RESUMEN
Auditory cognition is impaired in schizophrenia, and typically engages a complex, distributed, hierarchical network, including both auditory and frontal input. We recently demonstrated proof of principle for the target engagement of an N-methyl-D-aspartate-type glutamate receptor (NMDAR) agonist + auditory targeted remediation (d-serine+AudRem) combination, showing significant improvement in auditory-learning induced plasticity and mismatch negativity. In this secondary analysis, we report on frontal EEG outcomes, assessing for both generalized effects and the mechanism of auditory plasticity. 21 schizophrenia or schizoaffective disorder participants were randomized to three 1x weekly AudRem + double-blind d-serine (100 mg/kg) visits. In AudRem, participants indicated which paired tone was higher in pitch. The focus of this secondary analysis was a frontally (premotor) mediated EEG outcome- event-related desynchronization in the b band (b-ERD), which was shown to be sensitive to AudRem in previous studies. d-Serine+AudRem led to significant improvement in b-ERD power across the retention and motor preparation intervals (F 1,18 =6.0, p=0.025) vs. AudRem alone. b-ERD was significantly related to baseline cognition, but not auditory-learning induced plasticity. The principal finding of this prespecified secondary analysis are that in addition to improving auditory based biomarkers, the d-serine+AudRem combination led to significant improvement in biomarkers thought to represent frontally mediated dysfunction, suggesting potential generalization of effects. Changes in auditory-learning induced plasticity were independent of these frontally mediated biomarkers. Ongoing work will assess whether d-serine+AudRem is sufficient to remediate cognition or whether targeting frontal NMDAR deficits with higher-level remediation may also be required. Trial Registration: NCT03711500.
RESUMEN
TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.