Dynamic functional connectivity correlates of trait mindfulness in early adolescence.

Background: Trait mindfulness, the tendency to attend to present-moment experiences without judgement, is negatively correlated with adolescent anxiety and depression. Understanding the neural mechanisms underlying trait mindfulness may inform the neural basis of psychiatric disorders. However, few studies have identified brain connectivity states that correlate with trait mindfulness in adolescence, nor have they assessed the reliability of such states. Methods: To address this gap in knowledge, we rigorously assessed the reliability of brain states across 2 functional magnetic resonance imaging (fMRI) scan from 106 adolescents aged 12 to 15 (50% female). We performed both static and dynamic functional connectivity analyses and evaluated the test-retest reliability of how much time adolescents spent in each state. For the reliable states, we assessed associations with self-reported trait mindfulness. Results: Higher trait mindfulness correlated with lower anxiety and depression symptoms. Static functional connectivity (ICCs from 0.31-0.53) was unrelated to trait mindfulness. Among the dynamic brains states we identified, most were unreliable within individuals across scans. However, one state, an hyperconnected state of elevated positive connectivity between networks, showed good reliability (ICC=0.65). We found that the amount of time that adolescents spent in this hyperconnected state positively correlated with trait mindfulness. Conclusions: By applying dynamic functional connectivity analysis on over 100 resting-state fMRI scans, we identified a highly reliable brain state that correlated with trait mindfulness. The brain state may reflect a state of mindfulness, or awareness and arousal more generally, which may be more pronounced in those who are higher in trait mindfulness.

RIPK1: Inflamed if you do, inflamed if you don't.

RIPK1 is known as a driver of cell death and inflammation. In this issue of Immunity, Imai et al. and Mannion et al. find that these same processes are also induced by RIPK1 inactivation and highlight the therapeutic potential of RIPK1 elimination.

Striatal and Behavioral Responses to Reward Vary by Socioeconomic Status in Adolescents.

Disparities in socioeconomic status (SES) lead to unequal access to financial and social support. These disparities are believed to influence reward sensitivity, which in turn are hypothesized to shape how individuals respond to and pursue rewarding experiences. However, surprisingly little is known about how SES shapes reward sensitivity in adolescence. Here, we investigated how SES influenced adolescent responses to reward, both in behavior and the striatum-a brain region that is highly sensitive to reward. We examined responses to both immediate reward (tracked by phasic dopamine) and average reward rate fluctuations (tracked by tonic dopamine) as these distinct signals independently shape learning and motivation. Adolescents (n = 114; 12-14 years; 58 female) performed a gambling task during functional magnetic resonance imaging. We manipulated trial-by-trial reward and loss outcomes, leading to fluctuations between periods of reward scarcity and abundance. We found that a higher reward rate hastened behavioral responses, and increased guess switching, consistent with the idea that reward abundance increases response vigor and exploration. Moreover, immediate reward reinforced previously rewarding decisions (win-stay, lose-switch) and slowed responses (postreward pausing), particularly when rewards were scarce. Notably, lower-SES adolescents slowed down less after rare rewards than higher-SES adolescents. In the brain, striatal activations covaried with the average reward rate across time and showed greater activations during rewarding blocks. However, these striatal effects were diminished in lower-SES adolescents. These findings show that the striatum tracks reward rate fluctuations, which shape decisions and motivation. Moreover, lower SES appears to attenuate reward-driven behavioral and brain responses.

LITAF protects against pore-forming protein-induced cell death by promoting membrane repair.

Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous pore-forming proteins that induce cell death as part of host defense. To mitigate damage and promote survival, cells mobilize membrane repair mechanisms to neutralize and counteract pores, but how these pathways are activated is poorly understood. Here, we use a transposon-based gene activation screen to discover pathways that counteract the cytotoxicity of the archetypal PFT Staphylococcus aureus α-toxin. We identify the endolysosomal protein LITAF as a mediator of cellular resistance to PFT-induced cell death that is active against both bacterial toxins and the endogenous pore, gasdermin D, a terminal effector of pyroptosis. Activation of the ubiquitin ligase NEDD4 by potassium efflux mobilizes LITAF to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to repair damaged membrane. Cells lacking LITAF, or carrying naturally occurring disease-associated mutations of LITAF, are highly susceptible to pore-induced death. Notably, LITAF-mediated repair occurs at endosomal membranes, resulting in expulsion of damaged membranes as exosomes, rather than through direct excision of pores from the surface plasma membrane. These results identify LITAF as a key effector that links sensing of cellular damage to repair.