Molecular neuroanatomy of anorexia nervosa

Abstract

Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits. Anorexia nervosa is a complex eating disorder that primarily occurs in women with onset often occurring during adolescence. While a portion of anorexia nervosa patients sustain a full recovery, a substantial fraction suffer from protracted partial recovery or are afflicted with a chronic disease course 1. Currently, there are few effective treatments, and the standard-of-care is broadly aimed at psychological and nutritional recovery 2,3. Specifically, for youth, family-based treatment has been shown to be beneficial 4. Due to self-starvation and suicide, anorexia nervosa is consistently reported to be among psychiatric disorders with the highest all-cause mortality ratios 5,6. Our understanding of the neuroanatomical circuits involved in anorexia nervosa is limited. MRI studies of people affected with the illness are only able to examine large structures, and such studies find broad volume reductions and white matter alterations 7-9. Diffusion tensor imaging studies have found changes in several white matter tracts 10. Due to the coarse resolution of MR images, these studies cannot detect structural or functional changes at the microcircuit level. In addition, it is difficult to identify structural alterations that may underlie the disorder due to a lack of studies initiated prior to the onset of symptoms. While subjects with anorexia nervosa are noted to have widespread cortical thinning and decreased volume, recent studies report that measured alterations in brain structure reflect changes in nutritional status and that weight restoration can rapidly reverse these changes in younger patients 11-13. Regional analyses have found stronger differences in reward and somatosensory regions. The identification of the reward areas was hypothesized to mark aberrant reward responses to food...

Hypothalamic subregion alterations in anorexia nervosa and obesity: Association with appetite‐regulating hormone levels

“…After adjustment for TBV, patients with AN displayed a regional volume reduction in the ITS, which contains the arcuate nucleus, an important center for energy homeostasis and feeding control. This is consistent with observations of degenerative changes in the arcuate nucleus in animal models of AN (Nilsson et al, 2011) and a higher expression of AN‐associated genes in this region (Howard et al, 2020). Furthermore, projections between mesocorticolimbic regions and the hypothalamus have been found to be instrumental in the control of feeding behavior (Castro et al, 2015).…”

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability

“…Adult Human transcriptomic comparisons were performed with the Allen Human Brain Atlas data 25 . Co-expression analysis of BrainSpan datasets was performed as described previously 26 (https://hbaset. msl.ubc.ca/).…”

Microgliosis: a double‐edged sword in the control of food intake

“…Microglia depletion using PLX5622 worsens anorexia and muscle catabolism, demonstrating once again that microglial reactivity can be protective against a strong energy imbalance. Interestingly, data mining from human brain transcriptome databases found enrichment of microglia genes in anorexia nervosa (AN), a dramatic eating disorder, which is characterized by a profound energy imbalance with abnormally low body weight [71]. In the murine anx / anx model of anorexia, Iba1 immunoreactivity in the brain is increased, as well as the number of Iba1‐positive cells [72].…”