The Role of Human Milk Oligosaccharides in Myelination, Socio-Emotional and Language Development: Observational Data from Breast-Fed Infants in the United States of America.

Infancy is a critical period for neurodevelopment, which includes myelination, synaptogenesis, synaptic pruning, and the development of motor, social-emotional, and cognitive functions. Human milk provides essential nutrients to the infant's developing brain, especially during the first postnatal months. Human milk oligosaccharides (HMOs) are a major component of human milk, and there is growing evidence of the association of individual HMOs with cognitive development in early life. However, to our knowledge, no study has explained these associations with a mechanism of action. Here, we investigated possible mediating associations between HMOs in human milk, brain myelination (measured via myelin water fraction), and measures of motor, language (collected via the Bayley Scales of Infant and Toddler Development (Bayley-III)), and socioemotional development (collected via the Ages and Stages Questionnaire: Social-Emotional Version (ASQ-SE)) in healthy term-born breast-fed infants. The results revealed an association between 6'Sialyllactose and social skills that was mediated by myelination. Furthermore, associations of fucosylated HMOs with language outcomes were observed that were not mediated by myelination. These observations indicate the roles of specific HMOs in neurodevelopment and associated functional outcomes, such as social-emotional function and language development.

Interactions between Bifidobacterium and Bacteroides and human milk oligosaccharides and their associations with infant cognition.

While ample research on independent associations between infant cognition and gut microbiota composition and human milk (HM) oligosaccharides (HMOs) has been reported, studies on how the interactions between gut microbiota and HMOs may yield associations with cognitive development in infancy are lacking. We aimed to determine how HMOs and species of Bacteroides and Bifidobacterium genera interact with each other and their associations with cognitive development in typically developing infants. A total of 105 mother-infant dyads were included in this study. The enrolled infants [2.9-12 months old (8.09 ± 2.48)] were at least predominantly breastfed at 4 months old. A total of 170 HM samples from the mothers and fecal samples of the children were collected longitudinally. Using the Mullen Scales of Early Learning to assess cognition and the scores as the outcomes, linear mixed effects models including both the levels of eight HMOs and relative abundance of Bacteroides and Bifidobacterium species as main associations and their interactions were employed with adjusting covariates; infant sex, delivery mode, maternal education, site, and batch effects of HMOs. Additionally, regression models stratifying infants based on the A-tetrasaccharide (A-tetra) status of the HM they received were also employed to determine if the associations depend on the A-tetra status. With Bacteroides species, we observed significant associations with motor functions, while Bif. catenulatum showed a negative association with visual reception in the detectable A-tetra group both as main effect (value of p = 0.012) and in interaction with LNFP-I (value of p = 0.007). Additionally, 3-FL showed a positive association with gross motor (p = 0.027) and visual reception (p = 0.041). Furthermore, significant associations were observed with the interaction terms mainly in the undetectable A-tetra group. Specifically, we observed negative associations for Bifidobacterium species and LNT [breve (p = 0.011) and longum (p = 0.022)], and positive associations for expressive language with 3'-SL and Bif. bifidum (p = 0.01), 6'-SL and B. fragilis (p = 0.019), and LNFP-I and Bif. kashiwanohense (p = 0.048), respectively. Our findings suggest that gut microbiota and HMOs are both independently and interactively associated with early cognitive development. In particular, the diverse interactions between HMOs and Bacteroides and Bifidobacterium species reveal different candidate pathways through which HMOs, Bifidobacterium and Bacteroides species potentially interact to impact cognitive development in infancy.

Long-term consequences of reduced availability and compensatory supplementation of sialylated HMOs on cognitive capabilities.

