Transcranial direct current stimulation suggests a causal role of the medial prefrontal cortex in learning social hierarchy.

Social hierarchies can be inferred through observational learning of social relationships between individuals. Yet, little is known about the causal role of specific brain regions in learning hierarchies. Here, using transcranial direct current stimulation, we show a causal role of the medial prefrontal cortex (mPFC) in learning social versus non-social hierarchies. In a Training phase, participants acquired knowledge about social and non-social hierarchies by trial and error. During a Test phase, they were presented with two items from hierarchies that were never encountered together, requiring them to make transitive inferences. Anodal stimulation over mPFC impaired social compared with non-social hierarchy learning, and this modulation was influenced by the relative social rank of the members (higher or lower status). Anodal stimulation also impaired transitive inference making, but only during early blocks before learning was established. Together, these findings demonstrate a causal role of the mPFC in learning social ranks by observation.

Strengths of social ties modulate brain computations for third-party punishment.

Costly punishment of social norm transgressors by third-parties has been considered as a decisive stage in the evolution of human cooperation. An important facet of social relationship knowledge concerns the strength of the social ties between individuals, as measured by social distance. Yet, it is unclear how the enforcement of social norms is influenced by the social distance between a third-party and a norm violator at the behavioral and the brain system levels. Here, we investigated how social distance between punishers and norm-violators influences third-party punishment. Participants as third-party punished norm violators more severely as social distance between them increased. Using model-based fMRI, we disentangled key computations contributing to third-party punishment: inequity aversion, social distance between participant and norm violator and integration of the cost to punish with these signals. Inequity aversion increased activity in the anterior cingulate cortex and bilateral insula, and processing social distance engaged a bilateral fronto-parietal cortex brain network. These two brain signals and the cost to punish were integrated in a subjective value signal of sanctions that modulated activity in the ventromedial prefrontal cortex. Together, our results reveal the neurocomputational underpinnings of third-party punishment and how social distance modulates enforcement of social norms in humans.

Spillover effects of competition outcome on future risky cooperation.

There is growing evidence that risky cooperation is regulated by the experience of previous interactions with others. However, it is unclear how the evaluation of outcomes from competitive interactions can affect individuals' subsequent cooperative behavior. To address this issue, we examined how participants cooperated with a partner having just competed with them. While competing, participants (N = 164) were randomly assigned to receive one of four types of outcome feedback regarding their performance (victory vs. defeat vs. uncertain vs. no competition (control)). We found that both the experience of defeats and of uncertainty as competitive outcomes exerted a negative impact on the extent to which participants then engaged in cooperative behavior with their recent opponents. This only occurred when such subsequent cooperative behavior involved a high potential for incurring personal costs but not when there was no risk of incurring personal costs and a positive return. Finally, mediation analysis revealed that the effect of defeat was mediated by participants' level of interpersonal trust and the extent to which participants were willing to cooperate, while the effect of the uncertain competitive outcome was mediated only by the extent to which participants were willing to cooperate. These findings offer novel insights into how risky cooperation is modulated by previous competition.

Cross-cultural study of kinship premium and social discounting of generosity.

Social discounting predicts that one's concern for others decreases with increasing social distance. Cultural dimensions may influence this social behavior. Here, we used a dictator game, in which the participants and real members of their social entourage profited from the partition of the endowments determined by the participant, to compare how Chinese and French university students shared endowments with people at different social distances. We tested two hypotheses based on the concepts of kinship premium and cultural collectivism. Stronger ties between close family members were expected among Chinese. This may predict a larger "kinship premium," i.e., increased generosity to family members at close social distances, in Chinese relative to French participants. Similarly, because collectivism is thought to be stronger in Asian than western societies, greater generosity at larger social distances might also be expected among Chinese participants. The results showed that Chinese were more generous than French at close social distances but discounted more as social distance increased. This difference between French and Chinese was confined to family members and no significant difference in generosity was observed between French and Chinese for non-family members at any social distance. Our findings evidence a stronger kinship premium among Chinese than French students, and no significant effect of cultural collectivism.

ERPs responses to dominance features from human faces.

Social dominance is an important feature of social life. Dominance has been proposed to be one of two trait dimensions underpinning social judgments of human faces. Yet, the neural bases of the ability to identify different dominance levels in others based on intrinsically facial cues remains poorly understood. Here, we used event-related potentials to determine the temporal dynamics of facial dominance evaluation based on facial features signaling physical strength/weakness in humans. Twenty-seven participants performed a dominance perception task where they passively viewed faces with different dominance levels. Dominance levels did not modulate an early component of face processing, known as the N170 component, but did modulate the late positive potential (LPP) component. These findings indicate that participants inferred dominance levels at a late stage of face evaluation. Furthermore, the highest level of dominant faces and the lowest level of submissive faces both elicited higher LPP amplitudes than faces with a neutral dominance level. Taken together, the present study provides new insights regarding the dynamics of the neurocognitive processes underlying facial dominance evaluation.

