Olsen, T. | Search bioRxiv

bioRxiv2022

Cysteine Restriction-Specific Effects of Sulfur Amino Acid Restriction on Lipid Metabolism

Decreasing dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), i.e., sulfur amino acid restriction (SAAR). Contrarily, human diets used in clinical studies did not eliminate cysteine and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not with methionine, suggesting that CR, but not MR, is responsible for the antiadiposity effects of SAAR in rodents. Whether this is true, and if so, the underlying mechanisms are unknown. Using multiple diets with variable concentrations of methionine and cysteine, we demonstrate that the anti-adiposity effects of SAAR are due to CR. CR increased serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, essential for fatty acid/triglyceride cycling. Molecular data suggest that the CR results in glutathione depletion, which induces Nrf2 and downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. Using multiple mouse models, we show that the magnitude of SAAR-induced changes in molecular markers depends on dietary fat concentration (60 fat>10% fat), gender (males>females), and age-at-onset (young>adult). Our findings are translationally relevant as we found a negative correlation of plasma serine with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. SAAR-like diets with high polyunsaturated fatty acids increased plasma serine in a short-term human feeding study. Serinogenesis might be a potential target to correct hypertriglyceridemia.

biochemistry↗

bioRxiv2021

Visual modulation of spectrotemporal receptive fields in mouse auditory cortex

Recent studies have established significant anatomical and functional connections between visual areas and primary auditory cortex (A1), which may be important for perceptual processes such as communication and spatial perception. However, much remains unknown about the microcircuit structure of these interactions, including how visual context may affect different cell types across cortical layers, each with diverse responses to sound. The present study examined activity in putative excitatory and inhibitory neurons across cortical layers of A1 in awake male and female mice during auditory, visual, and audiovisual stimulation. We observed a subpopulation of A1 neurons responsive to visual stimuli alone, which were overwhelmingly found in the deep cortical layers and included both excitatory and inhibitory cells. Other neurons for which responses to sound were modulated by visual context were similarly excitatory or inhibitory but were less concentrated within the deepest cortical layers. Important distinctions in visual context sensitivity were observed among different spike rate and timing responses to sound. Spike rate responses were themselves heterogeneous, with stronger responses evoked by sound alone at stimulus onset, but greater sensitivity to visual context by sustained firing activity following transient onset responses. Minimal overlap was observed between units with visual-modulated firing rate responses and spectrotemporal receptive fields (STRFs) which are sensitive to both spike rate and timing changes. Together, our results suggest visual information in A1 is predominantly carried by deep layer inputs and influences sound encoding across cortical layers, and that these influences independently impact qualitatively distinct responses to sound. Significance statementMultisensory integration is ubiquitous throughout the brain, including primary sensory cortices. The present study examined visual responses in primary auditory cortex, which were found in both putative excitatory and inhibitory neurons and concentrated in the deep cortical layers. Visual-modulated responses to sound were similarly observed in excitatory and inhibitory neurons but were more evenly distributed throughout cortical layers. Visual modulation moreover differed substantially across distinct sound response types. Transient stimulus onset spike rate changes were far less sensitive to visual context than sustained spike rate changes during the remainder of the stimulus. Spike timing changes were often modulated independently of spike rate changes. Audiovisual integration in auditory cortex is thus diversely expressed among cell types, cortical layers, and response types.

neuroscience↗