An update to Hippocampome.org by integrating single-cell phenotypes with circuit function in vivo.

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.

Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

A three-year multifaceted intervention to prevent obesity in children of Mexican-heritage.

BACKGROUND: Obesity and overweight have increased dramatically in the United States over the last decades. The complexity of interrelated causal factors that result in obesity needs to be addressed within the cultural dynamic of sub-populations. In this study, we sought to estimate the effects of a multifaceted, community-based intervention on body mass index (BMI) among Mexican-heritage children. METHODS: Niños Sanos, Familia Sana (Healthy Children, Healthy Family) was a quasi-experimental intervention study designed to reduce the rate of BMI growth among Mexican-heritage children in California's Central Valley. Two rural communities were matched based on demographic and environmental characteristics and were assigned as the intervention or comparison community. The three-year intervention included parent workshops on nutrition and physical activity; school-based nutrition lessons and enhanced physical education program for children; and a monthly voucher for fruits and vegetables. Eligible children were between 3 and 8 years old at baseline. Intent-to-treat analyses were estimated using linear mixed-effect models with random intercepts. We ran a series of models for each gender where predictors were fixed except interactions between age groups and obesity status at baseline with intervention to determine the magnitude of impact on BMI. RESULTS: At baseline, mean (SD) BMI z-score (zBMI) was 0.97 (0.98) in the intervention group (n = 387) and 0.98 (1.02) in the comparison group (n = 313) (NS). The intervention was significantly associated with log-transformed BMI (ß = 0.04 (0.02), P = 0.03) and zBMI (ß = 0.25 (0.12), P = 0.04) among boys and log-transformed BMI among obese girls (ß = - 0.04 (0.02), P = 0.04). The intervention was significantly and inversely associated with BMI in obese boys and girls across all age groups and normal weight boys in the oldest group (over 6 years) relative to their counterparts in the comparison community. CONCLUSIONS: A community-based, multifaceted intervention was effective at slowing the rate of BMI growth among Mexican-heritage children. Our findings suggest that practitioners should consider strategies that address gender disparities and work with a variety of stakeholders to target childhood obesity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01900613 . Registered 16th July 2013.

Prevalence and Perception of Childhood Obesity in California's Farmworker Communities.

In California's central valley, childhood obesity rates are above the national average. The majority of families living in the rural, agricultural communities of this region are immigrant of Mexican heritage, and face numerous social and environmental challenges. Demographic and anthropometric data were collected from a population of Mexican-heritage children 3-8 years (N = 609) and families (N = 466) living in two central valley communities. Overall, 45 % of children and 82 % of mothers were classified as overweight or obese. Multivariable analyses indicated that mother's BMI and acculturation level were positively associated with child BMI z-score. Most children classified as overweight or obese (92 % and 53 %, respectively) were perceived as having 'normal' weight by their mothers. Childhood obesity remains a major public health issue in Mexican-heritage, central valley communities. Our model indicates that mother's BMI is predictor of child obesity, and parents tend to underestimate their child's weight status. These findings highlight a need for family-targeted and culturally-tailored approaches to address relevant perceptions of obesity and risk factors in these communities.

Correlates of food patterns in young Latino children at high risk of obesity.

OBJECTIVE: The present paper examines the influence of age and gender on food patterns of Latino children. DESIGN: Data are from baseline of a 5-year, quasi-experimental obesity prevention study: Niños Sanos, Familia Sana (NSFS; Healthy Children, Healthy Families). In 2012, the researchers interviewed Latino parents, using a thirty-item questionnaire to ask about their children's food consumption and feeding practices. Statistical tests included t tests and ANCOVA. SETTING: Rural communities in California's Central Valley, USA. SUBJECTS: Two hundred and seventeen parents (87-89% born in Mexico) and their children (aged 2-8 years). RESULTS: Fifty-one per cent of the children were overweight or obese (≥85th percentile of BMI for age and gender). Mean BMI Z-scores were not significantly different in boys (1·10 (SD 1·07)) and girls (0·92 (SD 1·04); P=0·12). In bivariate analysis, children aged 2-4 years consumed fast and convenience foods less often (P=0·04) and WIC (Supplemental Nutrition Program for Women, Infants, and Children)-allowable foods more often than children aged 5-8 years (P=0·01). In ANCOVA, neither age nor gender was significantly related to food patterns. Mother's acculturation level was positively related to children's consumption of fast and convenience foods (P=0·0002) and negatively related to consumption of WIC foods (P=0·01). Providing role modelling and structure in scheduling meals and snacks had a positive effect on the vegetable pattern (P=0·0007), whereas meal skipping was associated with more frequent fast and convenience food consumption (P=0·04). CONCLUSIONS: Acculturation and child feeding practices jointly influence food patterns in Latino immigrant children and indicate a need for interventions that maintain diet quality as children transition to school.

