Napoli, J. L. | bioRxiv Science

bioRxiv2021

Retinoic acid exerts sexually dimorphic effects over muscle energy metabolism and function

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and suppresses adiposity. Relative to WT, Rdh10+/- males experienced reduced fatty-acid oxidation, glucose intolerance and insulin resistance. Running endurance decreased 40%. Rdh10+/- females increased reliance on fatty acid oxidation and did not experience glucose intolerance nor insulin resistance. Running endurance improved 2.2-fold. Estrogen increased, revealed by a 40% increase in uterine weight. Because skeletal muscle energy use restricts adiposity and insulin resistance, we assessed the mixed fiber type gastrocnemius muscle (GM) to determine the effects of endogenous RA on muscle metabolism in vivo. RA in Rdh10+/- male GM decreased 38% relative to WT. TAG content increased 1.7-fold. Glut1 mRNA and glucose decreased >30%. Rdh10+/- male GM had impaired electron transport chain activity, and a 60% reduction in fasting ATP. The share of oxidative fibers increased, as did expression of the myogenic transcription factors Myog and Myf5. Centralized nuclei increased 5-fold in fibers--indicating muscle malady or repair. In Rdh10+/- female GM, RA decreased only 17%, due to a 1.8-fold increase in the estrogen-induced retinol dehydrogenase, Dhrs9. Rdh10+/- female GM did not amass TAG, increase oxidative fibers, decrease Glut1 mRNA or glucose, nor increase centralized nuclei. Expression of Myog and Myf5 decreased. Electron transport chain activity increased, elevating fasting ATP >3-fold. Thus, small decreases in skeletal muscle RA affect whole body energy use, insulin resistance and adiposity, in part through estrogen-related sexual dimorphic effects on mitochondria function.

biochemistry↗

bioRxiv2020

Correlates of auditory decision making in prefrontal, auditory, and basal lateral amygdala cortical areas

Auditory selective listening and decision making underlies important processes, including attending to a single speaker in a crowded room, often referred to as the cocktail party problem. To examine the neural mechanisms underlying these behaviors, we developed a novel auditory selective listening paradigm for monkeys. In this task, monkeys had to detect a difficult to discriminate target embedded in noise when presented in a pre-cued location (either left or right) and ignore it if it was in the opposite location. While the animals carried out the task we recorded neural activity in primary auditory cortex (AC), dorsal lateral prefrontal cortex (dlPFC) and the basal lateral amygdala (BLA), given that these areas have been implicated in auditory decision making, selective listing, and/or reward-guided decision making. There were two main findings in the neural data. First, primary AC encoded the side of the cue and target, and the monkeys choice, before either dlPFC or the amygdala. The BLA encoded cue and target variables negligibly, but was engaged at the time of the monkeys choice. Second, decoding analyses suggested that errors followed primarily from a failure to encode the target stimulus in both AC and PFC, but earlier in AC. Thus, AC neural activity is poised to represent the sensory volley and decision making during selective listening before dlPFC, and they both precede activity in BLA.

neuroscience↗