Olivei, A. | bioRxiv Science

bioRxiv2025

Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States. This is due in part to the limited availability of effective treatment options for patients, highlighting a significant need for new targets and approaches. Deregulated metabolism is a hallmark feature of PDA that has gained attention as a promising inroad for therapy. The aspartate transaminases (glutamate oxaloacetate transaminases, cytosolic GOT1 and mitochondrial GOT2) have several important metabolic functions, including maintaining energy and redox balance and generating aspartate, an essential building block in protein and nucleotide biosynthesis. Previous studies of GOT proteins in preclinical tumor transplant models have yielded conflicting results regarding the requirement of GOT1 and GOT2 for PDA tumor growth. To assess the role of GOT proteins in tumor development and tumor maintenance, we generated conditional knockout mice for Got1 and Got2 and crossed these into pancreas-specific models. Whereas loss of either Got does not impact pancreas development, double Got1 and Got2 knockout results in markedly reduced pancreas size and cellularity without overtly impacting endocrine or exocrine function. In genetically engineered cancer models, single Got loss does not impact lesion formation, tumor size, animal survival, or the composition of the tumor microenvironment. Identical results were also observed in orthotopic allograft mouse models. Together, these findings add to a growing body of work illustrating the adaptability of metabolism in cancer. They also emphasize the importance of model selection, the use of multiple independent models, and the in vivo context when studying the role of metabolic programs in cancer.

cancer biology↗

bioRxiv2023

A Cortico-Striatal Circuit for Sound-Triggered Prediction of Reward Timing

A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later; the sound of an approaching vehicle signals when it is safe to cross the street. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in reward-predictive licking. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impairs animals ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.

neuroscience↗