Regulation of social hierarchy learning by serotonin transporter availability.

Learning one's status in a group is a fundamental process in building social hierarchies. Although animal studies suggest that serotonin (5-HT) signaling modulates learning social hierarchies, direct evidence in humans is lacking. Here we determined the relationship between serotonin transporter (SERT) availability and brain systems engaged in learning social ranks combining computational approaches with simultaneous PET-fMRI acquisition in healthy males. We also investigated the link between SERT availability and brain activity in a non-social control condition involving learning the payoffs of slot machines. Learning social ranks was modulated by the dorsal raphe nucleus (DRN) 5-HT function. BOLD ventral striatal response, tracking the rank of opponents, decreased with DRN SERT levels. Moreover, this link was specific to the social learning task. These findings demonstrate that 5-HT plays an influence on the computations required to learn social ranks.

Perturbation of Right Dorsolateral Prefrontal Cortex Makes Power Holders Less Resistant to Tempting Bribes.

Bribery is a common form of corruption that takes place when a briber suborns a power holder to achieve an advantageous outcome at the cost of moral transgression. Although bribery has been extensively investigated in the behavioral sciences, its underlying neurobiological basis remains poorly understood. Here, we employed transcranial direct-current stimulation (tDCS) in combination with a novel paradigm (N = 119 adults) to investigate whether disruption of right dorsolateral prefrontal cortex (rDLPFC) causally changed bribe-taking decisions of power holders. Perturbing rDLPFC via tDCS specifically made participants more willing to take bribes as the relative value of the offer increased. This tDCS-induced effect could not be explained by changes in other measures. Model-based analyses further revealed that such neural modulation alters the concern for generating profits for oneself via taking bribes and reshapes the concern for the distribution inequity between oneself and the briber, thereby influencing the subsequent decisions. These findings reveal a causal role of rDLPFC in modulating corrupt behavior.

Neural basis of corruption in power-holders.

Corruption often involves bribery, when a briber suborns a power-holder to gain advantages usually at a cost of moral transgression. Despite its wide presence in human societies, the neurocomputational basis of bribery remains elusive. Here, using model-based fMRI, we investigated the neural substrates of how a power-holder decides to accept or reject a bribe. Power-holders considered two types of moral cost brought by taking bribes: the cost of conniving with a fraudulent briber, encoded in the anterior insula, and the harm brought to a third party, represented in the right temporoparietal junction. These moral costs were integrated into a value signal in the ventromedial prefrontal cortex. The dorsolateral prefrontal cortex was selectively engaged to guide anti-corrupt behaviors when a third party would be harmed. Multivariate and connectivity analyses further explored how these neural processes depend on individual differences. These findings advance our understanding of the neurocomputational mechanisms underlying corrupt behaviors.

Right Temporoparietal Junction Underlies Avoidance of Moral Transgression in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by a core difference in theory-of-mind (ToM) ability, which extends to alterations in moral judgment and decision-making. Although the function of the right temporoparietal junction (rTPJ), a key neural marker of ToM and morality, is known to be atypical in autistic individuals, the neurocomputational mechanisms underlying its specific changes in moral decision-making remain unclear. Here, we addressed this question by using a novel fMRI task together with computational modeling and representational similarity analysis (RSA). ASD participants and healthy control subjects (HCs) decided in public or private whether to incur a personal cost for funding a morally good cause (Good Context) or receive a personal gain for benefiting a morally bad cause (Bad Context). Compared with HC, individuals with ASD were much more likely to reject the opportunity to earn ill gotten money by supporting a bad cause than were HCs. Computational modeling revealed that this resulted from heavily weighing benefits for themselves and the bad cause, suggesting that ASD participants apply a rule of refusing to serve a bad cause because they evaluate the negative consequences of their actions more severely. Moreover, RSA revealed a reduced rTPJ representation of the information specific to moral contexts in ASD participants. Together, these findings indicate the contribution of rTPJ in representing information concerning moral rules and provide new insights for the neurobiological basis underpinning moral behaviors illustrated by a specific difference of rTPJ in ASD participants.SIGNIFICANCE STATEMENT Previous investigations have found an altered pattern of moral behaviors in individuals with autism spectrum disorder (ASD), which is closely associated with functional changes in the right temporoparietal junction (rTPJ). However, the specific neurocomputational mechanisms at play that drive the altered function of the rTPJ in moral decision-making remain unclear. Here, we show that ASD individuals are more inflexible when following a moral rule although an immoral action can benefit themselves, and experience an increased concern about their ill-gotten gains and the moral cost. Moreover, a selectively reduced rTPJ representation of information concerning moral rules was observed in ASD participants. These findings deepen our understanding of the neurobiological roots that underlie atypical moral behaviors in ASD individuals.

