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      Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects

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          Abstract

          Objective

          A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions play an important role in human health and disease, including hedonic food intake and obesity. We performed a tripartite network analysis based on graph theory to test the hypothesis that microbiota-derived fecal metabolites are associated with connectivity of key regions of the brain’s extended reward network and clinical measures related to obesity.

          Methods

          DTI and resting state fMRI imaging was obtained from 63 healthy subjects with and without elevated body mass index (BMI) (29 males and 34 females). Subjects submitted fecal samples, completed questionnaires to assess anxiety and food addiction, and BMI was recorded.

          Results

          The study results demonstrate associations between fecal microbiota-derived indole metabolites (indole, indoleacetic acid, and skatole) with measures of functional and anatomical connectivity of the amygdala, nucleus accumbens, and anterior insula, in addition to BMI, food addiction scores (YFAS) and anxiety symptom scores (HAD Anxiety).

          Conclusions

          The findings support the hypothesis that gut microbiota-derived indole metabolites may influence hedonic food intake and obesity by acting on the extended reward network, specifically the amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit. These cross sectional, data-driven results provide valuable information for future mechanistic studies.

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          Most cited references37

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          Preliminary validation of the Yale Food Addiction Scale.

          Previous research has found similarities between addiction to psychoactive substances and excessive food consumption. Further exploration is needed to evaluate the concept of "food addiction," as there is currently a lack of psychometrically validated measurement tools in this area. The current study represents a preliminary exploration of the Yale Food Addiction Scale (YFAS), designed to identify those exhibiting signs of addiction towards certain types of foods (e.g., high fat and high sugar). Survey data were collected from 353 respondents from a stratified random sample of young adults. In addition to the YFAS, the survey assessed eating pathology, alcohol consumption and other health behaviors. The YFAS exhibited adequate internal reliability, and showed good convergent validity with measures of similar constructs and good discriminant validity relative to related but dissimilar constructs. Additionally, the YFAS predicted binge-eating behavior above and beyond existing measures of eating pathology, demonstrating incremental validity. The YFAS is a sound tool for identifying eating patterns that are similar to behaviors seen in classic areas of addiction. Further evaluation of the scale is needed, especially due to a low response rate of 24.5% and a non-clinical sample, but confirmation of the reliability and validity of the scale has the potential to facilitate empirical research on the concept of "food addiction".
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            Amygdala to nucleus accumbens excitatory transmission facilitates reward seeking

            The basolateral amygdala (BLA) plays a crucial role in emotional learning irrespective of valence 1–5 . While the BLA projection to the nucleus accumbens (NAc) is hypothesized to modulate cue-triggered motivated behaviors 4, 6, 7,, our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural circuit elements of this pathway selectively during behavior. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibers from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. We show that optical stimulation of the BLA-to-NAc pathway in mice reinforces behavioral responding to earn additional optical stimulations of these synaptic inputs. Optical stimulation of BLA-to-NAc glutamatergic fibers required intra-NAc dopamine D1-type, but not D2-type, receptor signaling. Brief optical inhibition of BLA-to-NAc fibers reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behavior. Moreover, while optical stimulation of medial prefrontal cortex (mPFC) to NAc glutamatergic fibers also elicited reliable excitatory synaptic responses, optical self-stimulation behavior was not observed by activation of this pathway. These data suggest that while the BLA is important for processing both positive and negative affect, the BLA-to-NAc glutamatergic pathway in conjunction with dopamine signaling in the NAc promotes motivated behavioral responding.
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              Characteristics of compounds that cross the blood-brain barrier

              Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Visualization
                Role: Data curationRole: Formal analysis
                Role: Data curation
                Role: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 August 2018
                2018
                : 13
                : 8
                : e0201772
                Affiliations
                [1 ] G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, CA, United States of America
                [2 ] UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America
                [3 ] UCLA Department of Integrative Biology and Physiology, Los Angeles, CA, United States of America
                Instituto de Agroquimica y Tecnologia de Alimentos, SPAIN
                Author notes

                Competing Interests: EAM is a scientific advisory board member of Danone, Danone Northamerica, Axial Biotherapeutics, Viome, Amare, Pharmavite and Prolacta. None of these companies were in any way involved in the current study, and this board membership does not alter the adherence of the authors to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-3923-3349
                Article
                PONE-D-18-12368
                10.1371/journal.pone.0201772
                6078307
                30080865
                42e8e4cc-05f3-49cd-9227-f324c9ad4c89
                © 2018 Osadchiy et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 April 2018
                : 20 July 2018
                Page count
                Figures: 2, Tables: 2, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P50 DK 064539
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P30 DK 041301
                This study was supported in part by National Institutes of Health grants P50 DK 064539 (Emeran A Mayer) and P30 DK 041301. National Institutes of Health, who funded this study, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Heterocyclic Compounds
                Indoles
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Heterocyclic Compounds
                Indoles
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Metabolites
                Biology and Life Sciences
                Anatomy
                Brain
                Amygdala
                Medicine and Health Sciences
                Anatomy
                Brain
                Amygdala
                Computer and Information Sciences
                Network Analysis
                Metabolic Networks
                Computer and Information Sciences
                Neural Networks
                Biology and Life Sciences
                Neuroscience
                Neural Networks
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                Psychology
                Addiction
                Social Sciences
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                Computer and Information Sciences
                Network Analysis
                Centrality
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Body Mass Index
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
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