Despite widespread interest in neural mechanisms of decision-making, most investigations focus on decisions between just two options. Here we adapt a biophysically plausible model of decision-making to predict how a key decision variable, the value difference signal-encoding how much better one choice is than another-changes with the value of a third, but unavailable, alternative. The model predicts a surprising failure of optimal decision-making: greater difficulty choosing between two options in the presence of a third very poor, as opposed to very good, alternative. Both investigation of human decision-making and functional magnetic resonance imaging-based measurements of value difference signals in ventromedial prefrontal cortex (vmPFC) bore out this prediction. The vmPFC signal decreased in the presence of low-value third alternatives, and vmPFC effect sizes predicted individual variation in suboptimal decision-making in the presence of multiple alternatives. The effect contrasts with that of divisive normalization in parietal cortex.

very day, chacma baboons, an old world primate, navigate to and from the safety of their sleeping post and distant foraging or watering sites 1. The decision to move to alternative locations is not simply guided by accumulation of sensory evidence for that choice but by internal representation or memory of the alternative choice's value. The same is true when they move back toward the sleeping post in the evening. While sensory and associative decision-making have been well-studied 2 , less is known about how representations of counterfactual choices-choices not currently taken but which may be taken in the

SummaryRecent studies have challenged the view that orbitofrontal cortex (OFC) and amygdala mediate flexible reward-guided behavior. We trained macaques to perform an object discrimination reversal task during fMRI sessions and identified a lateral OFC (lOFC) region in which activity predicted adaptive win-stay/lose-shift behavior. Amygdala and lOFC activity was more strongly coupled on lose-shift trials. However, lOFC-amygdala coupling was also modulated by the relevance of reward information in a manner consistent with a role in establishing how credit for reward should be assigned. Day-to-day fluctuations in signals and signal coupling were correlated with day-to-day fluctuation in performance. A second experiment confirmed the existence of signals for adaptive stay/shift behavior in lOFC and reflecting irrelevant reward in the amygdala in a probabilistic learning task. Our data demonstrate that OFC and amygdala each make unique contributions to flexible behavior and credit assignment.

In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer-term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex.

The orbitofrontal cortex is critical for goal-directed behavior. Recent work in macaques has suggested the lateral orbitofrontal cortex (lOFC) is relatively more concerned with assignment of credit for rewards to particular choices during value-guided learning, whereas the medial orbitofrontal cortex (often referred to as ventromedial prefrontal cortex in humans; vmPFC/mOFC) is involved in constraining the decision to the relevant options. We examined whether people with damage restricted to subregions of prefrontal cortex showed the patterns of impairment observed in prior investigations of the effects of lesions to homologous regions in macaques. Groups of patients with either lOFC (predominantly right hemisphere), mOFC/vmPFC, or dorsomedial prefrontal (DMF), and a comparison group of healthy age-and education-matched controls performed a probabilistic 3-choice decision-making task. We report anatomically specific patterns of impairment. We found that credit assignment, as indexed by the normal influence of contingent relationships between choice and reward, is reduced in lOFC patients compared with Controls and mOFC/vmPFC patients. Moreover, the effects of reward contingency on choice were similar for patients with lesions in DMF or mOFC/vmPFC, compared with Controls. By contrast, mOFC/vmPFC-lesioned patients made more stochastic choices than Controls when the decision was framed by valuable distracting alternatives, suggesting that value comparisons were no longer independent of irrelevant options. Once again, there was evidence of regional specialization: patients with lOFC lesions were unimpaired relative to Controls. As in macaques, human lOFC and mOFC/vmPFC are necessary for contingent learning and value-guided decision-making, respectively.

People and other animals learn the values of choices by observing the contingencies between them and their outcomes. However, decisions are not guided by choice-linked reward associations alone; macaques also maintain a memory of the general, average reward ratethe global reward statein an environment. Remarkably, global reward state affects the way that each choice outcome is valued and influences future decisions so that the impact of both choice success and failure is different in rich and poor environments. Successful choices are more likely to be repeated but this is especially the case in rich environments. Unsuccessful choices are more likely to be abandoned but this is especially likely in poor environments. Functional magnetic resonance imaging (fMRI) revealed two distinct patterns of activity, one in anterior insula and one in the dorsal raphe nucleus, that track global reward state as well as specific outcome events.

The value of a third potential option or distractor can alter the way in which decisions are made between two other options. Two hypotheses have received empirical support: that a high value distractor improves the accuracy with which decisions between two other options are made and that it impairs accuracy. Recently, however, it has been argued that neither observation is replicable. Inspired by neuroimaging data showing that high value distractors have different impacts on prefrontal and parietal regions, we designed a dual route decision-making model that mimics the neural signals of these regions. Here we show in the dual route model and empirical data that both enhancement and impairment effects are robust phenomena but predominate in different parts of the decision space defined by the options' and the distractor's values. However, beyond these constraints, both effects co-exist under similar conditions. Moreover, both effects are robust and observable in six experiments.

Coordination of neural crest cell (NCC) induction and delamination is orchestrated by several transcription factors. Among these, Sry-related HMG box-9 (Sox9) and Snail2 have been implicated in both the induction of NCC identity and, together with phoshorylation, NCC delamination. How phosphorylation effects this function has not been clear. Here we show, in the developing chick neural tube, that phosphorylation of Sox9 on S64 and S181 facilitates its SUMOylation, and the phosphorylated forms of Sox9 are essential for trunk neural crest delamination. Both phosphorylation and to a lesser extent SUMOylation, of Sox9 are required to cooperate with Snail2 to promote delamination. Moreover, bone morphogenetic protein and canonical Wnt signaling induce phosphorylation of Sox9, thereby connecting extracellular signals with the delamination of NCCs. Together the data suggest a model in which extracellular signals initiate phosphorylation of Sox9 and its cooperation with Snail2 to induce NCC delamination.in ovo electroporation | basement membrane N eural crest cells (NCCs) belong to a transient population of embryonic multipotent stem cells that are induced at the interface between the neuroectoderm and the prospective epidermis. These cells delaminate from the epithelium and adopt a characteristic migratory pathway into the periphery, where they contribute to several tissues, notably cranial facial structures and peripheral nervous system (1). During delamination, NCCs undergo an epithelial-mesenchyme transition (EMT), characterized by loss of cell-cell contacts and polarity, as well as acquisition of migratory capabilities (2). Successful EMT and delamination are essential steps for the subsequent migration and differentiation of NCCs. Consequently, mutations in genes involved in NCCs EMT are often associated with congenital defects (3).Previous studies showed that Sry-related HMG box-9 (Sox9), a member of the SoxE family of transcription factors, plays several roles in NC formation, survival, EMT, and differentiation (4-6). In mice harboring a null mutation in Sox9, NCCs were still generated but died by apoptosis before or shortly after NC delamination, suggesting that Sox9 is required for NC survival (4). In chick, misexpression of Sox9 in the neural tube was sufficient to induce NC identity at the expense of neural fate but only inefficiently induced delamination and EMT (5). By contrast, coexpression of Sox9 with the zinc finger-type transcription factor, Snail2, promoted systematic ectopic EMT and NC delamination along the dorsal-ventral extent of the neural tube (4). In addition, in vitro studies showed that Sox9 physically interacts with Snail2 (6). Altogether, these data suggest that the partnership between Sox9 and Snail2 may underlie the ability of Sox9 to induce NC delamination and EMT. However, how the combination of Sox9 and Snail2 achieves this is unclear.The ability of Sox9 to initiate NC delamination appears to be regulated by protein kinase A (PKA)-mediated phosphorylation at two serine residues (S64 a...