Neurocomputational mechanisms underlying immoral decisions benefiting self or others.

Immoral behavior often consists of weighing transgression of a moral norm against maximizing personal profits. One important question is to understand why immoral behaviors vary based on who receives specific benefits and what are the neurocomputational mechanisms underlying such moral flexibility. Here, we used model-based functional magnetic resonance imaging to investigate how immoral behaviors change when benefiting oneself or someone else. Participants were presented with offers requiring a tradeoff between a moral cost (i.e. profiting a morally bad cause) and a benefit for either oneself or a charity. Participants were more willing to obtain ill-gotten profits for themselves than for a charity, driven by a devaluation of the moral cost when deciding for their own interests. The subjective value of an immoral offer, computed as a linear summation of the weighed monetary gain and moral cost, recruited the ventromedial prefrontal cortex (PFC) regardless of beneficiaries. Moreover, paralleling the behavioral findings, this region enhanced its functional coupling with mentalizing-related regions while deciding whether to gain morally tainted profits for oneself vs charity. Finally, individual differences in moral preference differentially modulated choice-specific signals in the dorsolateral PFC according to who benefited from the decisions. These findings provide insights for understanding the neurobiological basis of moral flexibility.

Hormonal responses in gambling versus alcohol abuse: A review of human studies.

The endocrine system plays an essential role in communication between various organs of the body to maintain homeostasis. Both substance use disorders (SUDs) and non-substance abuse disrupt this system and lead to hormonal dysregulations. Here, we focus on the comparison between the function of the endocrine system in gambling disorders and alcohol addiction to understand the commonalities and differences in their neurobiological and psychological underpinnings. We review human research to compare findings on gambling addiction and alcohol dependence pertaining to the dynamic interplay between testosterone and cortisol. Understanding and classifying similarities in hormonal responses between behavioural addiction and SUDs may facilitate development of treatments and therapeutic interventions across different types of addictive disorders, while describing differences may shed light on therapeutic interventions for specific disorders. Although research on gambling addiction is in its infancy, such evaluation may still have a positive effect for addiction research, thereby stimulating discovery of "crossover" pharmacotherapies with benefits for both SUDs and nonsubstance addictions.

Microenvironment-Driven Shift of Cohesion/Detachment Balance within Tumors Induces a Switch toward Metastasis in Neuroblastoma.

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. Disseminated forms have high frequency of multiple tumoral foci whose etiology remains unknown; NB embryonic origin limits investigations in patients and current models. We developed an avian embryonic model driving human NB tumorigenesis in tissues homologous to patients. We found that aggressive NBs display a metastatic mode, secondary dissemination via peripheral nerves and aorta. Through tumor transcriptional profiling, we found that NB dissemination is induced by the shutdown of a pro-cohesion autocrine signal, SEMA3C, which constrains the tumoral mass. Lowering SEMA3C levels shifts the balance toward detachment, triggering NB cells to collectively evade the tumor. Together with patient cohort analysis, this identifies a microenvironment-driven pro-metastatic switch for NB.

Molecular Memory of Morphologies by Septins during Neuron Generation Allows Early Polarity Inheritance.

Transmission of polarity established early during cell lineage history is emerging as a key process guiding cell differentiation. Highly polarized neurons provide a fascinating model to study inheritance of polarity over cell generations and across morphological transitions. Neural crest cells (NCCs) migrate to the dorsal root ganglia to generate neurons directly or after cell divisions in situ. Using live imaging of vertebrate embryo slices, we found that bipolar NCC progenitors lose their polarity, retracting their processes to round for division, but generate neurons with bipolar morphology by emitting processes from the same locations as the progenitor. Monitoring the dynamics of Septins, which play key roles in yeast polarity, indicates that Septin 7 tags process sites for re-initiation of process growth following mitosis. Interfering with Septins blocks this mechanism. Thus, Septins store polarity features during mitotic rounding so that daughters can reconstitute the initial progenitor polarity.

gdnf activates midline repulsion by Semaphorin3B via NCAM during commissural axon guidance.

