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Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Eating disorders and their core symptoms (eg, binge eating, body weight/shape concerns) disproportionately affect females, and these sex-differentiated effects become prominent during and after puberty. Although psychosocial influences such as heightened sociocultural pressures for thinness in girls and women contribute to this sex imbalance, biological factors could also play an important role. This narrative review summarizes evidence of biological factors underlying the sex-differentiated prevalence of eating pathology as well as within-sex variability in risk. There are sex differences in the pubertal emergence of genetic effects on eating pathology (adrenarche in males; gonadarche in females), and at least some genetic contributions to eating pathology seem to vary between the sexes. Furthermore, sex steroid hormones (eg, testosterone, estradiol, progesterone) are leading contributors to differential risk for eating pathology in males and females across the life span. Emerging data suggest that between-sex and within-sex variability in risk might occur via hormone-driven modulation (activation/deactivation) of genetic influences and neural responsiveness to food-related cues. There is a biological basis to heightened risk for eating pathology in females, relative to males, as well as unique biological influences within each sex. Findings from this review highlight the importance of studying both sexes and considering sex-specific biological mechanisms that may underlie differential risk for eating pathology •Some genetic effects on eating pathology vary between the sexes.•Sex steroids impact sex-specific genetic and phenotypic effects on eating pathology.•Testosterone exerts protective effects that reduce eating pathology in males.•Lower estradiol enhances genetic and phenotypic eating pathology risk in girls/women.•Neural responses to palatable food differ between the sexes, possibly via estradiol.

Obesity is a major health challenge facing many people throughout the world. Increased consumption of palatable, high-caloric foods is one of the major drivers of obesity. Both orexigenic and anorexic states have been thoroughly reviewed elsewhere; here, we focus on the cognitive control of feeding in the context of obesity, and how the orbitofrontal cortex (OFC) is implicated, based on data from preclinical and clinical research. The OFC is important in decision-making and has been heavily researched in neuropsychiatric illnesses such as addiction and obsessive–compulsive disorder. However, activity in the OFC has only recently been described in research into food intake, obesity and eating disorders. The OFC integrates sensory modalities such as taste, smell and vision, and it has dense reciprocal projections into thalamic, midbrain and striatal regions to fine-tune decision-making. Thus, the OFC may be anatomically and functionally situated to play a critical role in the etiology and maintenance of excess feeding behaviour. We propose that the OFC serves as an integrative hub for orchestrating motivated feeding behaviour and suggest how its neurobiology and functional output might be altered in the obese state.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

The gut microbiota has the capacity to affect host appetite via intestinal satiety pathways, as well as complex feeding behaviors. In this Review, we highlight recent evidence that the gut microbiota can modulate food preference across model organisms. We discuss effects of the gut microbiota on the vagus nerve and brain regions including the hypothalamus, mesolimbic system, and prefrontal cortex, which play key roles in regulating feeding behavior. Crosstalk between commensal bacteria and the central and peripheral nervous systems is associated with alterations in signaling of neurotransmitters and neuropeptides such as dopamine, brain-derived neurotrophic factor (BDNF), and glucagon-like peptide-1 (GLP-1). We further consider areas for future research on mechanisms by which gut microbes may influence feeding behavior involving these neural pathways. Understanding roles for the gut microbiota in feeding regulation will be important for informing therapeutic strategies to treat metabolic and eating disorders.

This review summarizes the current state of the literature regarding hormonal correlates of, and etiologic influences on, eating pathology. Several hormones (e.g., ghrelin, CCK, GLP-1, PYY, leptin, oxytocin, cortisol) are disrupted during the ill state of eating disorders and likely contribute to the maintenance of core symptoms (e.g., dietary restriction, binge eating) and/or co-occurring features (e.g., mood symptoms, attentional biases). Some of these hormones (e.g., ghrelin, cortisol) may also be related to eating pathology via links with psychological stress. Despite these effects, the role of hormonal factors in the etiology of eating disorders remains unknown. The strongest evidence for etiologic effects has emerged for ovarian hormones, as changes in ovarian hormones predict changes in phenotypic and genetic influences on disordered eating. Future studies would benefit from utilizing etiologically informative designs (e.g., high risk, behavioral genetic) and continuing to explore factors (e.g., psychological, neural responsivity) that may impact hormonal influences on eating pathology.

Eating disorders such as Anorexia Nervosa (AN) and Bulimia Nervosa (BN) were previously found to partly entail alterations in stress physiology including salivary cortisol (sC), and salivary alpha amylase (sAA) at rest and basal vagal tone (HF-HRV), compared to individuals without mental disorders or with mixed mental disorders (anxiety and depressive disorders), but corresponding data remain scarce and are not entirely consistent. HF-HRV, sC and sAA at rest were assessed in a female sample of 58 individuals with AN and 54 individuals with BN before and after psychotherapy and contrasted against measurements from 59 female individuals suffering from mixed disorders and 101female healthy controls. Values for sC were elevated in AN compared to all other groups, those for HF-HRV were highest in both AN and BN and lowest in mixed mental disorders and no differences were found at rest for sAA. During psychotherapy, HF-HRV changed more in AN and BN groups than in HC or mixed samples. sC and sAA remained unchanged. There was no association between BMI and stress physiology. Alterations in stress physiology present differently across EDs and mixed mental disorders. Correlates of physiological functioning remained mostly stable throughout 3 months of psychotherapy. Only basal vagal tone was normalized in AN/BN in comparison to HC. This might indicate that physiological changes can occur early, but mostly take longer to change during treatment. Trial registration: Data were assessed during a multi-site cross- and longitudinal experimental trial registered at the German Clinical Trials Registry (trial number: DRKS00005709; see [1] for details).

Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3 T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3 T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs. The VGLUT3-p.T8I mutation was identified in patients with SUDs and EDs and introduced in a mouse line. Here, authors show that mutant mice have an imbalanced DA signaling in the dorsal striatum associated with maladaptive cocaine and food consumption.

Electrolytes (sodium, potassium, calcium, magnesium, chloride, phosphate) are required in specific amounts for proper functioning of the human body. Although the body has different organ systems, such as the kidneys, that regulate electrolyte levels in the blood, electrolyte abnormalities occur frequently in people with eating disorders. The objective of this review will be to examine the association between electrolyte imbalances and adverse outcomes in people with eating disorders. A systematic review of studies on eating and electrolyte disorders shall be conducted. Electronic searches shall be done in the Ovid MEDLINE, EMBASE, and PsycINFO databases. Selected studies shall include randomized control trials (RCTs), non-randomized controlled trials, and cross-sectional studies published in English or French. Quality appraisal of studies and a narrative synthesis of extracted data shall be conducted. This review will synthesize existing evidence on electrolyte abnormalities in people with eating disorders. It will identify the type of electrolyte imbalances, their impact, and outcomes in people with eating disorders. We anticipate that information that will be useful to policy makers and clinicians in designing better policies to prevent eating disorders and or manage people with eating disorders shall be elucidated in this study. The final manuscript will be submitted for publication in a journal. This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number CRD42023477497.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing 1 – 4 . This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone 5 , 6 . This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders. An appetite-regulating subnetwork in humans involving the lateral hypothalamus and the dorsolateral hippocampus is implicated in obesity and related eating disorders.