Biology subjects

Zhou, Z.-Y.

Publications and source records attributed to Zhou, Z.-Y..

5 recordsLinked to original sources

bioRxiv2026

Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Transforming growth factor {beta}-activated kinase 1 (TAK1) is a serine/threonine kinase best known for its roles in immune and stress-response signaling, yet its physiological function in mature neurons remains poorly understood. Here we identify neuronal TAK1 as a regulator of excitatory synaptic integrity, hippocampal plasticity and memory. Conditional reduction of TAK1 in forebrain excitatory neurons impaired short- and long-term memory and was accompanied by attenuated long-term potentiation in the hippocampus. At the cellular level, TAK1 deficiency reduced dendritic spine density and suppressed excitatory synaptic transmission, whereas genetic or pharmacological disruption of TAK1 kinase activity recapitulated these synaptic deficits. Mechanistically, TAK1 localized to the postsynaptic compartment of excitatory synapses and associated with PSD-95. Phosphoproteomic analysis of isolated postsynaptic density fractions revealed coordinated changes in synaptic phosphorylation following TAK1 reduction, including decreased phosphorylation of the NMDA receptor subunit GluN2B at serine 920. Analyses of phosphodeficient and phosphomimetic GluN2B mutants supported a role for S920 phosphorylation downstream of TAK1 in maintaining dendritic spine density, excitatory synaptic transmission and spontaneous synaptic calcium activity. Notably, synaptic TAK1 level was reduced in the aged hippocampus. Re-expressing neuronal TAK1 in aged mice increased dendritic spine density, enhanced hippocampal synaptic plasticity, and improved memory performance. Together, these findings define a postsynaptic TAK1-GluN2B signaling axis that supports excitatory synaptic function and suggest that reduced synaptic TAK1 signaling may contribute to hippocampal vulnerability during aging.

neuroscience↗

bioRxiv2026

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

bioRxiv2025

α2A-AR-Kv dysfunction drives LC hyperactivity and early sleep disturbance in amyloidogenic mice

Disrupted sleep-wake patterns are common in neurodegenerative disorders such as Alzheimers disease (AD), can emerge early, and are proposed as potent risk factors for disease onset and progression. However, the underlying mechanisms remain poorly understood. Here, we report that 5xFAD transgenic mice exhibit hyperarousal and reduced brain-state transitions, particularly during the dark phase, as early as two months of age. The Locus Coeruleus (LC), a key regulator of arousal and brain-state transitions and a region highly vulnerable in AD, shows time-specific hyperactivity during this phase. This increased tonic LC activity is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 potassium channel conductance. Pharmacological activation of 2A adrenergic receptors restored Kv4 and Kv7 function and normalized LC activity. Furthermore, local administration of the 2A agonist guanfacine or the Kv7 positive allosteric modulator retigabine substantially rescued the sleep-wake disturbances in young 5xFAD mice. These findings identify dark-phase-selective LC hyperexcitability as a key driver of early-onset sleep disruption in AD mice and implicate 2A adrenergic receptors and Kv7 channels as promising targets for early intervention.

neuroscience↗

bioRxiv2021

Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population

Vaginal microbiota-host interactions are linked to preterm birth (PTB), which continues to be the primary cause of global childhood mortality. Despite the majority of PTB occuring in Asia, studies of the pregnancy vaginal microbiota are largely limited to Northern American and European populations. Here, we characterised the vaginal microbiome of 2689 pregnant Chinese women using metataxonomics and in a subset (n=823), the relationship between vaginal microbiota composition, sialidase activity and leukocyte presence and pregnancy outcomes. Vaginal microbiota were most frequently dominated by Lactobacillus crispatus or L. iners, with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including Gardnerella, Atopobium and Prevotella. Vaginal microbiota composition, high sialidase activity and/or leukocyte presence was not associated with PTB risk suggesting underlying differences in the vaginal microbiota and/or host immune responses of Chinese women, possibly accounting for low PTB rates in this population. ImportanceSpecific vaginal microorganisms or vaginal microbiota, are associated with preterm birth, which is the primary cause of death in children under 5yrs of age worldwide. Despite most preterm births occuring in Asia, almost all studies of the pregnancy vaginal microbiota have been limited to Northern American and European women. Here, we studied the vaginal microbiota in a large cohort of 2689 pregnant Chinese women and showed that it was most frequently dominated by Lactobacillus crispatus or L. iners. The latter was associated with leukocyte infiltration of vaginal secretions. Women with high activity of the enzyme sialidase, were frequently colonised by species associated with the common condition bacterial vaginosis, including Gardnerella, Atopobium and Prevotella species. Vaginal microbiota, high sialidase activity and/or leukocyte presence was not associated with preterm birth risk indicating differences in the microbe-host immune responses of Chinese women, possibly explaining why preterm birth rates in this population are low.

systems biology↗

bioRxiv2020

Worldwide tracing of mutations and the evolutionary dynamics of SARS-CoV-2

Understanding the mutational and evolutionary dynamics of SARS-CoV-2 is essential for treating COVID-19 and the development of a vaccine. Here, we analyzed publicly available 15,818 assembled SARS-CoV-2 genome sequences, along with 2,350 raw sequence datasets sampled worldwide. We investigated the distribution of inter-host single nucleotide polymorphisms (inter-host SNPs) and intra-host single nucleotide variations (iSNVs). Mutations have been observed at 35.6% (10,649/29,903) of the bases in the genome. The substitution rate in some protein coding regions is higher than the average in SARS-CoV-2 viruses, and the high substitution rate in some regions might be driven to escape immune recognition by diversifying selection. Both recurrent mutations and human-to-human transmission are mechanisms that generate fitness advantageous mutations. Furthermore, the frequency of three mutations (S protein, F400L; ORF3a protein, T164I; and ORF1a protein, Q6383H) has gradual increased over time on lineages, which provides new clues for the early detection of fitness advantageous mutations. Our study provides theoretical support for vaccine development and the optimization of treatment for COVID-19. We call researchers to submit raw sequence data to public databases.

microbiology↗