👤 Natacha Cordonier

Difficulties understanding nonliteral language (especially hints) are frequently reported following acquired brain injury (ABI). Several cognitive mechanisms, such as context processing, executive functions, and theory of mind (ToM), may underlie these disorders. However, their role remains controversial, mainly because of the characteristic heterogeneity of this population. Therefore, our study aimed to identify cognitive-pragmatic profiles in individuals with ABI. A new task of hint comprehension, manipulating executive demand, markers of hints, and ToM and neuropsychological tests were administered to 33 participants with frontal ABI and 33 control participants. Cluster analysis, a method sensitive to profile heterogeneity, was applied and coupled with error analysis. We highlighted two cognitive-pragmatic profiles. One subgroup of participants with ABI exhibited contextual insensitivity, leading them to infer the utterance meaning based on linguistic decoding alone-literal meaning. This difficulty in understanding hints was associated with deficits in working memory, inhibition, and ToM. The second subgroup of participants with ABI showed difficulty with literal statements, associated with impaired inhibition and ToM. In addition, the two subgroups differed only on the ToM task. This result suggests that various types of ToM deficit (misunderstanding vs. incorrect attribution of mental states) could contribute to the variability of the pragmatic profiles observed (difficulties in interpreting hints vs. literal statements). The experimental design adopted in this study provides valuable insight into the explanatory hypotheses of nonliteral language comprehension disorders and has important clinical implications. https://doi.org/10.23641/asha.24069516. Show less

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions. Show less

The voltage-gated Na(+) channels (Na(v)) form a family composed of 10 genes. The COOH termini of Na(v) contain a cluster of amino acids that are nearly identical among 7 of the 10 members. This COOH-terminal sequence, PPSYDSV, is a PY motif known to bind to WW domains of E3 protein-ubiquitin ligases of the Nedd4 family. We recently reported that cardiac Na(v)1.5 is regulated by Nedd4-2. In this study, we further investigated the molecular determinants of regulation of Na(v) proteins. When expressed in HEK-293 cells and studied using whole cell voltage clamping, the neuronal Na(v)1.2 and Na(v)1.3 were also downregulated by Nedd4-2. Pull-down experiments using fusion proteins bearing the PY motif of Na(v)1.2, Na(v)1.3, and Na(v)1.5 indicated that mouse brain Nedd4-2 binds to the Na(v) PY motif. Using intrinsic tryptophan fluorescence imaging of WW domains, we found that Na(v)1.5 PY motif binds preferentially to the fourth WW domain of Nedd4-2 with a K(d) of approximately 55 muM. We tested the binding properties and the ability to ubiquitinate and downregulate Na(v)1.5 of three Nedd4-like E3s: Nedd4-1, Nedd4-2, and WWP2. Despite the fact that along with Nedd4-2, Nedd4-1 and WWP2 bind to Na(v)1.5 PY motif, only Nedd4-2 robustly ubiquitinated and downregulated Na(v)1.5. Interestingly, coexpression of WWP2 competed with the effect of Nedd4-2. Finally, using brefeldin A, we found that Nedd4-2 accelerated internalization of Na(v)1.5 stably expressed in HEK-293 cells. This study shows that Nedd4-dependent ubiquitination of Na(v) channels may represent a general mechanism regulating the excitability of neurons and myocytes via modulation of channel density at the plasma membrane. Show less