Utsav Gyawali, Jacqueline B Mehr, Abnanoub Armanious, Nicholas T Bello, Morgan H James

Background: It has been proposed that binge eating can serve as a form of ‘self-medication’ against dysphoric states in persons of higher weight. Despite this, the neurobiological system(s) underlying this phenomenon remain uncharacterized. Here, using rats, we developed a model of diet-induced obesity model that promotes a depression-like phenotype. We tested the hypothesis that binge eating would restore hedonic deficits associated with higher weight, in part via recruitment of a hypothalamic-midbrain circuit. Methods: Female Long Evans rats were maintained on a regular chow or high fat diet (HFD; 45% fat) for 8w; binge-like eating was then promoted via intermittent access to sweetened fat for 4w. Hedonic tone was measured using intracranial self-stimulation (n=6-7/group). We determined brain levels of orexin, a hypothalamic peptide involved in reward, using immunohistochemistry (n=8-10/group), qPCR (n=6-9/group), and fiber photometry recordings of the OxLight1 sensor (n=5-6/group) in ventral tegmental area (VTA). We also assessed ‘food addiction’ behaviors by measuring sucrose seeking (n=12-15/group). Results: HFD rats had higher ICSS thresholds vs. controls, indicating reward system deficit. These changes were associated with blunted orexin levels and lower orexin release in VTA. Binge eating partially restored reward thresholds and orexin release in VTA, but also promoted the development of several 'food addiction' behaviors, which were normalized by inhibition of the orexin-VTA circuit. Conclusions: Binge-like eating is 'self-medicating' against dysphoric states associated with higher weight, however this pattern of food intake promotes 'food addiction' behaviors. The orexin-VTA circuit is a target to normalize mood and eating outcomes in higher weight states.

Renee Papaluca¹, Eva Guerrero-Hreins¹, Nikeisha J Caruana¹, David A Stroud^1,2,3, Michael P Mendon^1,4, Aneta Stefanidis^5,6, Brian J Oldfield^5,6, Claire J Foldi^5,6, Priya Sumithran^7,8, Robyn M Brown¹*

People seeking obesity treatment often display compulsive disordered eating behaviours towards calorie-dense food high in fat and sugar which parallels behaviour observed in substance use disorder towards drugs. Indeed, chronic overconsumption of high-fat/high-sugar (HFHS) foods is associated with dysregulation of striatal brain reward areas. Evidence suggests bariatric surgery reduces motivation for HFHS foods post-surgery, however the gut-brain mechanisms underlying this change are unknown. Interestingly, a small subset of patients receiving bariatric surgery report adverse mental health outcomes following surgery such as depression, yet the determinants of this phenomenon are also unknown. The striatum is a key brain region at the centre of both hedonic processing of food reward and mood. This presentation will report on differentially expressed genes and proteins in the striatum underlying changes in food motivated behaviour and propensity for negative changes in mood following bariatric surgery in a mouse model.

1. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.

1. Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia.

1. Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Victoria, Australia.

1. Institute of Computational Biology, Computational Health Center, Helmholtz Munich, Munich, Germany.

1. Department of Physiology, Monash University, Clayton, Victoria, Australia.
2. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
3. Department of Surgery, School of Translational Medicine, Monash University, Victoria, Australia
4. Department of Endocrinology and Diabetes, Alfred Health, Victoria, Australia

K Huang^1,2, MA Magateshvaren Saras^3,4, K Conn^1,2, H Munguba⁵, E Greaves^1,2, F Reed^1,2, S Tyagi^4,6 & CJ Foldi^1,2

Activity-based anorexia (ABA) is a biobehavioural rodent model recapitulating key phenotypes of anorexia nervosa (AN), and we have previously shown that suppressing neural activity in the medial prefrontal cortex (mPFC)-nucleus accumbens shell (AcbSh) circuit could prevent pathological weight loss. Here, we used the translating ribosome affinity purification (TRAP) technique within this neural pathway to identify risk genes associated with susceptibility and resistance to pathological weight loss in female ABA rats. Female Sprague-Dawley rats (n=12) with viral TRAP construct expression were exposed to ABA conditions, which consisted of 90-minute food access and voluntary running wheel access, until they lost >20% body weight (Susceptible) or for a maximum of 10 days (Resistant). Following weight recovery, pathway-specific RNA was extracted and differentially expressed genes (DEGs) were identified. Gene ontology (GO) and Gene-set enrichment analysis (GSEA) were used for biological interpretation of DEGs. 1424 DEGs between Resistant and Susceptible were identified, including five risk genes previously reported to be associated with AN. The DEGs were involved in pathways associated with metabolic functions and neurodegenerative diseases, including Parkinson’s, Alzheimer’s and Huntington’s disease. Our conservative GO analysis revealed 2 upregulated and 24 downregulated genes in Resistant rats, with upregulated genes related to metabolism and downregulated genes associated with postsynaptic, cytoskeletal and axonal functions. This study revealed transcriptional changes in a specific neural circuit related to vulnerability to pathological weight loss that were not influenced by current calorie deficit. It highlights the utility of this model for examining the causal role these genes play in anorectic behaviours.

¹Department of Physiology, Monash University, Clayton VIC, Australia; ²Monash Biomedicine Discovery Institute, Clayton VIC, Australia; ³IITB-Monash Research Academy, Mumbai, Maharashtra, India; ⁴Central Clinical School, Monash University, Melbourne VIC, Australia; ⁵Department of Biochemistry, Weill Cornell Medicine, New York, USA; ⁶School of Computing Technologies, RMIT, Melbourne VIC, Australia

Maia Choi¹, Holly Poore¹, Nathaniel Thomas¹, Travis Mallard², Fazil Aliev¹, Jonathan Coleman³, Cynthia Bulik⁴, Danielle Dick¹

Binge eating disorder is the most common eating disorder, yet its etiology remains poorly understood. In epidemiological data, binge eating is correlated with both internalizing (e.g., depression, anxiety) and externalizing (e.g., substance use problems, ADHD) disorders. Further, preliminary analyses from the first genome wide association study (GWAS) of binge eating suggested that binge eating showed moderate genetic correlations with both externalizing and internalizing outcomes. In our project, we used data from the first GWAS of binge eating, a multivariate GWAS of externalizing, and a multivariate GWAS of internalizing, to assess the extent to which genetic influences on binge eating are shared with internalizing and/or externalizing, and/or specific to binge eating. By combining data from several million individuals, we find evidence that binge eating is genetically correlated with both externalizing and internalizing behaviors, indicating that genes underlying both behavioral and emotional regulation are involved in binge eating disorder. Additional analyses parsed out the effect of comorbid anorexia to better understand the nature of these associations. Although we find that binge eating is significantly genetically associated with both internalizing and externalizing psychopathology, the associations with externalizing are weaker and seem to be driven by the shared variance with internalizing. Further, associations between binge eating and internalizing psychopathology are in part unique from the comorbidity between binge eating and anorexia. These analyses provide insight into the genetic nature of influences on human eating disorders.

¹Rutgers Addiction Research Center, Rutgers University

²Massachusetts General Hospital, Harvard University

³King’s College, London

⁴UNC Center of Excellence for Eating Disorders