Mu, C. | Search bioRxiv

bioRxiv2018

The claustrum is required for reward acquisition under high cognitive demand

The claustrum is proposed to mediate a variety of functions ranging from sensory binding to top-down cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking. Here we employ the guanine nucleotide-binding subunit beta-4 cre driver line in mice to selectively monitor and manipulate claustrum projection neurons. Using fiber photometry, we find elevated claustrum activity prior to an expected cue during correct performance on a cognitively demanding five-choice response assay relative to a less-demanding one-choice version of the task. Claustrum activity during reward acquisition is also enhanced when cognitive demand is higher. Furthermore, we use optogenetic inhibition of claustrum prior to the expected cue to demonstrate that claustrum is critical for accurate performance on the five-choice, but not the one-choice, task. These results suggest the claustrum supports a cognitive control function necessary for reward acquisition under cognitively demanding conditions.

neuroscience↗

bioRxiv2018

Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromes

Mitochondrial respiratory complex II utilizes succinate, key substrate of the Krebs cycle, for oxidative phosphorylation, which is essential for glucose metabolism. Mutations of complex II cause cancers and mitochondrial diseases, raising a critical question of the (patho-)physiological functions. To address the fundamental role of complex II in systemic energy metabolism, we specifically knockout SDHB in mice liver, a key complex II subunit that tethers the catalytic SDHA subunit and transfers the electrons to ubiquinone, and found that SHDB deficiency abolishes the assembly of complex II without affecting other respiration complexes while largely retaining SDHA stability. SHDB ablation reprograms energy metabolism and hyperactivates the glycolysis, Krebs cycle and {beta}-oxidation pathways, leading to catastrophic energy deficit and early death. Strikingly, sucrose supplementation or high fat diet resumes both glucose and lipid metabolism and prevent early death. Also, SDHB deficient mice are completely resistant to high fat diet induced obesity. Our findings reveal that the unanticipated role of complex II orchestrating both lipid and glucose metabolisms, and suggest that SDHB is an ideal therapeutic target for combating obesity.

molecular biology↗