Adaptation of a culturally relevant nutrition and physical activity program for low-income, Mexican-origin parents with young children.

Latino children experience higher rates of obesity than do non-Latino white children. Family-centered nutrition interventions can slow the rate of weight gain in this population. Niños Sanos, Familia Sana (Healthy Children, Healthy Family) is a 5-year, community-based, participatory research study that targets rural Mexican-origin farmworker families with children aged 2 to 8 years in California's Central Valley. Adaptation of a culturally relevant obesity prevention program involved qualitative research to tailor key obesity prevention messages, pilot testing and implementation of key messages and activities at family nights, and continual modification to incorporate culturally innovative elements. Of the 238 families enrolled, 53% (125) attended the recommended minimum of 5 (of 10 possible) classes during the first year. A university and community partnership can guide development of a culturally tailored obesity prevention program that is suitable for reaching a high-risk Mexican-origin audience through cooperative extension and other public health programs.

Assessment of social behavior and chemosensory cue detection in an animal model of neurodegeneration.

Numerous studies have shown that aging in humans leads to a decline in olfactory function, resulting in deficits in acuity, detection threshold, discrimination, and olfactory-associated memories. Furthermore, impaired olfaction has been identified as a potential indicator for the onset of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Studies conducted on mouse models of AD have largely mirrored the findings in humans, thus providing a valuable system to investigate the cellular and circuit adaptations of the olfactory system during natural and pathological aging. However, the majority of previous research has focused on assessing the detection of neutral or synthetic odors, with little attention given to the impact of aging and neurodegeneration on the recognition of social cues-a critical feature for the survival of mammalian species. Therefore, in this study, we present a battery of olfactory tests that use conspecific urine samples to examine the changes in social odor recognition in a mouse model of neurodegeneration.

Tannin-based supplementation influences gut microbiota composition and activity in IBS-D patients with a potential impact on symptoms: a pilot study.

As the involvement of the intestinal microbiota in the etiopathology of irritable bowel syndrome, subtype diarrhoea (IBS-D) is now increasingly recognised, a preliminary, quasi-experimental, before-after and prospective study was conducted on 28 patients to test the effect of a tannin-based supplement on the composition and activity of the microbiota, after 8 weeks of treatment. No statistically significant differences were found in α- or ß-diversity. However, sparse Partial Least Squares Discriminant Analysis (sPLS-DA) and Boruta algorithm did reveal significant changes in the relative abundance of specific groups of bacteria, highlighting the involvement of recognized of IBS-D biomarkes, namely Blautia (adj p = 3.5 × 10-11), Eubacterium hallii group (adj p = 5.1 × 10-12) and Dorea (adj p = 1.8 × 10-18), which resulted significantly depleted by the treatment. The modulation of the composition of the gut microbiota had an impact also in the production of short chain fatty acids (SCFAs), which were modulated: acetate and butyrate (n.s. and p = 0.000143) increased while propionate and formate resulted to be significantly reduced (p = 0.00476 and p = 0.00011, respectively), following the supplementation. Finally, the sPLS analysis showed that the strongest association between faecal microbiome composition and clinical symptoms of IBS-D was given by Catenibacterium, which showed a positive correlation with evacuation-related symptoms. Such preliminary findings suggest that tannin supplementation could play an outstanding role in microbiota modulation in IBS-D patients, potentially improving their symptomatology, by selectively acting on the growth and the activity of specific groups of taxa.

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes.

Introduction: Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes. Methods: To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity). Results: According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02). Discussion: Our data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

Evaluation of Tannin-Delivery Approaches for Gut Microbiota Modulation: Comparison of Pectin-Based Microcapsules and Unencapsulated Extracts.

