Rong Huang’s research while affiliated with Xi'an Jiaotong University and other places
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Neurotransmitters and neuromodulators can be released via either action potential (AP)–evoked transient or AP-independent continuous neurotransmission. The elevated AP-evoked neurotransmission in the primary sensory neurons plays crucial roles in hyperalgesia. However, whether and how the AP-independent continuous neurotransmission contributes to hyperalgesia remains largely unknown. Here, we show that primary sensory dorsal root ganglion (DRG) neurons exhibit frequent spontaneous microdomain Ca ²⁺ (smCa) activities independent of APs across the cell bodies and axons, which are mediated by the spontaneous opening of TRPA1 channels and trigger continuous neurotransmission via the cyclic adenosine monophosphate-protein kinase A signaling pathway. More importantly, the frequency of smCa activity and its triggered continuous neurotransmission in DRG neurons increased dramatically in mice experiencing inflammatory pain, inhibition of which alleviates hyperalgesia. Collectively, this work revealed the AP-independent continuous neurotransmission triggered by smCa activities in DRG neurons, which may serve as a unique mechanism underlying the nociceptive sensitization in hyperalgesia and offer a potential target for the treatment of chronic pain.
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.
Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage‐sensing site at D131 and can be deactivated in a frequency‐dependent manner by membrane depolarization. This voltage‐dependent D2R inhibition of DA release is mediated via the facilitation of voltage‐gated Ca²⁺ channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage‐sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA‐dependent functions in vivo.
Synaptic transmission plays an important and time-sensitive role in the nervous system. Although the amplitude of neurotransmission is positively related to the intensity of external stimulus, whether stronger stimulus could trigger synaptic transmission faster remains unsolved. Our present work in the primary sensory system shows that besides the known effect of larger amplitude, stronger stimulus triggers the synaptic transmission faster, which is regulated by the earlier started action potential (AP), independent of the AP’s amplitude. More importantly, this model is further extended from the sensory system to the hippocampus, implying broad applicability in the nervous system. Together, we found that stronger stimulus induces AP faster, which suggests to trigger the neurotransmission faster, implying that the occurrence time of neurotransmission, as well as the amplitude, plays an important role in the timely and effective response of nervous system.
Background:
Adverse eating behaviors and a high rate of obesity have been identified among children diagnosed with attention deficit hyperactivity disorder (ADHD). In this study, we investigate the relationships between eating behaviors and body fat mass among children with ADHD.
Methods:
All participants were recruited from the Children's Health Care Department of the Children's Hospital of Nanjing Medical University from June 2019 to June 2020. ADHD was diagnosed according to the diagnostic criteria of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by psychiatrists. Core ADHD symptoms defined by the DSM-5 were inattention and hyperactivity/impulsivity. The anthropomorphic indices defined by the World Health Organization (WHO) were utilized in this study (body mass index [BMI], underweight, normal body mass, overweight, obesity, short stature). Body fat mass, fat mass percentage (FM%), skeletal muscle mass, skeletal muscle mass percentage (SMM%) were tested via body composition meter, and eating behaviors were assessed by parents using the Chinese version of the Children's Eating Behavior Questionnaire (CEBQ). The CEBQ was comprised of subscales related to food avoidant behaviors (satiety responsiveness, slowness in eating, fussiness, and emotional undereating) and food approach behaviors (food responsiveness, enjoyment of Food, desire to drink, and emotional overeating). The associations among ADHD, obesity and adverse eating behavior were tested through correlation analysis, and a mediating effect model was established to explore the effect of eating behaviors.
Results:
A total of 548 participants aged 4-12 years were recruited. Among them, 396 were diagnosed with ADHD, with the remaining 152 enrolled in a control group. Compared with the control group, the ADHD group had higher incidences of overweight (22.5% vs. 14.5%) and obesity (13.4% vs. 8.6%) (p < 0.05). The ADHD group was more likely to display "slowness in eating" (11.01 ± 3.32 vs. 9.74 ± 2.95), "fussiness" (15.61 ± 3.54 vs. 15.03 ± 2.84), "food responsiveness" (11.96 ± 4.81 vs. 9.88 ± 3.71) and "desire to drink" (8.34 ± 3.46 vs. 6.58 ± 2.72) (p < 0.05). Moreover, The FM% of children with ADHD was positively correlated with inattention (β = 0.336, 95% CI: 0.001 to 0.673) and "food responsiveness" (β = 0.509, 95% CI: 0.352 to 0.665) in the multiple linear regression model. The mediation effect model showed that "food responsiveness" accounted for a significant portion (64.2%) of the mediating effect.
Conclusion:
Children with ADHD had higher prevalence of overweight and obesity. As an important risk factor, food responsiveness may connect core symptoms of ADHD with obesity.
... For the past and present decades, China has witnessed the rapid blossoming of narrative medicine since it was formally introduced to Chinese medical professionals in 2011 [5]. With the recognition of Chinese narrative medicine, there is an increasing consensus that narrative medicine needs to be introduced to medical students in as many classes and as early as possible [6]. This trend has found resonance in the teaching of College English, a foundational course in undergraduate medical education. ...
... In addition, we also J u s t A c c e p t e d revealed the regulating mechanism of vesicle exocytosis coupled endocytosis in DRG neurons (Chen et al, 2022;Wang et al, 2016). Collectively, we have abundant experiences in DRG neuron isolation, culture, and the corresponding patch-clamp recording (Huang et al, 2019;Zhang & Huang, 2024). Building upon the strategies outlined in published works and our group's abundant research experiences on DRG neurons' functions by patch-clamp, we have summarized and put forward a comprehensive step-by-step protocol with a combination of DRG neuron isolation and culture, and patch-clamp recording, which is much improved when compared with previous reports. ...
