Yuhao Gu’s research while affiliated with Xi'an Jiaotong University and other places

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Publications (6)


Fig. 1 Absence of PD-like motor phenotype and DA release alterations in systemic parkin knockout mice. A Schematic representation of the rotarod test for the assessment of motor coordination of wild-type (WT) and parkin knockout (KO) mice. B Statistics of duration time of WT and parkin KO mice in the rotarod test. C Diagram illustrating the cylinder test for locomotor asymmetry evaluation in mice. D Statistics of rearing times of WT and parkin KO mice in the cylinder test. E Diagram illustrating the carbon fiber electrode (CFE) amperometric recording of DA release upon local electrical stimulation (Estim) in striatal slices. Scale bar, 50 μm. F Representative amperometric currents (I amp ) of DA release in striatal slices from control and parkin KO mice, with key parameters including amplitude, charge, half-height duration (HHD), and decay time (τ decay ) are defined and indicated in control trace. G-J Statistics showing no alterations in the amplitude (G), charge (H), HHD (I), and decay time (τ decay , J) of DA release in striatal slices of WT and parkin KO mice. Data are presented as box and whisker plots with medians (central line within the box), interquartile ranges (25th to 75th percentiles, forming the box), and minimum-maximum ranges (whiskers). Mann-Whitney test, n.s. non-significant, P > 0.05
Fig. 2 Parkin knockdown in the SNpc induces impaired DA release and motor abnormalities. A Schematic illustration of unilateral lentivirus injection in the SNpc. B Representative micrograph of TH-staining in an SNpc-containing slice showing the infection of DA neurons (white arrowheads) by shParkin (KD, GFP)-carrying lentivirus. Scale bars, 500 μm (upper panel) and 100 μm (lower panels). C Representative amperometric currents (I amp ) of DA release in striatal slices from control and parkin KD mice. D-G Statistics showing the amplitude, charge, HHD, and decay time (τ decay ) of DA release from parkin KD striatal slices and the contralateral side within the same parkin KD mice. H, I Methamphetamine (METH)-induced progressive asymmetric rotation (within 90 min) in mice with unilateral parkin KD in the SNpc, compared with the control group. J-L Footprint analysis showing defects in the contralateral motor stability of mice with unilateral parkin KD. The dashed red lines in J represent the 5th and 95th percentiles of stride length. Contra, contralateral; Ipsi, ipsilateral. Data are presented as box and whisker plots illustrating medians, interquartile ranges (25th to 75th percentiles), and the minimum-maximum ranges. Mann-Whitney test for D-G, K, L; repeated measures of one-way ANOVA for H, I. ** P < 0.01, *** P < 0.001
Fig. 3 Synaptotagmin-11 (Syt11) expression in parkin KO and parkin KD mice. A Representative Western blots and statistics showing increased Syt11 expression in the SNpc of parkin KO mice at postnatal day 4 (P4). B Representative Western blots and statistics showing unchanged Syt11 expression in the SNpc of adult parkin KO mice. C Schematic diagram depicting the unilateral injection of shParkin virus and the subsequent tissue sampling of the bilateral SNpc in parkin KD mice. D Representative Western blots and statistics indicating decreased parkin expression and increased Syt11 expression in the ipsilateral SNpc from mice with unilateral parkin KD one-month post-virus injection. E Schematic diagram of unilateral injection of control virus and tissue sampling from the bilateral SNpc in control virus-injected mice. F Representative Western blots and statistics showing unchanged expression of parkin and Syt11 in the ipsilateral SNpc compared with the contralateral side in control virus-injected mice one-month post-virus injection. Contra, contralateral; Ipsi, ipsilateral. Data are presented as box and whisker plots displaying medians, interquartile ranges (25th to 75th percentiles), and the minimum-maximum ranges. Mann-Whitney test, * P < 0.05, *** P < 0.001
Compensatory synaptotagmin-11 expression conceals parkinson’s disease-like phenotypes in parkin knockout mice
  • Article
  • Full-text available

February 2025

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11 Reads

Cell Communication and Signaling

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Zhenli Xie

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Anqi Wei

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[...]