Breast milk (BM) is the optimal source of nutrition for mammals' early life. It exerts multiple benefits, including the development of cognitive capabilities and protection against several diseases like obesity and infection of the respiratory tract. However, which components of BM are involved in individual development has remained elusive. Sialylated human milk oligosaccharides (HMOs) may constitute a valid candidate, whereby they represent the principal source of sialic acid and act as building blocks for brain development. We hypothesize that the reduced availability of two HMOs, sialyl(alpha2,6)lactose (6'SL) and sialyl(alpha2,3)lactose (3'SL), may impair attention, cognitive flexibility, and memory in a preclinical model and that the exogenous supplementation of these compounds may contrast the observed deficits. We evaluated cognitive capabilities in a preclinical model exposed to maternal milk containing reduced concentrations of 6'SL and 3'SL during lactation. To modulate their concentrations, we utilized a preclinical model characterized by the absence of genes that synthesize 3'SL and 6'SL (B6.129-St3gal4 tm1.1Jxm and St6gal1tm2Jxm , double genetic deletion), producing milk lacking 3'SL and 6'SL. Then, to ensure exposure to 3'SL-6'SL-poor milk in early life, we adopted a cross-fostering protocol. The outcomes assessed in adulthood were different types of memory, attention and information processing, some of which are part of executive functions. Then, in the second study, we evaluated the long-term compensatory potential of the exogenous oral supplementation of 3'SL and 6'SL during lactation. In the first study, exposure to HMO-poor milk resulted in reduced memory and attention. Specifically, it resulted in impaired working memory in the T-maze test, in reduced spatial memory in the Barnes maze, and in impaired attentional capabilities in the Attentional set-shifting task. In the second part of the study, we did not observe any difference between experimental groups. We hypothesize that the experimental procedures utilized for the exogenous supplementation may have impacted our ability to observe the cognitive read-out in vivo. This study suggests that early life dietary sialylated HMOs play a crucial role in the development of cognitive functions. Future studies are needed to clarify if an exogenous supplementation of these oligosaccharides may compensate for these affected phenotypes.

Formula supplementation with human and bovine milk oligosaccharides modulates blood IgG and T-helper cell populations, and ex vivo LPS-stimulated cytokine production in a neonatal preclinical model.

Introduction: Human milk contains structurally diverse oligosaccharides (HMO), which are multifunctional modulators of neonatal immune development. Our objective was to investigate formula supplemented with fucosylated (2'FL) + neutral (lacto-N-neotetraose, LNnt) oligosaccharides and/or sialylated bovine milk oligosaccharides (BMOS) on immunological outcomes. Methods: Pigs (n=46) were randomized at 48h of age to four diets: sow milk replacer formula (CON), BMOS (CON + 6.5 g/L BMOS), HMO (CON + 1.0 g/L 2'FL + 0.5 g/L LNnT), or BMOS+HMO (CON + 6.5 g/L BMOS + 1.0 g/L 2'FL + 0.5 g/L LNnT). Blood and tissues were collected on postnatal day 33 for measurement of cytokines and IgG, phenotypic identification of immune cells, and ex vivo lipopolysaccharide (LPS)-stimulation of immune cells. Results: Serum IgG was significantly lower in the HMO group than BMOS+HMO but did not differ from CON or BMOS. The percentage of PBMC T-helper cells was lower in BMOS+HMO than the other groups. Splenocytes from the BMOS group secreted more IL-1ß when stimulated ex vivo with LPS compared to CON or HMO groups. For PBMCs, a statistical interaction of BMOS*HMO was observed for IL-10 secretion (p=0.037), with BMOS+HMO and HMO groups differing at p=0.1. Discussion: The addition of a mix of fucosylated and sialylated oligosaccharides to infant formula provides specific activities in the immune system that differ from formulations supplemented with one oligosaccharide structure.

Joint analyses of human milk fatty acids, phospholipids, and choline in association with cognition and temperament traits during the first 6 months of life.

Early dietary exposure via human milk nutrients offers a window of opportunity to support cognitive and temperament development. While several studies have focused on associations of few pre-selected human milk nutrients with cognition and temperament, it is highly plausible that human milk nutrients synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of three major classes of human milk nutrients with cognition and temperament during the first 6 months of life when human milk is the primary source of an infant's nutrition and explore whether there were persistent effects up to 18 months old. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of 54 exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12, and 12-18 months old. Human milk samples were obtained from the mothers of the participants at less than 6 months of age and analyzed for fatty acids [total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)], phospholipids [phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin], and choline [free choline, phosphocholine (PCho), glycerophosphocholine]. Feature selection was performed to select nutrients associated with cognition and temperament. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). A significant effect of DHA, n-6/n-3, PE, and TSFA concentrations on receptive language (R 2 = 0.39, p = 0.025) and the elevated ARA, PCho, and PI with increased surgency (R 2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of human milk nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our study highlighted that various human milk nutrients work together to support the development of cognition and temperament traits during early infancy.

Dietary sialylated oligosaccharides in early-life may promote cognitive flexibility during development in context of obesogenic dietary intake.