The aim of this study was to investigate the impact of tannins on gut microbiota composition and activity, and to evaluate the use of pectin-microencapsulation of tannins as a potential mode of tannin delivery. Thus, pectin-tannin microcapsules and unencapsulated tannin extracts were in vitro digested and fermented, and polyphenol content, antioxidant capacity, microbiota modulation, and short-chain fatty acid (SCFA) production were analyzed. Pectin microcapsules were not able to release their tannin content, keeping it trapped after the digestive process, and are therefore not recommended for tannin delivery. Unencapsulated tannin extracts were found to exert a positive effect on the human gut microbiota. The digestion step resulted to be a fundamental requirement in order to maximize tannin bioactive effects, especially with regard to condensed tannins, as the antioxidant capacity exerted and the SCFAs produced were greater when tannins were submitted to digestion prior to fermentation. Moreover, tannins interacted differently with the intestinal microbiota depending on whether they underwent prior digestion or not. Polyphenol content and antioxidant capacity correlated with SCFA production and with the abundance of several bacterial taxa.

Topological analysis of sharp-wave ripple waveforms reveals input mechanisms behind feature variations.

The reactivation of experience-based neural activity patterns in the hippocampus is crucial for learning and memory. These reactivation patterns and their associated sharp-wave ripples (SWRs) are highly variable. However, this variability is missed by commonly used spectral methods. Here, we use topological and dimensionality reduction techniques to analyze the waveform of ripples recorded at the pyramidal layer of CA1. We show that SWR waveforms distribute along a continuum in a low-dimensional space, which conveys information about the underlying layer-specific synaptic inputs. A decoder trained in this space successfully links individual ripples with their expected sinks and sources, demonstrating how physiological mechanisms shape SWR variability. Furthermore, we found that SWR waveforms segregated differently during wakefulness and sleep before and after a series of cognitive tasks, with striking effects of novelty and learning. Our results thus highlight how the topological analysis of ripple waveforms enables a deeper physiological understanding of SWRs.

Effects of different foods and cooking methods on the gut microbiota: an in vitro approach.

To support personalized diets targeting the gut microbiota, we employed an in vitro digestion-fermentation model and 16S rRNA gene sequencing to analyze the microbiota growing on representative foods of the Mediterranean and Western diets, as well as the influence of cooking methods. Plant- and animal-derived foods had significantly different impacts on the abundances of bacterial taxa. Animal and vegetable fats, fish and dairy products led to increases in many taxa, mainly within the Lachnospiraceae. In particular, fats favored increases in the beneficial bacteria Faecalibacterium, Blautia, and Roseburia. However, butter, as well as gouda cheese and fish, also resulted in the increase of Lachnoclostridium, associated to several diseases. Frying and boiling produced the most distinct effects on the microbiota, with members of the Lachnospiraceae and Ruminococcaceae responding the most to the cooking method employed. Nevertheless, cooking effects were highly individualized and food-dependent, challenging the investigation of their role in personalized diets.

Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits.

A high percentage of patients with brain metastases frequently develop neurocognitive symptoms; however, understanding how brain metastasis co-opts the function of neuronal circuits beyond a tumor mass effect remains unknown. We report a comprehensive multidimensional modeling of brain functional analyses in the context of brain metastasis. By testing different preclinical models of brain metastasis from various primary sources and oncogenic profiles, we dissociated the heterogeneous impact on local field potential oscillatory activity from cortical and hippocampal areas that we detected from the homogeneous inter-model tumor size or glial response. In contrast, we report a potential underlying molecular program responsible for impairing neuronal crosstalk by scoring the transcriptomic and mutational profiles in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help predict the presence and subtype of metastasis.

Evaluation of the Effects of a Short Supplementation With Tannins on the Gut Microbiota of Healthy Subjects.

Western diet, high in fats and sugars and low in greens, contributes to dysbiosis of the gut microbiota, which can lead to a variety of chronic diseases related with inflammation. Supplementation with bioactive compounds can help to maintain a healthy eubiotic state. Thus, we performed a 4-weeks nutritional intervention on healthy volunteers to investigate whether a blend of natural tannin extracts could induce healthy changes in the microbial intestinal ecosystem. Changes in the composition and functionality of the microbiota could be observed from the first two weeks onward. 16S rRNA amplicon next-generation sequencing (NGS) revealed a significant increase in microbial diversity at the end of the intervention, as well as trends toward increases in the relative abundances of several beneficial taxa, such as Ruminococcus bicirculans, Faecalibacterium prausnitzii, Lachnospiraceae UCG 010, Lachnospiraceae NK4A136, Bacteroides thetaiotaomicron and B. uniformis. Remarkably, some of the identified taxa were also identified as responsible for an increase in the production of short-chain fatty acids (SCFAs), microbial metabolites that contribute to the modulation of the immune system and have various other anti-inflammatory functions in the gut. Taken together, these results suggest that the tannin supplementation could exert a prebiotic effect by selectively stimulating the growth and the activity of bacteria that are advantageous for the host.

Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus.

Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity.

Enrichment of Food With Tannin Extracts Promotes Healthy Changes in the Human Gut Microbiota.

Food and food bioactive components are major drivers of modulation of the human gut microbiota. Tannin extracts consist of a mix of bioactive compounds, which are already exploited in the food industry for their chemical and sensorial properties. The aim of our study was to explore the viability of associations between tannin wood extracts of different origin and food as gut microbiota modulators. 16S rRNA amplicon next-generation sequencing (NGS) was used to test the effects on the gut microbiota of tannin extracts from quebracho, chestnut, and tara associated with commercial food products with different composition in macronutrients. The different tannin-enriched and non-enriched foods were submitted to in vitro digestion and fermentation by the gut microbiota of healthy subjects. The profile of the short chain fatty acids (SCFAs) produced by the microbiota was also investigated. The presence of tannin extracts in food promoted an increase of the relative abundance of the genus Akkermansia, recognized as a marker of a healthy gut, and of various members of the Lachnospiraceae and Ruminococcaceae families, involved in SCFA production. The enrichment of foods with tannin extracts had a booster effect on the production of SCFAs, without altering the profile given by the foods alone. These preliminary results suggest a positive modulation of the gut microbiota with potential benefits for human health through the enrichment of foods with tannin extracts.

Effect of Freezing on Gut Microbiota Composition and Functionality for In Vitro Fermentation Experiments.

The gut microbiota has a profound effect on human health and is modulated by food and bioactive compounds. To study such interaction, in vitro batch fermentations are performed with fecal material, and some experimental designs may require that such fermentations be performed with previously frozen stools. Although it is known that freezing fecal material does not alter the composition of the microbial community in 16S rRNA gene amplicon and metagenomic sequencing studies, it is not known whether the microbial community in frozen samples could still be used for in vitro fermentations. To explore this, we undertook a pilot study in which in vitro fermentations were performed with fecal material from celiac, cow's milk allergic, obese, or lean children that was frozen (or not) with 20% glycerol. Before fermentation, the fecal material was incubated in a nutritious medium for 6 days, with the aim of giving the microbial community time to recover from the effects of freezing. An aliquot was taken daily from the stabilization vessel and used for the in vitro batch fermentation of lentils. The microbial community structure was significantly different between fresh and frozen samples, but the variation introduced by freezing a sample was always smaller than the variation among individuals, both before and after fermentation. Moreover, the potential functionality (as determined in silico by a genome-scaled metabolic reconstruction) did not differ significantly, possibly due to functional redundancy. The most affected genus was Bacteroides, a fiber degrader. In conclusion, if frozen fecal material is to be used for in vitro fermentation purposes, our preliminary analyses indicate that the functionality of microbial communities can be preserved after stabilization.

Effect of roasting conditions on cocoa bioactivity and gut microbiota modulation.

Cocoa is a highly consumed food with beneficial effects on human health. Cocoa roasting has an important influence on its sensory and nutritional characteristics; therefore, roasting could also play a role in cocoa bioactivity. Thus, the aim of this paper is to unravel the effect of cocoa roasting conditions on its antioxidant capacity and modifications of gut microbiota after in vitro digestion-fermentation. HMF and furfural, chemical markers of non-enzymatic browning, were analyzed in unroasted and roasted cocoa powder at different temperatures, as well as different chocolates. The antioxidant capacity decreased with roasting, most probably due to the loss of phenolic compounds during heating. In the case of the evaluated chocolates, the antioxidant capacity was 2-3 times higher in the fermented fraction. On the other hand, HMF and furfural content increased during roasting due to increasing temperatures. Moreover, unroasted and roasted cocoa powder have different effects on gut microbial communities. Roasted cocoa favored butyrate production, whereas unroasted cocoa favored acetate and propionate production in a significant manner. In addition, unroasted and roasted cocoa produced significantly different gut microbial communities in terms of composition. Although many bacteria were affected, Veillonella and Faecalibacterium were some of the most discriminant ones; whereas the former is a propionate producer, the latter is a butyrate producer that has also been linked to positive effects on the inflammatory health of the gut and the immune system. Therefore, unroasted and roasted cocoa (regardless of the roasting temperature) promote different bacteria and a different SCFA production.