Action Dominates Valence in Anticipatory Representations in the Human Striatum and Dopaminergic Midbrain

The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However,the separate pathways inthe striatumfor go and no-go appearto violatethis independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action- outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects" requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipatedto be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Evolutionary dynamics of collective action in spatially structured populations.

Many models proposed to study the evolution of collective action rely on a formalism that represents social interactions as n-player games between individuals adopting discrete actions such as cooperate and defect. Despite the importance of spatial structure in biological collective action, the analysis of n-player games games in spatially structured populations has so far proved elusive. We address this problem by considering mixed strategies and by integrating discrete-action n-player games into the direct fitness approach of social evolution theory. This allows to conveniently identify convergence stable strategies and to capture the effect of population structure by a single structure coefficient, namely, the pairwise (scaled) relatedness among interacting individuals. As an application, we use our mathematical framework to investigate collective action problems associated with the provision of three different kinds of collective goods, paradigmatic of a vast array of helping traits in nature: "public goods" (both providers and shirkers can use the good, e.g., alarm calls), "club goods" (only providers can use the good, e.g., participation in collective hunting), and "charity goods" (only shirkers can use the good, e.g., altruistic sacrifice). We show that relatedness promotes the evolution of collective action in different ways depending on the kind of collective good and its economies of scale. Our findings highlight the importance of explicitly accounting for relatedness, the kind of collective good, and the economies of scale in theoretical and empirical studies of the evolution of collective action.