Human cognitive control is uniquely flexible and has been shown to depend on prefrontal cortex (PFC). But exactly how the biological mechanisms of the PFC support flexible cognitive control remains a profound mystery. Existing theoretical models have posited powerful task-specific PFC representations, but not how these develop. We show how this can occur when a set of PFC-specific neural mechanisms interact with breadth of experience to self organize abstract rule-like PFC representations that support flexible generalization in novel tasks. The same model is shown to apply to benchmark PFC tasks (Stroop and Wisconsin card sorting), accurately simulating the behavior of neurologically intact and frontally damaged people.generalization ͉ abstraction ͉ adaptive gating A fundamental human cognitive faculty is the capacity for cognitive control: the ability to behave in accord with rules, goals, or intentions, even when this runs counter to reflexive or otherwise highly compelling competing responses (e.g., the ability to keep typing rather than scratch a mosquito bite). A hallmark of cognitive control in humans is its remarkable flexibility: we can perform novel tasks with very little additional experience (e.g., playing a card game for the first time by observing the play or hearing the rules described). This ability appears to depend on the prefrontal cortex (PFC) (1-5) and in particular on abstract rule-like representations localized to this brain area (6-8). However, this capacity emerges only slowly over a protracted period through late adolescence, closely tracking the development of the PFC (9-11). At the psychological level, flexible cognitive control has been modeled abstractly in terms of symbol processing computations that support arbitrary variable binding (12). However, it remains unclear whether or how such models correspond to the increasingly rich body of knowledge about the neural mechanisms underlying cognitive control and in particular the functioning of the PFC. At the biological level, a number of neural models have proposed that cognitive control relies on the active maintenance of abstract rule-like representations in PFC that guide processing in posterior cortex (13-17). However, none of these existing frameworks have explained how such representations might develop, and why this development should take so long; indeed, most models rely on hand-coded representations designed explicitly for solving a specific set of tasks. Thus, a major challenge to theories of the neural bases of cognitive control remains unanswered: how it can be explained in terms of self-organizing mechanisms that develop on their own, over time, without recourse to unexplained sources of influence or intelligence (i.e., a ''homunculus'') (18).Here, we present a computational model that provides an explanation for the development of cognitive flexibility. This model shows how neurobiological mechanisms specific to the PFC result in the self organization of abstract rule-like PFC representations that support flexible cognit...

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)–rich protein aggregates [termed “Lewy bodies” (LBs)], is a well-established characteristic of Parkinson’s disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning–based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.