The Neurotrophic factor gdnf plays diverse developmental roles, supporting survival and also acting as a chemoattractant for axon and cell migration. We report that in the developing spinal cord, a focal source of gdnf is present in the floor plate (FP) where commissural axons cross the midline. Gdnf has no direct guidance properties but switches on the responsiveness of crossing commissural growth cones to the midline repellent Semaphorin3B by suppressing calpain-mediated processing of the Sema3B signaling coreceptor Plexin-A1. Analysis of single and double mutant mouse models indicates that although gdnf is the principal trigger of Sema3B midline repulsion, it acts with another FP cue, NrCAM. Finally, genetic and in vitro experiments provide evidence that this gdnf effect is RET independent and mediated by NCAM/GFRα1 signaling. This study identifies a regulator of midline crossing and reveals interplays between Semaphorin and gdnf signaling during axon guidance.

Dicistronic MLV-retroviral vectors transduce neural precursors in vivo and co-express two genes in their differentiated neuronal progeny.

Dicistronic MLV-based retroviral vectors, in which two IRESes independently initiate the translation of two proteins from a single RNA, have been shown to direct co-expression of proteins in several cell culture systems. Here we report that these dicistronic retroviral vectors can drive co-expression of two gene products in brain cells in vivo. Injection of retroviral vector producer cells leads to the transduction of proliferating precursors in the external granular layer of the cerebellum and throughout the ventricular regions. Differentiated neurons co-expressing both transgenes were observed in the cerebellum and in lower numbers in distant brain regions such as the cortex. Thus, we describe an eukaryotic dicistronic vector system that is capable of transducing mouse neural precursors in vivo and maintaining the expression of genes after cell differentiation.

Trafficking of TrkA-green fluorescent protein chimerae during nerve growth factor-induced differentiation.

A chimera of the nerve growth factor (NGF) receptor, TrkA, and green fluorescent protein (GFP) was engineered by expressing GFP in phase with the carboxyl terminus of TrkA. TrkA-GFP becomes phosphorylated on tyrosine residues in response to NGF and is capable of initiating signaling cascades leading to prolonged MAPK activation and differentiation in PC12 nnr5 cells. TrkA constructs, progressively truncated in the carboxyl-terminal domain, were prepared as GFP chimerae in order to identify which part of the receptor intracellular domain is involved in its trafficking. Immunofluorescence observations show that TrkA-GFP is found mainly in cell surface membrane ruffles and in endosomes. Biochemical analysis indicated that the cytoplasmic domain of TrkA is not necessary for correct maturation and cell surface translocation of the receptor. An antibody against the extracellular domain of TrkA (RTA) was used as ligand to stimulate internalization and phosphorylation of TrkA. Co-localization studies with anti-phosphorylated TrkA antibodies support a role for such complexes in the propagation of signaling from the cell surface, resulting in the activation of TrkA in areas of the endosome devoid of receptor-ligand complexes. Confocal time-lapse analysis reveals that the TrkA-GFP chimera shows highly dynamic trafficking between the cell surface and internal locations. TrkA-positive vesicles were estimated to move 0.46 +/- 0.09 microm/s anterograde and 0.48 +/- 0.07 microm/s retrograde. This approach and the fidelity of the biochemical properties of the TrkA-GFP demonstrate that real-time visualization of trafficking of tyrosine kinase receptors in the presence or absence of the ligand is feasible.

PrPC has nucleic acid chaperoning properties similar to the nucleocapsid protein of HIV-1.

The function of the cellular prion protein (PrPC) remains obscure. Studies suggest that PrPC functions in several processes including signal transduction and Cu2+ metabolism. PrPC has also been established to bind nucleic acids. Therefore we investigated the properties of PrPC as a putative nucleic acid chaperone. Surprisingly, PrPC possesses all the nucleic acid chaperoning properties previously specific to retroviral nucleocapsid proteins. PrPC appears to be a molecular mimic of NCP7, the nucleocapsid protein of HIV-1. Thus PrPC, like NCP7, chaperones the annealing of tRNA(Lys) to the HIV-1 primer binding site, the initial step of retrovirus replication. PrPC also chaperones the two DNA strand transfers required for production of a complete proviral DNA with LTRs. Concerning the functions of NCP7 during budding, PrPC also mimices NCP7 by dimerizing the HIV-1 genomic RNA. These data are unprecedented because, although many cellular proteins have been identified as nucleic acid chaperones, none have the properties of retroviral nucleocapsid proteins.