Genetics and neurobiology of eating disorders

Abstract

Eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) are a heterogeneous class of complex illnesses marked by weight and appetite dysregulation coupled with distinctive behavioral and psychological features. Our understanding of their genetics and neurobiology is evolving thanks to global cooperation on genome-wide association studies, neuroimaging, and animal models. Until now, however, these approaches have advanced the field in parallel, with inadequate cross-talk. This review covers overlapping advances in these key domains and encourages greater integration of hypotheses and findings to create a more unified science of eating disorders. We highlight ongoing and future work designed to identify implicated biological pathways that will inform staging models based on biology as well as targeted prevention and tailored intervention, and will galvanize interest in the development of pharmacologic agents that target the core biology of the illnesses, for which we currently have few effective pharmacotherapeutics.

Figure 1.. Genetic correlations between anorexia nervosa and selected top traits.

The error bar represents the 95% confidence interval. Values retrieved from.

Figure 2.

Human neuroimaging circuitry involved in eating disorders. (A) Represents the structures comprising two major dopaminergic pathways, mesolimbic and mesocortical pathways, supported by prior work in animal models. Both originate in the ventral tegmental area (red); mesolimbic pathways project to the nucleus accumbens, and is part of the complex circuit involving the amygdala (pink), hippocampus (green), and the bed nucleus of the stria terminalis (yellow). The mesocortical pathway projects primarily to the prefrontal cortex (orange) and insula (purple). (B) Represents sub-structures involved in the cortico-striatal-thalamo-cortical (CSTC) pathway that are supported by recent genetic/GWAS studies with shared functional networks that exhibit overlapping phenotypes. The CSTC pathway is a multi-synaptic neuronal circuit that connects the cortex with the striatum and thalamus. The striatum (green) receives glutamatergic input from the cortex and the thalamus (blue) sends out GABAergic inputs to the sub-thalamic nucleus (pink, purple, red).

Figure 3.

Forward and backward translation of eating disorder-relevant traits at different levels of biological hierarchy. Activity-based anorexia (ABA) and binge-like eating (BLE) are behavioral models for restrictive eating in AN and for binge eating in BN and BED. Within the use of animal models, there are four primary approaches that seek to elucidate the fundamental biology of eating disorders: QTL mapping, Omics, neural circuit manipulations, and in vivo gene editing. QTL mapping is used to discover genetic loci and ultimately candidate causal genes and variants that regulate phenotypic traits at the molecular, cellular, or behavioral level. QT mapping capitalizes on natural variation across different strains or substrains of laboratory models like mice. Omics investigations are carried out at the genomic, transcriptomic(not shown), proteomic, microbiomic, or metabolomic levels and can reveal novel biological pathways that regulate feeding and/or metabolism. In vivo gene editing research can be used to establish causality for candidate genomic variants identified from rodent QTL/GWAS or in silico studies. Neural circuit approaches are also used to establish causal molecular, cellular, or circuit elements that drive eating behavior and metabolism. They span the range of observing neural activity and synaptic function, manipulating those circuits in real time (e.g., via optogenetic. chemogenetic, or pharmacological approaches), and layering these experiments with pathological models.

Figure 4.. Mesocorticolimbic reward dysfunction in activity-based anorexia.

VTA: ventral tegmental area; NAC: nucleus accumbens; LH: lateral hypothalamus; mPFC: medial prefrontal cortex; DREADD = designer receptor exclusively activated by designer drugs; Gi = G inhibitory DREADDS; Gs = G stimulatory DREADDS; D2 = D2 dopamine receptor overexpression. Green indicates excitation of cell type and pathway. Red indicates inhibition of pathway. Purple indicates overexpression. Overexpression of D2 dopamine receptors in medium spiny neurons of NAc core increased ABA phenotypes and combined with scheduled fasting alone (no wheel running), was sufficient to induce weight loss and glucose intolerance in females without affecting food intake. Chemogenetic activation of the mPFC->NAc shell pathway decreased cognitive flexibility and increased ABA; inhibition had the opposite effect. Chemogenetic activation of VTA neurons decreased ABA and increased survival. Leptin injections into the VTA decreased wheel running. Blue arrows indicate pathway proposed by Zhang and Dulawa to mediate mesocorticolimbic reward modulation of energy expenditure and metabolism in ABA. Additional work is necessary to delineate the circuits, neurotransmitters, and hormones that link ABA reward dysfunction with increased energy expenditure.

Figure 5.. Mesolimbic-centered neural circuits that modulate binge-like eating (BLE).

Converging on the VTA to NAc dopaminergic circuit, behavioral neuroscientists have used circuit-level techniques like chemogenetics and optogenetics to study BLE, normal feeding, and reward-like behavior. Inputs to the VTA from the DR, BNST, and LH modulate reward and food consumption as shown by pathway-specific optogenetics. Within the VTA, chemogenetic activation of VTA DA neuron reduces BLE and direct optogenetic activation has no impact on feeding. Within the NAc, pathway specific optogenetic inhibition of the inputs from the insular cortex reduces BLE. Similarly, chemogenetic activation of the NAc-projecting input cells from the vmPFC or VIP-expressing neurons in the prelimbic and infralimbic PFC also reduces BLE. Abbreviations: BLE – binge-like eating; BNST – bed nucleus of the stria terminalis; ChR2 – Channelrhodopsin2; DA – dopamine; D1R – dopamine D1 receptor; D2R – dopamine D2 receptor; DR – dorsal raphe; GABA – gamma aminobutyric acid; GLU – glutamate; IC – insular cortex; LH – lateral hypothalamus; NAc – nucleus accumbens; PET-1 - PC12 ETS Domain-Containing Transcription Factor; PFC – prefrontal cortex; VIP – vasoactive intestinal polypeptide; vmPFC – ventromedial prefrontal cortex; VTA – Ventral tegmental area.