To decide whether a course of action is worth pursuing, individuals typically weigh its expected costs and benefits. Optimal decision-making relies upon accurate effort cost anticipation, which is generally assumed to be performed independently from goal valuation. In two experiments (n = 46), we challenged this independence principle of standard decision theory. We presented participants with a series of treadmill routes randomly associated to monetary rewards and collected both ‘accept’ versus ‘decline’ decisions and subjective estimates of energetic cost. Behavioural results show that higher monetary prospects led participants to provide higher cost estimates, although reward was independent from effort in our design. Among candidate cognitive explanations, they support a model in which prospective cost assessment is biased by the output of an automatic computation adjusting effort expenditure to goal value. This decision bias might lead people to abandon the pursuit of valuable goals that are in fact not so costly to achieve.

Synaptic communication relies on the fusion of synaptic vesicles with the plasma membrane, which leads to neurotransmitter release. This exocytosis is triggered by brief and local elevations of intracellular Ca²⁺ with remarkably high sensitivity. How this is molecularly achieved is unknown. While synaptotagmins confer the Ca²⁺ sensitivity of neurotransmitter exocytosis, biochemical measurements reported Ca²⁺ affinities too low to account for synaptic function. However, synaptotagmin's Ca²⁺ affinity increases upon binding the plasma membrane phospholipid PI(4,5)P₂ and, vice versa, Ca²⁺-binding increases synaptotagmin's PI(4,5)P₂ affinity, indicating a stabilization of the Ca²⁺/PI(4,5)P₂ dual-bound syt. Here we devise a molecular exocytosis model based on this positive allosteric stabilization and the assumptions that (1.) synaptotagmin Ca²⁺/PI(4,5)P₂ dual binding lowers the energy barrier for vesicle fusion and that (2.) the effect of multiple synaptotagmins on the energy barrier is additive. The model, which relies on biochemically measured Ca²⁺/PI(4,5)P₂ affinities and protein copy numbers, reproduced the steep Ca²⁺ dependency of neurotransmitter release. Our results indicate that each synaptotagmin dual binding Ca²⁺/PI(4,5)P₂ lowers the energy barrier for vesicle fusion by ~5 k_BT and that allosteric stabilization of this state enables the synchronized engagement of several (typically three) synaptotagmins for fast exocytosis. Furthermore, we show that mutations altering synaptotagmin’s allosteric properties may show dominant-negative effects, even though synaptotagmins act independently on the energy barrier, and that dynamic changes of local PI(4,5)P₂ (e.g. upon vesicle movement) dramatically impact synaptic responses. We conclude that allosterically stabilized Ca²⁺/PI(4,5)P₂ dual binding enables synaptotagmins to exert their coordinated function in neurotransmission.