Brain dynamics of meal size selection in humans.

Although neuroimaging research has evidenced specific responses to visual food stimuli based on their nutritional quality (e.g., energy density, fat content), brain processes underlying portion size selection remain largely unexplored. We identified spatio-temporal brain dynamics in response to meal images varying in portion size during a task of ideal portion selection for prospective lunch intake and expected satiety. Brain responses to meal portions judged by the participants as 'too small', 'ideal' and 'too big' were measured by means of electro-encephalographic (EEG) recordings in 21 normal-weight women. During an early stage of meal viewing (105-145ms), data showed an incremental increase of the head-surface global electric field strength (quantified via global field power; GFP) as portion judgments ranged from 'too small' to 'too big'. Estimations of neural source activity revealed that brain regions underlying this effect were located in the insula, middle frontal gyrus and middle temporal gyrus, and are similar to those reported in previous studies investigating responses to changes in food nutritional content. In contrast, during a later stage (230-270ms), GFP was maximal for the 'ideal' relative to the 'non-ideal' portion sizes. Greater neural source activity to 'ideal' vs. 'non-ideal' portion sizes was observed in the inferior parietal lobule, superior temporal gyrus and mid-posterior cingulate gyrus. Collectively, our results provide evidence that several brain regions involved in attention and adaptive behavior track 'ideal' meal portion sizes as early as 230ms during visual encounter. That is, responses do not show an increase paralleling the amount of food viewed (and, in extension, the amount of reward), but are shaped by regulatory mechanisms

Face engagement during infancy predicts later face recognition ability in younger siblings of children with autism

Face recognition difficulties are frequently documented in children with autism spectrum disorders (ASD). It has been hypothesized that these difficulties result from a reduced interest in faces early in life, leading to decreased cortical specialization and atypical development of the neural circuitry for face processing. However, a recent study by our lab demonstrated that infants at increased familial risk for ASD, irrespective of their diagnostic status at 3 years, exhibit a clear orienting response to faces. The present study was conducted as a follow-up on the same cohort to investigate how measures of early engagement with faces relate to face-processing abilities later in life. We also investigated whether face recognition difficulties are specifically related to an ASD diagnosis, or whether they are present at a higher rate in all those at familial risk. At 3 years we found a reduced ability to recognize unfamiliar faces in the high-risk group that was not specific to those children who received an ASD diagnosis, consistent with face recognition difficulties being an endophenotype of the disorder. Furthermore, we found that longer looking at faces at 7 months was associated with poorer performance on the face recognition task at 3 years in the high- risk group. These findings suggest that longer looking at faces in infants at risk for ASD might reflect early face-processing difficulties and predicts difficulties with recognizing faces later in life

Face engagement during infancy predicts later face recognition ability in younger siblings of children with autism

Face recognition difficulties are frequently documented in children with autism spectrum disorders (ASD). It has been hypothesized that these difficulties result from a reduced interest in faces early in life, leading to decreased cortical specialization and atypical development of the neural circuitry for face processing. However, a recent study by our lab demonstrated that infants at increased familial risk for ASD, irrespective of their diagnostic status at 3 years, exhibit a clear orienting response to faces. The present study was conducted as a follow-up on the same cohort to investigate how measures of early engagement with faces relate to face-processing abilities later in life. We also investigated whether face recognition difficulties are specifically related to an ASD diagnosis, or whether they are present at a higher rate in all those at familial risk. At 3 years we found a reduced ability to recognize unfamiliar faces in the high-risk group that was not specific to those children who received an ASD diagnosis, consistent with face recognition difficulties being an endophenotype of the disorder. Furthermore, we found that longer looking at faces at 7 months was associated with poorer performance on the face recognition task at 3 years in the high- risk group. These findings suggest that longer looking at faces in infants at risk for ASD might reflect early face-processing difficulties and predicts difficulties with recognizing faces later in life

APOE4 derived from astrocytes leads to blood-brain barrier impairment

Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood-brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood-brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood-brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood-brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood-brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood-brain barrier.</p

Effect of a 1-Year Nutritional Blend Supplementation on Plasma p-tau181 and GFAP Levels among Community-Dwelling Older Adults: A Secondary Analysis of the Nolan Trial

BACKGROUND: Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD). As measuring amyloid-β and tau pathophysiology by positron emission tomography (PET) or cerebrospinal fluid (CSF) analyses may be perceived as complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. OBJECTIVES: This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 and glial fibrillary acidic protein (GFAP) levels in community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to p-tau status (with the third tertile considered as high: ≥15.1 pg/ mL) and to apolipoprotein E (APOE) ε4 allele status. METHODS: A total of 289 participants ≥70 years (56.4% female, mean age 78.1 years, SD=4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed, and daily took either a nutritional blend (composed of thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, vitamin E, vitamin C, vitamin D, choline, selenium, citrulline, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) or placebo for 1 year. RESULTS: After 1-year, both groups presented a significant increase in plasma p-tau181 and GFAP values, with no effect of the intervention (p-tau181 between-group difference: 0.27pg/mL, 95%CI: -0.95, 1.48; p=0.665; GFAP between-group difference: -3.28 pg/mL, 95%CI: -17.25, 10.69; p=0.644). P-tau-and APOE ε4-stratified analyses provided similar findings. CONCLUSIONS: In community-dwelling older adults, we observed an increase in plasma p-tau181 and GFAP levels that was not different between the supplementation groups after one year

Sex differences in intestinal carbohydrate metabolism promote food intake and sperm maturation

Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signalling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this malebiased intestinal metabolic state in controlling food intake and sperm production through gutderived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, and reveals that metabolic communication across organs is physiologically significant. The instructive role of citrate in inter-organ communication may be significant in more biological contexts than previously recognised

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia.

Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homoeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease