Differential consequences of habitual responding in a mouse model of repetitive behavior.

Restricted, repetitive behavior (RRB) is diagnostic for autism spectrum disorder (ASD) and characteristic of a number of neurodevelopmental, psychiatric, and neurological disorders. RRB seen in ASD includes repetitive motor behavior and behaviors reflecting resistance to change and insistence on sameness. C58 mice provide a robust model of repetitive motor behavior and have shown resistance to change in a reversal learning task. We further characterized resistance to change in this model by inducing habitual responding and testing for differences in the ability to suppress habitual behavior and shift to goal-directed responding. We found no differences between C58 and control (C57BL/6) mice in the acquisition of operant tasks, habit formation, and expression of habitual responding. Habitual responding, however, induced significant reversal learning and contingency reversal performance deficits in C58 mice compared with C57BL/6 mice. Decreased dendritic spine density of the dorsomedial striatum in C58 mice was related to higher repetitive motor behavior, whereas dendritic spine density in the subthalamic nucleus was significantly positively correlated with improved contingency reversal performance in both C58 and C57BL/6 mice. Our results demonstrate that induction of habitual responding markedly impaired the ability of C58 mice to shift to goal-directed behavior. Such impairment may have resulted from the effects of the induction of habitual responding on already compromised basal ganglia circuitry mediating repetitive motor behavior. These findings provide additional evidence for the translational value of the C58 model in modeling RRB in neurodevelopmental disorders. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Correction to: Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia.

Following publication of the original article [1], the authors found an error in Figure 3. The middle panel of Figure 3a was inadvertently duplicated.

Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia.

BACKGROUND: There is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML). Triptolide, a diterpenoid tri-epoxide compound isolated from the herb Tripterygium wilfordii and its water-soluble pro-drug-Minnelide have shown promising anti-cancer activity. A recent clinical trial for patients with solid tumors confirmed the safety and efficacy at biologically equivalent doses of 0.2 mg/kg/day and lower. METHODS: Cell viability of multiple AML cell lines as well as patient apheresis samples were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) based assay. Apoptosis was evaluated by estimating the amount of cleaved caspase. AML cell line (THP1-Luc) was implanted in immunocompromised mice and treated with indicated doses of Minnelide. Leukemic burden before and after treatment was evaluated by imaging in an In Vivo Imaging System (IVIS). RESULTS: In the current study, we show that Minnelide, at doses below maximum tolerated dose (MTD) demonstrates leukemic clearance of both primary AML blasts and luciferase expressing THP-1 cells in mice. In vitro, multiple primary AML apheresis samples and AML cell lines (THP-1, KG1, Kasumi-1, HL-60) were sensitive to triptolide mediated cell death and apoptosis in low doses. Treatment with triptolide led to a significant decrease in the colony forming ability of AML cell lines as well as in the expression of stem cell markers. Additionally, it resulted in the cell cycle arrest in the G1/S phase with significant downregulation of c-Myc, a major transcriptional regulator mediating cancer cell growth and stemness. CONCLUSION: Our results suggest that Minnelide, with confirmed safety and activity in the clinic, exerts a potent anti-leukemic effect in multiple models of AML at doses easily achievable in patients.