2025-05-18 | | Total: 3
MECP2 is commonly mutated in Rett syndrome, where MECP2’s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants with no known clinical significance. To assess these nine as risk alleles for ASD, we developed MECP2 variant function assays using yeast, Drosophila and human cell lines. We calibrated these assays with known reference pathogenic and benign variants. Our data predict that four ASD variants are loss of function (LoF) and five are functional. Protein destabilization or nuclear delocalization offers insight into the altered function of a number of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett reference pathogenic and ASD variants in the methyl DNA binding domain that we analyzed proved to be LoF, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2.
This systematic and meta-analytical review examined how a reduction in oxygen availability to tissue (hypoxia) affects cognitive function. Hypoxia had a moderate-to-large detrimental effect on general cognitive ability and across domains, including memory, attention, executive function, processing speed, and psychomotor speed. Increased hypoxic severity was associated with greater declines in general cognitive ability and executive function, while longer duration of exposure was associated with greater declines in executive function and psychomotor speed. Participant age was a moderator for executive function and psychomotor speed, with older adults experiencing greater impairments. For executive function and psychomotor speed, the magnitude of these effects was less pronounced during intermittent and hypobaric exposures, potentially due to adaptive physiological mechanisms. While our models accounted for exposure characteristics and age of participants, substantial unexplained variance remained. These findings highlight hypoxias impact on cognition and emphasize the need to investigate underlying neurophysiological mechanisms that may influence individual vulnerability.
Changing one’s mind is a complex cognitive phenomenon involving a continuous re-appraisal of the trade-off between past costs and future value. Recent work modeling this behavior across species has established associations between aspects of this choice process and their contributions to altered decision-making in psychopathology. Here, we investigated the actions in medial prefrontal cortex (mPFC) neurons of long intergenic non-coding RNA, LINC00473, known to induce stress resilience in a striking sex-dependent manner, but whose role in cognitive function is unknown. We characterized complex decision-making behavior in male and female mice longitudinally in our neuroeconomic foraging paradigm, Restaurant Row, following virus-mediated LINC00473 expression in mPFC neurons. On this task, mice foraged for their primary source of food among varying costs (delays) and subjective value (flavors) while on a limited time-budget during which decisions to accept and wait for rewards were separated into discrete stages of primary commitments and secondary re-evaluations. We discovered important differences in decision-making behavior between female and male mice. LINC00473 expression selectively influenced multiple features of re-evaluative choices, without affecting primary decisions, in female mice only. These behavioral effects included changing how mice (i) cached the value of the passage of time and (ii) weighed their history of economically disadvantageous choices. Both processes were uniquely linked to change-of-mind decisions and underlie the computational bases of distinct aspects of counterfactual thinking. These findings reveal a key bridge between a molecular driver of stress resilience and psychological mechanisms underlying sex-specific decision-making proclivities.