Biology subjects

Gao, X.-B.

Publications and source records attributed to Gao, X.-B..

4 recordsLinked to original sources

bioRxiv2025

Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep

Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark cycle. Here, we show that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide (VIP)-expressing neurons show circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons cause disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons leading to desynchronization of entrainment to the light/dark cycle in Mfn2 deficient mice that resulted in advanced phase angle of their locomotor activity onset, alterations in core body temperature and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.

neuroscience↗

bioRxiv2021

LINE-1 activation in the cerebellum drives ataxia

Previous studies have revealed that dysregulation of long interspersed nuclear element 1 (LINE-1), a dominant class of transposable elements in the human genome, correlates with neurodegeneration1-3. Yet whether LINE-1 dysregulation is causal to disease pathogenesis has not been proven directly. Here, we demonstrate that expression of evolutionarily younger LINE-1 families is elevated in the cerebella of ataxia telangiectasia (AT) patients, which was correlated with extensive downregulation of epigenetic silencers. To examine whether LINE-1 activation causes neurologic disease, we established an approach to directly target and activate the promoter of a young family of LINE-1 in mice. LINE-1 activation in the cerebellum was sufficient to lead to robust progressive ataxia. Purkinje cells in the diseased mice exhibited marked electrophysiological dysfunctions and degeneration with a significant accumulation of cytoplasmic ribonucleoprotein LINE-1Orf1p aggregates, endoplasmic reticulum (ER) stress, and DNA damage. Treatment with lamivudine, a nucleoside reverse transcriptase inhibitor, blunted the disease progression by reducing DNA damage, attenuating gliosis and interferon gene signature, and recovering the loss of key functional molecules for calcium homeostasis in Purkinje cells. This study provides direct evidence that young LINE-1 activation drives ataxia phenotype, and points to its pleiotropic effects leading to DNA damage, inflammation, and dysfunction and degeneration of neurons.

neuroscience↗

bioRxiv2020

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain. However, the underlying mechanism of such process is ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglial phagocytosis. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and uncoupling protein 2 (Ucp2) expression, which is a regulator of mitochondrial ROS generation. Conditional ablation of microglial Ucp2 hindered phasic elimination of spine synapses, increased accumulations of ROS and lysosome-lipid droplet complexes leading to hippocampal circuitry disruption assessed by electrophysiology, and, altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in control of brain functions.

neuroscience↗

bioRxiv2020

Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances learning of cue-reward contingency

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and principal neuron activity in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and activity of nucleus basalis of Meynert (NBM) cholinergic terminals in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the tone-reward contingency. BLA principal neuron activity followed reward retrieval and moved to the reward-predictive tone after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers during cue-reward learning led to more rapid learning of the cue-reward contingency. These results indicate that BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.

neuroscience↗