HYPOTHESIS AND THEORY ARTICLE The optimal calibration hypothesis: how life history modulates the brain's social pain network EVOLUTIONARY NEUROSCIENCE

A growing body of work demonstrates that the brain responds similarly to physical and social injury. Both experiences are associated with activity in the dorsal anterior cingulate cortex (dACC) and anterior insula. This dual functionality of the dACC and anterior insula underscores the evolutionary importance of maintaining interpersonal bonds. Despite the weight that evolution has placed on social injury, the pain response to social rejection varies substantially across individuals. For example, work from our lab demonstrated that the brain's social pain response is moderated by attachment style: anxious-attachment was associated with greater intensity and avoidant-attachment was associated with less intensity in dACC and insula activation. In an attempt to explain these divergent responses in the social pain network, we propose the optimal calibration hypothesis, which posits variation in social rejection in early life history stages shifts the threshold of an individual's social pain network such that the resulting pain sensitivity will be increased by volatile social rejection and reduced by chronic social rejection. Furthermore, the social pain response may be exacerbated when individuals are rejected by others of particular importance to a given life history stage (e.g., potential mates during young adulthood, parents during infancy and childhood). Keywords: social pain, social rejection, life history, attachment style, anterior cingulate cortex, anterior insula Pain is as diverse as man. One suffers as one can. -Victor Hugo Social rejection hurts. Indeed, instances of rejection activate the same brain regions as physical pain In the present article, we begin by reviewing the literature on social pain and its neural correlates. Second, we couch our theoretical model in the literature on attachment style, arguing that early-life experiences of rejection are the principal causes of calibration in social pain. Third, we review fitness benefits derived from calibrating the social pain network. Finally, we extend the optimal calibration hypothesis to all life history stages, putting forth testable predictions that the social pain network is sensitive to the source of rejection, responding preferentially to rejecters of utmost importance to a given life history stage. SOCIAL PAIN AND THE NEED TO BELONG People are driven to seek out and maintain positive relationships with others through a fundamental need to belong, which is pervasive across time and cultures Frontiers in Evolutionary Neuroscience www.frontiersin.or

Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren's Contracture

Abstract Background Dupuytren's contracture (DC) is a fibroproliferative disorder characterized by the progressive development of a scar-like collagen-rich cord that affects the palmar fascia of the hand and leads to digital flexion contractures. DC is most commonly treated by surgical resection of the diseased tissue, but has a high reported recurrence rate ranging from 27% to 80%. We sought to determine if the transcriptomic profiles of fibroblasts derived from DC-affected palmar fascia, adjacent phenotypically normal palmar fascia, and non-DC palmar fascial tissues might provide mechanistic clues to understanding the puzzle of disease predisposition and recurrence in DC. Methods To achieve this, total RNA was obtained from fibroblasts derived from primary DC-affected palmar fascia, patient-matched unaffected palmar fascia, and palmar fascia from non-DC patients undergoing carpal tunnel release (6 patients in each group). These cells were grown on a type-1 collagen substrate (to better mimic their in vivo environments). Microarray analyses were subsequently performed using Illumina BeadChip arrays to compare the transcriptomic profiles of these three cell populations. Data were analyzed using Significance Analysis of Microarrays (SAM v3.02), hierarchical clustering, concordance mapping and Venn diagram. Results We found that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected fascia of DC patients exhibited a much greater overlap than fibroblasts derived from the palmar fascia of patients undergoing carpal tunnel release. Quantitative real time RT-PCR confirmed the differential expression of select genes validating the microarray data analyses. These data are consistent with the hypothesis that predisposition and recurrence in DC may stem, at least in part, from intrinsic similarities in the basal gene expression of diseased and phenotypically unaffected palmar fascia fibroblasts. These data also demonstrate that a collagen-rich environment differentially alters gene expression in these cells. In addition, Ingenuity pathway analysis of the specific biological pathways that differentiate DC-derived cells from carpal tunnel-derived cells has identified the potential involvement of microRNAs in this fibroproliferative disorder. Conclusions These data show that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected palmar fascia in DC patients are highly similar, and differ significantly from the transcriptomic profiles of fibroblasts from the palmar fascia of patients undergoing carpal tunnel release.</p