Introduction: Oligosaccharides found in mammalian milk have shown the potential to alter brain development across multiple species. The diversity and concentration of these oligosaccharides is species-specific and varies greatly between individuals, thus understanding their role in cognitive development is warranted. We investigated the impact of early life dietary fucosylated/neutral or sialylated human milk oligosaccharides (HMO) on behaviours in tasks assessing anxiety, motivation, appetite, learning, and memory.Methods: Sixty-four female Göttingen minipigs were artificially reared from 2 weeks postnatal and provided milk replacers. The study used four groups: no additional oligosaccharides (Con), fucosylated and neutral oligosaccharides (FN, 4 g/L), sialylated oligosaccharides (SL, 0.68 g/L), or both FN and SL (FN + SL, 4 g/L) from 2 to 11 weeks postnatal. One reference group was sow-reared. Weaning occurred between 10 and 11 weeks postnatal, and thereafter an obesogenic diet was provided. Behavioral tasks were conducted over three periods: 1) 0-11 weeks; 2) 16-29 weeks; 3) 39-45 weeks. Tasks included a spatial holeboard task, open field task, exposure to a novel object, runway task, single-feed task, and home pen behaviour observation.Results: In the holeboard, the SL group demonstrated improved reference memory during reversal trials between 16-29 weeks. All groups demonstrated equivalent behavior in open field, novel object, runway, and single-feed tasks, as well as in their home pens (Ps > 0.05).Discussion: These results suggest that early life dietary intake of sialylated oligosaccharides may provide an improvement to cognition during the equivalent developmental stage of adolescence.

Effects of Post-natal Dietary Milk Fat Globule Membrane Polar Lipid Supplementation on Motor Skills, Anxiety, and Long-Term Memory in Adulthood.

Early life nutrition critically impacts post-natal brain maturation and cognitive development. Post-natal dietary deficits in specific nutrients, such as lipids, minerals or vitamins are associated with brain maturation and cognitive impairments. Specifically, polar lipids (PL), such as sphingolipids and phospholipids, are important cellular membrane building blocks and are critical for brain connectivity due to their role in neurite outgrowth, synaptic formation, and myelination. In this preclinical study, we assessed the effects of a chronic supplementation with a source of PL extracted from an alpha-lactalbumin enriched whey protein containing 10% lipids from early life (post-natal day (PND) 7) to adulthood (PND 72) on adult motor skills, anxiety, and long-term memory. The motor skills were assessed using open field and rotarod test. Anxiety was assessed using elevated plus maze (EPM). Long-term object and spatial memory were assessed using novel object recognition (NOR) and Morris water maze (MWM). Our results suggest that chronic PL supplementation improved measures of spatial long-term memory accuracy and cognitive flexibility in the MWM in adulthood, with no change in general mobility, anxiety and exploratory behavior. Our results indicate memory specific functional benefits of long-term dietary PL during post-natal brain development.

Exposure to 3'Sialyllactose-Poor Milk during Lactation Impairs Cognitive Capabilities in Adulthood.

Breast milk exerts pivotal regulatory functions early in development whereby it contributes to the maturation of brain and associated cognitive functions. However, the specific components of maternal milk mediating this process have remained elusive. Sialylated human milk oligosaccharides (HMOs) represent likely candidates since they constitute the principal neonatal dietary source of sialic acid, which is crucial for brain development and neuronal patterning. We hypothesize that the selective neonatal lactational deprivation of a specific sialylated HMOs, sialyl(alpha2,3)lactose (3'SL), may impair cognitive capabilities (attention, cognitive flexibility, and memory) in adulthood in a preclinical model. To operationalize this hypothesis, we cross-fostered wild-type (WT) mouse pups to B6.129-St3gal4tm1.1Jxm/J dams, knock-out (KO) for the gene synthesizing 3'SL, thereby providing milk with approximately 80% 3'SL content reduction. We thus exposed lactating WT pups to a selective reduction of 3'SL and investigated multiple cognitive domains (including memory and attention) in adulthood. Furthermore, to account for the underlying electrophysiological correlates, we investigated hippocampal long-term potentiation (LTP). Neonatal access to 3'SL-poor milk resulted in decreased attention, spatial and working memory, and altered LTP compared to the control group. These results support the hypothesis that early-life dietary sialylated HMOs exert a long-lasting role in the development of cognitive functions.

Influence of Dietary Polar Lipid Supplementation on Memory and Longitudinal Brain Development.

