Social threat processing in adults and children: Faster orienting to, but shorter dwell time on, angry faces during visual search.

Attention to emotional signals conveyed by others is critical for gleaning information about potential social partners and the larger social context. Children appear to detect social threats (e.g., angry faces) faster than non-threatening social signals (e.g., neutral faces). However, methods that rely on behavioral responses alone are limited in identifying different attentional processes involved in threat detection or responding. To address this question, we used a visual search paradigm to assess behavioral (i.e., reaction time to select a target image) and attentional (i.e., eye-tracking fixations, saccadic shifts, and dwell time) responses in children (ages 7-10 years old, N = 42) and adults (ages 18-23 years old, N = 46). In doing so, we compared behavioral responding and attentional detection and engagement with threatening (i.e., angry and fearful faces) and non-threatening (i.e., happy faces) social signals. Overall, children and adults were faster to detect social threats (i.e., angry faces), but spent a smaller proportion of time dwelling on them and had slower behavioral responses. Findings underscore the importance of combining different measures to parse differences between processing versus responding to social signals across development. RESEARCH HIGHLIGHTS: Children and adults are slower to select angry faces when measured by time to mouse-click but faster to detect angry faces when measured by time to first eye fixation. The use of eye-tracking addresses some limitations of prior visual search tasks with children that rely on behavioral responses alone. Results suggest shorter time to first fixation, but subsequently, shorter duration of dwell on social threat in children and adults.

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis.

Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.