Hsiao, C.-J. | Search bioRxiv

bioRxiv2025

Responses of inferior colliculus neurons to notched noises in awake mice: putative neural correlates of auditory enhancement and Zwicker tone

Sensory systems are well adapted to constantly changing statistics of the environment and to process specific spectral features of sounds, such as spectral notch (i.e. low energy frequency band) embedded in broadband stimuli. Spectral notches can be added to the stimulus spectrum due to filtering by the outer ear, and can be used as monaural cues related to head or pinna position for localizing sound sources. In addition, broadband sounds with spectral notch are known to produce auditory enhancement, a perceptual phenomenon in which a target within a spectrally notched masker can become salient if preceded by a copy of the masker. Notched noise can also produce an auditory illusion, called Zwicker Tone (ZT), which is perceived immediately after stimulation and whose pitch corresponds to the spectral notch. The present study aimed to further investigate the mechanisms of auditory enhancement, including those of ZT, in the inferior colliculus of awake mice. We show that neural activity can be strongly suppressed during NN stimulation and enhanced immediately after NN stimulation. These effects depend on notch center frequency relative to the best frequency of neurons, stimulus level and notch width. Our results are consistent with the mechanisms described for post-inhibitory rebound in the central auditory system: NN could hyperpolarize the membrane potential, which can then activate several cationic conductances, leading to a rebound of neural activity. We discuss auditory enhancement and ZT as collateral effects of an essential neural mechanism aimed at enhancing the central representation of acoustic spectral contrasts.

neuroscience↗

bioRxiv2020

Aerobic glycolysis supports hepatitis B virus biosynthesis through interaction between viral surface antigen and pyruvate kinase isoform M2

As an intracellular pathogen, the reproduction of hepatitis B virus (HBV) depends on the occupancy of host metabolism machinery. Here we test a hypothesis if HBV may govern intracellular biosynthesis to achieve a productive reproduction. To test this hypothesis, we set up an affinity purification screen for host factors that interact with viral large surface antigen (LHBS). This identified pyruvate kinase isoform M2 (PKM2), a key regulator of glucose metabolism, as a binding partner of LHBS. We showed that the expression of LHBS affected oligomerization of PKM2 in hepatocytes, and thereby increased glucose consumption and lactate production, a phenomenon known as aerobic glycolysis. Interestingly, recovering PKM2 activity in hepatocytes by chemical activators, TEPP-46 or DASA-58, reduced biosynthesis of viral surface and core antigens. In addition, reduction of glycolysis by culturing in low-glucose condition or treatment with 2-deoxyglucose also decreased biosynthesis of viral surface antigen, without affecting general host proteins. Finally, TEPP-46 largely suppressed proliferation of LHBS-positive cells on 3-dimensional agarose plates, but showed no effect on the traditional 2-dimensional cell culture. Taken together, these results indicate that virus-induced metabolic switch may support de novo biosynthesis of HBV in hepatocytes. In addition, aerobic glycolysis is likely essential for LHBS-mediated oncogenesis. Accordingly, restriction of glucose metabolism may be considered as a novel strategy to restrain viral mediated biosynthesis and oncogenesis during chronic HBV infection. Author summaryChronic HBV infection is a life-long threat of patients, with a 25~40% increased risk of developing liver cirrhosis and cancer. Persistent expression of oncogenic viral products in the liver, especially LHBS, is an oncogenic caveat and resistant to current antiviral agents. Here we show that viral LHBS binds to host PKM2 and diminishes its kinase activity. This virus-host interaction induces metabolic switch from oxidative phosphorylation to aerobic glycolysis, with increased glucose consumption and lactate production. We show that such metabolic switch not only favors biosynthesis of HBV but also provokes hepatocarcinogenesis. Notably, restoration of PKM2 activity by chemical activators decreases expressions of viral products and largely suppresses virus-mediated hepatocarcinogenesis. This study highlights the importance of host metabolism in supporting viral biosynthesis and indicates a novel therapeutic approach to control chronic HBV infection via modulating host metabolic switch.

microbiology↗