Polar lipids, which are found in human milk, serve essential functions within biological membranes, hence their importance in brain development and cognition. Therefore, we aimed to evaluate the longitudinal effects on brain macrostructural and microstructural development and recognition memory of early-life polar lipid supplementation using the translational pig model. Twenty-eight intact (i.e., not castrated) male pigs were provided either a control diet (n = 14) or the control diet supplemented with polar lipids (n = 14) from postnatal day 2 until postnatal week 4. After postnatal week 4, all animals were provided the same nutritionally-adequate diets until postnatal week 24. Pigs underwent magnetic resonance imaging at 8 longitudinal time-points to model brain macrostructural and microstructural developmental trajectories. The novel object recognition task was implemented at postnatal weeks 4 and 8 to evaluate recognition memory. Subtle differences were observed between groups in hippocampal absolute brain volumes and fractional anisotropy, and no differences in myelin water fraction developmental patterns were noted. Behavioral outcomes did not differ in recognition memory, and only minimal differences were observed in exploratory behaviors. Our findings suggest that early-life dietary supplementation of polar lipids has limited effect on brain developmental patterns, object recognition memory, and exploratory behaviors.

Human milk 3'-Sialyllactose is positively associated with language development during infancy.

BACKGROUND: Genetic polymorphisms leading to variations in human milk oligosaccharide (HMO) composition have been reported. Alpha-Tetrasaccharide (A-tetra), an HMO, has been shown to only be present (>limit of detection; A-tetra+) in the human milk (HM) of women with blood type A, suggesting genetic origins determining the presence or absence (A-tetra-) of A-tetra in HM. OBJECTIVES: This study aimed to determine whether associations exist between HMO concentrations and cognitive development, and whether the associations vary between A-tetra+ and A-tetra- groups in children (<25 months old). METHODS: We enrolled typically developing children (2-25 months old; mean, 10 months old) who were at least partially breastfed at the study visit. The Mullen Scales of Early Learning (MSEL) were used as the primary outcome measure to assess early cognitive development. Linear mixed effects models were employed by stratifying children based on A-tetra levels (A-tetra+ or A-tetra-) to assess associations between age-removed HMO concentrations and both MSEL composite scores and the 5 subdomain scores. RESULTS: A total of 99 mother-child dyads and 183 HM samples were included (A-tetra+: 57 samples, 33 dyads; A-tetra-: 126 samples, 66 dyads). No significant association was observed between HMOs and MSEL when all samples were analyzed together. The composite score and 3'-sialyllactose (3'-SL) levels were positively associated [P = 0.002; effect size (EF), 13.12; 95% CI, 5.36-20.80] in the A-tetra + group. This association was driven by the receptive (adjusted P = 0.015; EF, 9.95; 95% CI, 3.91-15.99) and expressive (adjusted P = 0.048; EF, 7.53; 95% CI, 2.51-13.79) language subdomain scores. Furthermore, there was an interaction between 3'-SL and age for receptive language (adjusted P = 0.03; EF, -14.93; 95% CI, -25.29 to -4.24). CONCLUSIONS: Our study reports the association of 3'-SL and cognition, particularly language functions, in typically developing children who received HM containing detectable A-tetra during infancy.

Bovine Milk Oligosaccharides and Human Milk Oligosaccharides Modulate the Gut Microbiota Composition and Volatile Fatty Acid Concentrations in a Preclinical Neonatal Model.

Milk oligosaccharides (OS) shape microbiome structure and function, but their relative abundances differ between species. Herein, the impact of the human milk oligosaccharides (HMO) (2'-fucosyllactose [2'FL] and lacto-N-neotetraose [LNnT]) and OS isolated from bovine milk (BMOS) on microbiota composition and volatile fatty acid (VFA) concentrations in ascending colon (AC) contents and feces was assessed. Intact male piglets received diets either containing 6.5 g/L BMOS (n = 12), 1.0 g/L 2'FL + 0.5 g/L LNnT (HMO; n = 12), both (HMO + BMOS; n = 10), or neither (CON; n = 10) from postnatal day (PND) 2 to 34. Microbiota were assessed by 16S rRNA gene sequencing and real-time PCR, and VFA were measured by gas chromatography. The microbiota was affected by OS in an intestine region-specific manner. BMOS reduced (p < 0.05) microbial richness in the AC, microbiota composition in the AC and feces, and acetate concentrations in AC, regardless of HMO presence. HMO alone did not affect overall microbial composition, but increased (p < 0.05) the relative proportion of specific taxa, including Blautia, compared to other groups. Bacteroides abundance was increased (p < 0.05) in the AC by BMOS and synergistically by BMOS + HMO in the feces. Distinct effects of HMO and BMOS suggest complementary and sometimes synergistic benefits of supplementing a complex mixture of OS to formula.

