A Mendelian Trait for Olfactory Sensitivity Affects Odor Experience and Food Selection

SummaryHumans vary in acuity to many odors [1–4], with variation within olfactory receptor (OR) genes contributing to these differences [5–9]. How such variation also affects odor experience and food selection remains uncertain [10], given that such effects occur for taste [11–15]. Here we investigate β-ionone, which shows extreme sensitivity differences [4, 16, 17]. β-ionone is a key aroma in foods and beverages [18–21] and is added to products in order to give a pleasant floral note [22, 23]. Genome-wide and in vitro assays demonstrate rs6591536 as the causal variant for β-ionone odor sensitivity. rs6591536 encodes a N183D substitution in the second extracellular loop of OR5A1 and explains >96% of the observed phenotypic variation, resembling a monogenic Mendelian trait. Individuals carrying genotypes for β-ionone sensitivity can more easily differentiate between food and beverage stimuli with and without added β-ionone. Sensitive individuals typically describe β-ionone in foods and beverages as “fragrant” and “floral,” whereas less-sensitive individuals describe these stimuli differently. rs6591536 genotype also influences emotional associations and explains differences in food and product choices. These studies demonstrate that an OR variant that influences olfactory sensitivity can affect how people experience and respond to foods, beverages, and other products

Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice

Effect of sex and HD mutation on saccharin-preference test and total fluid intake.

<p>(A) We found a significant interaction between sex and genotype (F_(1,44) = 5.84, p<0.05) on saccharin preference (expressed as % of total fluid intake). Indeed compared to WT animals, only HD female mice exhibited reduced saccharin preference. (B) Interestingly looking at total fluid intake (expressed in mL), we revealed an overall effect of genotype (F_(1,44) = 12.3, p<0.01) but no significant effect of sex or interactions. Values represent means (± SEM) of n = 8–14 mice per group. WT vs. HD: (*) p<0.05, (**) p<0.01.</p

In vivo assessment of 5-HT_1A and 5-HT₂ post-synaptic receptor function using 8-OH-DPAT-induced change of corticosterone levels and DOI-induced head-twitches.

<p>Compared to paired-saline injected animals, administration of the 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg, s.c.) significantly increased corticosterone levels in both (A) male and (B) female mice, regardless of the genotype. In the DOI-induced head-twitches experiment (bottom panel), there was a significant effect of genotype in both sexes. Indeed, the number of head-twitches following DOI (1 mg/kg) were decreased in (C) HD male and (D) HD female mice when compared to WT animals. Values represent means (± SEM) of n = 5–10 mice per group. Saline vs. DPAT0.3: (+) p<0.05, (++) p<0.01, (+++) p<0.001 WT vs. HD: (*) p<0.05, (**) p<0.01, (***) p<0.001.</p

Concentrations of 5-HT and 5-HIAA in brain tissue.

<p>Using the HPLC system, we measured the tissue levels of serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in several brain areas. Both 5-HT and 5-HIAA concentrations were decreased in the hippocampus (A/B), the cortex (C/D) and the striatum (E/F) in female HD mice when compared to WT animals. Levels of 5-HIAA were also reduced in male HD. Finally, male mice exhibited higher hippocampal tissue levels of both 5-HT and 5-HIAA when compared to female animals. 5-HT and 5-HIAA are expressed in ng/g tissue. Values represent means (± SEM) of n = 6–8 mice per group. WT vs. HD: (*) p<0.05, (**) p<0.01, (***) p<0.001. Male vs. female: (##) p<0.01.</p

Effect of sex and HD mutation on the novelty suppressed feeding test (NSFT).

<p>(A) Analyzing the time (expressed in sec) to complete the task in the NSFT, we found a significant interaction between sex and genotype (F_(1,55) = 4.2, p<0.05). Indeed compared to WT animals, only HD female mice exhibited greater delay to complete the NSFT. (B) Interestingly measuring the amount of food consumed after NSFT, we did not find any effect of genotype (F_(1,55) = 1.7, p = 0.19) or interaction with the sex (F_(1,55) = 0.39, p = 0.54). Values represent means (± SEM) of n = 12–17 mice per group. WT vs. HD: (***) p<0.001.</p

Gene expression of 5-HT transporter (5-HTT), 5-HT_1A receptor (5-HT_1AR) and tryptophan hydroxylase-2 (TPH2) in the raphe.

<p>Measuring mRNA levels of several genes encoding proteins that regulate 5-HT homeostasis, we found significant genotype-sex interactions for both mRNA levels of (A) 5-HTT and (B) TPH2 but not for (C) 5-HT_1AR gene expression. Both 5-HTT and TPH2 mRNA levels were decreased in female WT when compared to male WT. In addition, HD mutation decreased both 5-HTT and TPH2 gene expressions in male only. Finally 5-HT_1AR mRNA levels were not affected by either the sex or the genotype. Values represent means (± SEM) of n = 5–6 mice per group. WT vs. HD: (**) p<0.01. Male vs. female: (##) p<0.01.</p