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Sexually dimorphic dopaminergic circuits determine sex preference

January 2025

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169 Reads

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2 Citations

Science

Sociosexual preference is critical for reproduction and survival. However, neural mechanisms encoding social decisions on sex preference remain unclear. In this study, we show that both male and female mice exhibit female preference but shift to male preference when facing survival threats; their preference is mediated by the dimorphic changes in the excitability of ventral tegmental area dopaminergic (VTA DA ) neurons. In males, VTA DA projections to the nucleus accumbens (NAc) mediate female preference, and those to the medial preoptic area mediate male preference. In females, firing-pattern (phasic-like versus tonic-like) alteration of the VTA DA -NAc projection determines sociosexual preferences. These findings define VTA DA neurons as a key node for social decision-making and reveal the sexually dimorphic DA circuit mechanisms underlying sociosexual preference.


Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission

December 2024

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81 Reads

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1 Citation

Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and dopamine over-transmission as a mechanism in the development of schizophrenia. Syt11 expression is reduced in individuals with schizophrenia but restored following the treatment with antipsychotics. Syt11 deficiency in dopamine neurons in early adolescence, but not in adults, leads to persistent social deficits and other schizophrenia-like behaviors by mediating dopamine over-transmission in mice. Accordingly, dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits, along with the structural and functional alternations in the mPFC. Notably, local intervention of D2R with clinical drugs presynaptically or postsynaptically exhibits both acute and long-lasting therapeutic effects on social deficits in schizophrenia mice models. These findings not only define Syt11 as a risk factor and DA over-transmission as a potential risk factor initiating schizophrenia, but also propose two D2R-targeting strategies for the comprehensive and long-term recovery of schizophrenia-associated social withdrawal.


An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences

January 2024

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430 Reads

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33 Citations

Nature Neuroscience

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu–VTAGABA–VTADA–ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.



Synaptotagmin-1 is a bidirectional Ca 2+ sensor for neuronal endocytosis

May 2022

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167 Reads

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17 Citations

Proceedings of the National Academy of Sciences

Significance Precise and efficient coupling of endocytosis to exocytosis is critical for neurotransmission. The activity-dependent facilitation of endocytosis has been well established for efficient membrane retrieval; however, whether neural activity clamps endocytosis to avoid excessive membrane retrieval remains debatable with the mechanisms largely unknown. The present work provides compelling evidence that synaptotagmin-1 (Syt1) functions as a primary bidirectional Ca ²⁺ sensor to promote slow, small-sized clathrin-mediated endocytosis but inhibit the fast, large-sized bulk endocytosis during elevated neural activity, the disruption of which leads to inefficient vesicle recycling under mild stimulation but excessive membrane retrieval following sustained neurotransmission. Thus, Syt1 serves as a fine-tuning Ca ²⁺ sensor to ensure both efficient and precise coupling of endocytosis to exocytosis in response to different neural activities.

Citations (3)


... Amperometric CFE recordings in dorsal striatal slices were conducted as previously described [28,35,40]. Parkin KO, parkin KD and Syt11 OE mice were anesthetized with avertin (i.p.) and perfused with approximately 50 mL of ice-cold artificial cerebrospinal fluid (sectioning aCSF) containing (in mM): 110 C 5 H 14 NClO, 2.5 KCl, 0.5 CaCl 2 , 7.0 MgCl 2 , 1.3 NaH 2 PO 4 , 25 NaCO 3 , 10 glucose, saturated with 95% O 2 and 5% CO 2 . ...

Reference:

Compensatory synaptotagmin-11 expression conceals parkinson’s disease-like phenotypes in parkin knockout mice
Sexually dimorphic dopaminergic circuits determine sex preference

Science

... Given that the impairment of DA release is a pathological hallmark of PD, we next performed electrochemical carbon fiber electrode (CFE) amperometric recordings [28][29][30] to monitor DA release in the striatum with a patch clamp-class super-high spatiotemporal resolution and sensitivity (Fig. 1E). Upon the application of a local electric stimulus (E-stim) to the striatal slice, a transient increase in amperometric current (I amp , with an amplitude of ~ 350 pA) occurred, followed by a decay back to the baseline, representing the release and subsequent reuptake of DA (Fig. 1F). ...

An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences

Nature Neuroscience

... Ca 2+ is a major player of all stages of the SV cycle, including endocytosis [45]. Certain Ca 2+ -binding proteins (calmodulin, protein kinase C, calcineurin, and synaptotagmin) can serve as bidirectional regulators of SV endocytosis [10,12,38]. There are also Ca 2+ -independent exo-endocytosis coupling and control of endocytosis [70,74]. ...

Synaptotagmin-1 is a bidirectional Ca 2+ sensor for neuronal endocytosis

Proceedings of the National Academy of Sciences