A Mediation Analysis to Identify Links between Gut Bacteria and Memory in Context of Human Milk Oligosaccharides.

Elucidating relationships between the gut and brain is of intense research focus. Multiple studies have demonstrated that modulation of the intestinal environment via prebiotics or probiotics can induce cognitively beneficial effects, such as improved memory or reduced anxiety. However, the mechanisms by which either act remain largely unknown. We previously demonstrated that different types of oligosaccharides affected short- and long-term memory in distinct ways. Given that the oligosaccharide content of human milk is highly variable, and that formula-fed infants typically do not consume similar amounts or types of oligosaccharides, their potential effects on brain development warrant investigation. Herein, a mediation analysis was performed on existing datasets, including relative abundance of bacterial genera, gene expression, brain volume, and cognition in young pigs. Analyses revealed that numerous bacterial genera in both the colon and feces were related to short- and/or long-term memory. Relationships between genera and memory appeared to differ between diets. Mediating variables frequently included GABAergic and glutamatergic hippocampal gene expression. Other mediating variables included genes related to myelination, transcription factors, brain volume, and exploratory behavior. Overall, this analysis identified multiple pathways between the gut and brain, with a focus on genes related to excitatory/inhibitory neurotransmission.

Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode.

Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1tm2Jxm/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6'SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6'SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6'SL-deficient milk. To test whether lactational 6'SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6'SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6'SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.

Human and Bovine Milk Oligosaccharides Elicit Improved Recognition Memory Concurrent With Alterations in Regional Brain Volumes and Hippocampal mRNA Expression.

Human milk contains a unique profile of oligosaccharides (OS) and preliminary evidence suggests they impact brain development. The objective of this study was to assess the impact of bovine and/or human milk oligosaccharides (HMO) (2'-fucosyllactose and Lacto-N-neotetraose) on cognition, brain development, and hippocampal gene expression. Beginning on postnatal day (PND) 2, male pigs received one of four milk replacers containing bovine milk oligosaccharides (BMOS), HMO, both (BMOS + HMO), or neither. Pigs were tested on the novel object recognition task using delays of 1- or 48-h at PND 22. At PND 32-33, magnetic resonance imaging procedures were used to assess structural brain development and hippocampal tissue was collected for analysis of mRNA expression. Pigs consuming only HMO exhibited recognition memory after a 1-h delay and those consuming BMOS + HMO exhibited recognition memory after a 48-h delay. Both absolute and relative volumes of cortical and subcortical brain regions were altered by diet. Hippocampal mRNA expression of GABRB2, SLC1A7, CHRM3, and GLRA4 were most strongly affected by diet. HMO and BMOS had distinct effects on brain structure and cognitive performance. These data suggest different mechanisms underlie their influence on brain development.

Prenatal exposure to the probiotic Lactococcus lactis decreases anxiety-like behavior and modulates cortical cytoarchitecture in a sex specific manner.

Development of the cerebral cortex may be influenced by the composition of the maternal gut microbiota. To test this possibility, we administered probiotic Lactococcus lactis in drinking water to mouse dams from day 10.5 of gestation until pups reached postnatal day 1 (P1). Pups were assessed in a battery of behavioral tests starting at 10 weeks old. We found that females, but not males, exposed to probiotic during prenatal development spent more time in the center of the open field and displayed decreased freezing time in cue associated learning, compared to controls. Furthermore, we found that probiotic exposure changed the density of cortical neurons and increased the density of blood vessels in the cortical plate of P1 pups. Sex-specific differences were observed in the number of mitotic neural progenitor cells, which were increased in probiotic exposed female pups. In addition, we found that probiotic treatment in the latter half of pregnancy significantly increased plasma oxytocin levels in mouse dams, but not in the offspring. These results suggest that exposure of naïve, unstressed dams to probiotic may exert sex-specific long-term effects on cortical development and anxiety related behavior in the offspring.

Dietary Oligofructose Alone or in Combination with 2'-Fucosyllactose Differentially Improves Recognition Memory and Hippocampal mRNA Expression.

