bioRxiv Science⌕ Search

Biology subjects

Puliyadi, R.

Publications and source records attributed to Puliyadi, R..

2 recordsLinked to original sources

Dorsal striatal dopamine integrates sensory and reward prediction errors to guide perceptual decisions

Perceptual decisions are shaped by expectations about sensory stimuli and rewards, learned through sensory and reward prediction errors. Dopamine is known to convey reward prediction errors that shape perceptual decisions. However, whether dopamine also signals sensory prediction errors during perceptual decision-making remains unknown. We recorded dopamine release in the dorsal striatum of mice performing a visual decision-making task while manipulating sensory and reward expectations. The two manipulations produced similar behavioral biases but elicited opposite dopamine signals, indicating that dopamine within the same striatal region encoded both sensory and reward prediction errors. Sensory prediction error signaling was specific to dopamine as striatal acetylcholine showed no such error signals. Optogenetically stimulating striatal dopamine at stimulus onset biased subsequent perceptual decisions, consistent with updating sensory expectations. A computational model learning from both sensory and reward prediction errors captured behavioral biases and dopamine data, revealing distinct but spatially overlapping dopaminergic teaching signals.

neuroscience↗

Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models

DNA polymerase theta (Pol{theta}) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Pol{theta} has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Pol{theta} DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, normal fibroblasts are not radiosensitized by Pol{theta} inhibition. Mechanistically, we show that the radiosensitization caused by Pol{theta} inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Pol{theta} inhibitor with improved metabolic stability. In vivo, the combination of Pol{theta} inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared to radiation alone. These results pave the way for future clinical trials of Pol{theta} inhibitors in combination with radiotherapy.

cancer biology↗