retinol status (R(2) = 0.99; P = 0.002). The VAD hippocampal volume decreased beginning at wk 9 and was 22% lower than that of the control group at wk 14 (P < 0.001). Compared with the control, VAD led to lower N acetyl aspartate:creatine+phosphocreatine (Cr) in cortex (-36%), striatum (-22%), and hippocampus (-19%) and higher myoinositol:Cr in cortex (+127%) and striatum (+150%). VAD induced anatomic and metabolic changes comparable to those associated with neurodegenerative disorders. By wk 7 of deprivation, the slowing in cerebral growth that correlated with the retinol level could be considered as a predictive marker of brain disorders, confirmed by metabolic data from VAD rats after 14 wk.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11ß-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11ß-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11ß-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11ß-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11ß-HSD1.