Mounting evidence suggests that dietary oligosaccharides promote brain development. This study assessed the capacity of oligofructose (OF) alone or in combination with 2'-fucosyllactose (2'-FL) to alter recognition memory, structural brain development, and hippocampal gene expression. Beginning on postnatal day (PND) 2, male pigs received one of three milk replacers formulated to contain OF, OF + 2'-FL, or no oligosaccharides (CON). Pigs were tested on the novel object recognition task using delays of 1 or 48 h at PND 22. At PND 32-33, magnetic resonance imaging (MRI) procedures were used to assess structural brain development and hippocampal tissue was collected for analysis of mRNA expression. Pigs that consumed the OF diet demonstrated increased recognition memory after a 1 h delay, whereas those consuming diets containing OF + 2'-FL displayed increased recognition memory after a 48 h delay. Pigs fed OF or OF + 2'-FL exhibited a larger relative volume of the olfactory bulbs compared with CON pigs. Provision of OF or OF + 2'-FL altered gene expression related to dopaminergic, GABAergic, cholinergic, cell adhesion, and chromatin remodeling processes. Collectively, these data indicate that dietary OF and OF + 2'-FL differentially improve cognitive performance and affect olfactory bulb structural development and hippocampal gene expression.

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval, and combining them attenuates the acquisition rate of spatial reference memory.

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over-generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.

A blend containing docosahexaenoic acid, arachidonic acid, vitamin B12, vitamin B9, iron and sphingomyelin promotes myelination in an in vitro model.

During the development of the central nervous system, oligodendrocytes (OLs) are responsible for myelination, the formation of the myelin sheath around axons. This process enhances neuronal connectivity and supports the maturation of emerging cognitive functions. In humans, recent evidence suggests that early life nutrition may affect myelination. In the present study, we investigated the impact of a blend containing docosahexaenoic acid, arachidonic acid, vitamin B12, vitamin B9, iron and sphingomyelin, or each of these nutrients individually, on oligodendrocyte precursor cells (OPCs) proliferation and maturation into OLs as well as their myelinating properties. By using an in vitro model, developed to study each step of myelination, we found that the nutrient blend increased the number of OPCs and promoted their differentiation and maturation into OLs, as measured by quantifying A2B5 positive cells, myelin-associated glycoprotein (MAG) positive cells and area, myelin binding protein (MBP) positive cells and area, respectively. Moreover, measuring myelination by quantifying the overlapping signal between neurofilament and either MAG or MBP revealed a positive effect of the blend on OLs myelinating properties. In contrast, treatment with each individual nutrient resulted in differential effects on the various readouts. This work suggests that dietary intake of these nutrients during early life, might be beneficial for myelination.

Sphingomyelin in Brain and Cognitive Development: Preliminary Data.

Sphingomyelin (SM) supports brain myelination, a process closely associated with cognitive maturation. The presence of SM in breast milk suggests a role in infant nutrition; however, little is known about SM contribution to healthy cognitive development. We investigated the link between early life dietary SM, later cognitive development and myelination using an exploratory observational study of neurotypical children. SM levels were quantified in infant nutrition products fed in the first three months of life and associated with myelin content (brain MRI) as well as cognitive development (Mullen scales of early learning; MSEL). Higher levels of SM were significantly associated with higher rates of change in verbal development in the first two years of life (r = 0.65, p < 0.001), as well as, higher levels of myelin content at 12-24 months, delayed onset and/or more prolonged rates of myelination in different brain areas. Second, we explored mechanisms of action using in vitro models (Sprague Dawley rat pups). In vitro data showed SM treatment resulted in increased proliferation [p = 0.0133 and p = 0.0434 at 4 and 10 d in vitro (DIV)], maturation (p = 0.467 at 4 d DIV) and differentiation (p = 0.0123 and p = 0.0369 at 4 and 10 DIV) of oligodendrocyte precursor cells (OPCs), as well as increased axon myelination (p = 0.0005 at 32 DIV). These findings indicate an impact of dietary SM on cognitive development in healthy children, potentially modulated by oligodendrocytes and increased axon myelination. Future research should include randomized controlled trials to substantiate efficacy of SM for cognitive benefits together with preclinical studies examining SM bioavailability and brain uptake.

A Developmental Switch in Place Cell Accuracy Coincides with Grid Cell Maturation.

Place cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries.