A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus-pituitary-adrenal axis activity early in ontogeny.

We comprehensively characterized the effects of a unique natural gain-of-function mutation in the glucocorticoid receptor (GR), GRAla610Val, in domestic pigs to expand current knowledge of the phenotypic consequences of GR hypersensitivity. Cortisol levels were consistently reduced in one-week-old piglets, at weaning and in peripubertal age, probably due to a reduced adrenal capacity to produce glucocorticoids (GC), which was indicated by an adrenocortical thinning in GRAla610Val carriers. Adrenocorticotrophic hormone (ACTH) levels were significantly reduced in one-week-old piglets only. Expression analyses in peripubertal age revealed significant downregulation of hypothalamic expression of CRH and AVP, the latter only in females, and upregulation of hepatic expression of SERPINA6, by GRAla610Val Transcriptional repression of proinflammatory genes in peripheral blood mononuclear cells (PBMCs) from GRAla610Val carriers was more sensitive to dexamethasone treatment ex vivo However, no significant effects on growth, body composition, blood chemistry or cell counts were observed under baseline conditions. These results suggest that GRAla610Val-induced GR hypersensitivity elicits a compensatory reduction in endogenous, bioactive glucocorticoid levels via readjustment of the hypothalamus-pituitary-adrenal (HPA) axis early in ontogeny to maintain an adequate response, but carriers are more sensitive to exogenous GC. Therefore, GRAla610Val pigs represent a valuable animal model to explore GR-mediated mechanisms of HPA axis regulation and responses to glucocorticoid-based drugs.

Genetic variation of the porcine NR5A1 is associated with meat color.

Because of the central role of Steroidogenic factor 1 in the regulation of the development and function of steroidogenic tissues, including the adrenal gland, we chose the encoding gene NR5A1 as a candidate for stress response, meat quality and carcass composition in the domestic pig. To identify polymorphisms of the porcine NR5A1 we comparatively sequenced the coding, untranslated and regulatory regions in four commercial pig lines. Single nucleotide polymorphisms could be found in the 3' UTR and in an intronic enhancer, whereas no polymorphisms were detected in the proximal promoter and coding region. A subset of the detected polymorphisms was genotyped in Piétrain x (German Large White x German Landrace) and German Landrace pigs. For the same animals, carcass composition traits, meat quality characteristics and parameters of adrenal function were recorded. Associations with meat color were found for two of the discovered SNPs in Piétrain x (German Large White x German Landrace) and German Landrace pigs but no connections to parameters of adrenal function could be established. We conclude that NR5A1 variations influence meat color in a hypothalamus-pituitary-adrenal axis independent manner and that further regulatory regions need to be analyzed for genetic variations to understand the discovered effects.

Sensory modality of smoking cues modulates neural cue reactivity.

RATIONALE: Behavioral experiments have demonstrated that the sensory modality of presentation modulates drug cue reactivity. OBJECTIVES: The present study on nicotine addiction tested whether neural responses to smoking cues are modulated by the sensory modality of stimulus presentation. METHODS: We measured brain activation using functional magnetic resonance imaging (fMRI) in 15 smokers and 15 nonsmokers while they viewed images of smoking paraphernalia and control objects and while they touched the same objects without seeing them. RESULTS: Haptically presented, smoking-related stimuli induced more pronounced neural cue reactivity than visual cues in the left dorsal striatum in smokers compared to nonsmokers. The severity of nicotine dependence correlated positively with the preference for haptically explored smoking cues in the left inferior parietal lobule/somatosensory cortex, right fusiform gyrus/inferior temporal cortex/cerebellum, hippocampus/parahippocampal gyrus, posterior cingulate cortex, and supplementary motor area. CONCLUSIONS: These observations are in line with the hypothesized role of the dorsal striatum for the expression of drug habits and the well-established concept of drug-related automatized schemata, since haptic perception is more closely linked to the corresponding object-specific action pattern than visual perception. Moreover, our findings demonstrate that with the growing severity of nicotine dependence, brain regions involved in object perception, memory, self-processing, and motor control exhibit an increasing preference for haptic over visual smoking cues. This difference was not found for control stimuli. Considering the sensory modality of the presented cues could serve to develop more reliable fMRI-specific biomarkers, more ecologically valid experimental designs, and more effective cue-exposure therapies of addiction.

Smoking experience modulates the cortical integration of vision and haptics.

Human neuroplasticity of multisensory integration has been studied mainly in the context of natural or artificial training situations in healthy subjects. However, regular smokers also offer the opportunity to assess the impact of intensive daily multisensory interactions with smoking-related objects on the neural correlates of crossmodal object processing. The present functional magnetic resonance imaging study revealed that smokers show a comparable visuo-haptic integration pattern for both smoking paraphernalia and control objects in the left lateral occipital complex, a region playing a crucial role in crossmodal object recognition. Moreover, the degree of nicotine dependence correlated positively with the magnitude of visuo-haptic integration in the left lateral occipital complex (LOC) for smoking-associated but not for control objects. In contrast, in the left LOC non-smokers displayed a visuo-haptic integration pattern for control objects, but not for smoking paraphernalia. This suggests that prolonged smoking-related multisensory experiences in smokers facilitate the merging of visual and haptic inputs in the lateral occipital complex for the respective stimuli. Studying clinical populations who engage in compulsive activities may represent an ecologically valid approach to investigating the neuroplasticity of multisensory integration.