Directed evolution of cyclic peptides for inhibition of autophagy.

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B-two essential components of the autophagosome maturation machinery-with mid-nanomolar affinities and disrupted protein-protein interactions (PPIs) between LC3 and its binding partners in vitro. The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery in vitro and in vivo.

Sex differences in relationship regret: the role of perceived mate characteristics.

The current set of studies examined regret involving action and inaction in the realm of romantic relationships by testing whether such regret is associated with the characteristics of one's mate. In study 1, 394 participants reported on a previous casual sexual encounter, and in study 2, 358 participants reported on a previous romantic relationship. In both, instances of actual engagement and instances of passing up opportunities were studied. Study 3 was experimental and elicited reactions to hypothetical scenarios from 201 participants. Regret reported by men in both study 1 and study 2 varied as a function of the perceived attractiveness of the participants' actual and potential mate. Regret reported by women in study 2 varied as a function of the perceived stinginess of the participant's mate and perceived wealth of the participants' potential mate. Study 3 found that sex differences in type of regret (with men regretting inaction more than women) occurred only when the mate presented in the scenario was described in ways consistent with mate preferences. Together these findings suggest that regret differs between the sexes in ways consistent with sex differences in mate preferences.

Prefrontal cortex mediation of cognitive enhancement in rewarding motivational contexts.

Increasing the reward value of behavioral goals can facilitate cognitive processes required for goal achievement. This facilitation may be accomplished by the dynamic and flexible engagement of cognitive control mechanisms operating in distributed brain regions. It is still not clear, however, what are the characteristics of individuals, situations, and neural activation dynamics that optimize motivation-linked cognitive enhancement. Here we show that highly reward-sensitive individuals exhibited greater improvement of working memory performance in rewarding contexts, but exclusively on trials that were not rewarded. This effect was mediated by a shift in the temporal dynamics of activation within right lateral prefrontal cortex, from a transient to predominantly tonic mode, with an additional anticipatory transient boost. In contexts with intermittent rewards, a strategy of proactive cognitive control may enable globally optimal performance to facilitate reward attainment. Reward-sensitive individuals appear preferentially motivated to adopt this resource-demanding strategy, resulting in paradoxical benefits selectively for nonrewarded events.

Primary and secondary rewards differentially modulate neural activity dynamics during working memory.

BACKGROUND: Cognitive control and working memory processes have been found to be influenced by changes in motivational state. Nevertheless, the impact of different motivational variables on behavior and brain activity remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The current study examined the impact of incentive category by varying on a within-subjects basis whether performance during a working memory task was reinforced with either secondary (monetary) or primary (liquid) rewards. The temporal dynamics of motivation-cognition interactions were investigated by employing an experimental design that enabled isolation of sustained and transient effects. Performance was dramatically and equivalently enhanced in each incentive condition, whereas neural activity dynamics differed between incentive categories. The monetary reward condition was associated with a tonic activation increase in primarily right-lateralized cognitive control regions including anterior prefrontal cortex (PFC), dorsolateral PFC, and parietal cortex. In the liquid condition, the identical regions instead showed a shift in transient activation from a reactive control pattern (primary probe-based activation) during no-incentive trials to proactive control (primary cue-based activation) during rewarded trials. Additionally, liquid-specific tonic activation increases were found in subcortical regions (amygdala, dorsal striatum, nucleus accumbens), indicating an anatomical double dissociation in the locus of sustained activation. CONCLUSIONS/SIGNIFICANCE: These different activation patterns suggest that primary and secondary rewards may produce similar behavioral changes through distinct neural mechanisms of reinforcement. Further, our results provide new evidence for the flexibility of cognitive control, in terms of the temporal dynamics of activation.

Flexible neural mechanisms of cognitive control within human prefrontal cortex.

A major challenge in research on executive control is to reveal its functional decomposition into underlying neural mechanisms. A typical assumption is that this decomposition occurs solely through anatomically based dissociations. Here we tested an alternative hypothesis that different cognitive control processes may be implemented within the same brain regions, with fractionation and dissociation occurring on the basis of temporal dynamics. Regions within lateral prefrontal cortex (PFC) were examined that, in a prior study, exhibited contrasting temporal dynamics between older and younger adults during performance of the AX-CPT cognitive control task. The temporal dynamics in younger adults fit a proactive control pattern (primarily cue-based activation), whereas in older adults a reactive control pattern was found (primarily probe-based activation). In the current study, we found that following a period of task-strategy training, these older adults exhibited a proactive shift within a subset of the PFC regions, normalizing their activity dynamics toward young adult patterns. Conversely, under conditions of penalty-based monetary incentives, the younger adults exhibited a reactive shift some of the same regions, altering their temporal dynamics toward the older adult baseline pattern. These experimentally induced crossover patterns of temporal dynamics provide strong support for dual modes of cognitive control that can be flexibly shifted within PFC regions, via modulation of neural responses to changing task conditions or behavioral goals.

Intrinsic motivation in schizophrenia: relationships to cognitive function, depression, anxiety, and personality.

The goal of the current project was to assess subjective reports of intrinsic motivation and their relationship to cognitive function, mood, and personality in schizophrenia. The authors used the Motivational Trait Questionnaire to examine 3 components of intrinsic motivation (personal mastery, competitive excellence, motivation related to anxiety). They also examined fluid intelligence, context processing, and working memory, as well as self-reports of mood and personal traits related to motivation. Participants were 66 individuals with schizophrenia or schizoaffective disorder and 44 healthy controls. Self-reports of personal mastery and competitive excellence did not differ between controls and individuals with schizophrenia, though patients did report significantly higher motivation related to anxiety. Among controls, but not patients, self-reports of intrinsic motivation were strongly related to cognitive performance. In contrast, both controls and patients showed similar strong relationships between self-reports of intrinsic motivation and related measures of mood and personality. These results are not consistent with the hypothesis that motivational deficits in schizophrenia reflect impairments in intrinsic motivation. However, they do suggest that the normal relationship between self-reports of intrinsic motivation and cognitive function is disrupted in schizophrenia.

Motivational influences on cognitive control: behavior, brain activation, and individual differences.

What changes in brain activity are associated with changes in motivational state? The present study addressed this question by having participants perform a cognitive task (AX variant of the Continuous Performance Test; AX-CPT) under three different blocked motivational conditions (reward-incentive, penalty-incentive, and baseline). Behavioral data showed that the incentive conditions modulated task performance, potentially by altering participants' cognitive control strategy. Neuroimaging data indicated that the reward condition was associated with a sustained increase in a primarily right-lateralized network that included parietal and prefrontal cortex. Additionally, individual differences were observed, such that activation in both reward-related brain regions and frontopolar cortex was linked to the degree of motivation-induced performance enhancement and to motivation-related personality variables. These results suggest that changes in motivational state may modulate performance through sustained activity in cognitive control regions and that the effect of incentives may be affected by the personalities of the participants.