February 2025
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11 Reads
Cell Communication and Signaling
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February 2025
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11 Reads
Cell Communication and Signaling
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.
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.
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.
February 2023
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35 Reads
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3 Citations
Biophysical Journal
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.
... 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 . ...
January 2025
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). ...
January 2024
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]. ...
May 2022
Proceedings of the National Academy of Sciences