... Studies focusing on medication-naïve children with ADHD support this relationship, although reported rates of obesity (13-23%) and overweight (20.8-22.5%) vary across studies [31,32]. Our findings align with this trend, revealing obesity and overweight rates of 13.8% in the DNG-the highest among all groups studied. ...
... However, our findings suggest that the number of monocytes in the osteoporosis group was lower than that in the other two groups, which contradicts the findings of previous studies. 32,33 To explain this inconsistency, we propose multiple contributing factors. First, our recruited patients were characterized by an advanced mean age, which is known to be associated with diminished monocyte functionality due to ageing effects. ...
... Adiponectin also exhibits anti-osteoporotic activity, promoting differentiation and mineralization of osteoblasts and inhibiting the secretion of OPG [100]. Adiponectin stimulates the expression of osteocalcin, which acts as a hormone regulating glucose metabolism and fat mass [72,73,87,[101][102][103][104][105][106]. The potential effect of adiponectin on osteoblasts and osteoclasts, and therefore on bone remodeling, may be mediated through the endocrine system and may influence lipid metabolism. ...
... Briefly, external stimuli induce the APs to activate the voltage gated calcium channels [3,4] for Ca 2+ influx, which indirectly triggers presynaptic vesicles fusion with the plasma membrane [5][6][7] to release the neurotransmitters [8][9][10]. Apart from the above Ca 2+ dependent secretion, in some types of neurons like the sensory neurons and sympathetic neurons, the APs can directly trigger vesicular secretion, independent of Ca 2+ [11][12][13]. In other words, the APs are the upstream trigger of neurotransmission. ...
... 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]. ...
... When stenosis is severe, it can cause intermittent claudication, resting pain, and even foot ulcers and gangrene, which not only seriously affect the patient's quality of life but may also lead to amputation or even death [39]. Serum LGMN was significantly higher in PAD patients than in non-PAD patients, and high serum LGMN was independently associated with an increased risk of PAD [40]. These findings suggest LGMN could be a blood biomarker and predictor of PAD. ...
... [2][3][4] LH is characterized by pathological alterations such as hypertrophy, degeneration, fibrosis, and reduced vascularity in the subcutaneous fat cells at insulin injection sites in individuals with diabetes. 5 These pathological changes can lead to decreased insulin efficacy, thereby causing unexpected episodes of hypoglycemia and postprandial hyperglycemia. 6 Earlier screening methods for LH have primarily relied on visual and tactile clinical examinations. ...
... This novel mechanism has been coined "Ca 2+ -voltage hypothesis" of neurotransmitter release, by its authors [65]. Another type of regulation of neurotransmitter release by voltage sensitive GPCRs has been detected for P2YRs, whose voltage dependence (activation by depolarization) facilitated catecholamine release in sympathetic chromaffin cells [66]. Thus, voltage dependence fine-tunes the affinity of the presynaptic feedback receptors during neurotransmitter release. ...
![Modulation of dopamine release by GPCR‐D2R autoreceptor is dependent on the frequency of action potentials in mouse striatum in vivo. A) Diagram of the experimental setup (left) of real‐time recording of action potential (AP)‐induced DA overflow [DA] (right) in a mouse striatum in vivo (see the Experimental Section). Right, a typical amperometric recording (Iamp) of [DA] following 36 E‐stim pulses at 80 Hz at the MFB. The amplitude and charge are defined to quantify the [DA]. B) DA transmission model in a striatal terminal. DA release is evoked by Ca²⁺ influx through voltage‐gated Ca²⁺ channels (VGCCs) opened by the APs. The released DA in turn targets the presynaptic D2R auto‐receptor to regulate DA release. C,D) Pharmacology in WT‐mice, with the low (C, [20 Hz, 36 P]) or high (D, [80 Hz, 36 P]) frequency AP‐pattern stimuli at the MFB by the D2R‐antagonist haloperidol (HP, 0.4 mg kg⁻¹, i.p.) and subsequent D2R‐agonist quinpirole (QP, 8 mg kg⁻¹, i.p.) [One‐way ANOVA, post hoc Tukey's multiple comparisons test; (C) and (D) were from the same nine mice]. E,F) Typical traces and statistics of E‐stim (20 Hz vs 80 Hz)‐evoked DA release in WT or D2R‐KO mice pre‐ and post‐HP treatment [paired Student's t‐test for (E) and (F), n = 9 for each group]. G) Statistics of DA release in WT and D2R‐KO mice show significant difference at Estim 20 Hz but not 80 Hz (Welch's t‐test, n = 9 for each group). H) AP frequency‐dependence of [DA] ratio (HP/Ctrl) in WT versus D2R‐KO mice at different frequencies. Increasing AP frequency from 20 to 100 Hz gradually reduces HP/Ctrl in WT mice (black line), but not in D2R‐KO mice (gray line), indicating that (1) the effect of HP on [DA] is via D2R; (2) the D2R modulation of [DA] depends on AP frequency in vivo (two‐way ANOVA test; n = 9 for each group). Data are presented as the mean ± SEM. **p < 0.01, ***p < 0.001; p > 0.05, n.s., not significant.](https://www.researchgate.net/publication/387483320/figure/fig1/AS:11431281300249236@1735372263135/Modulation-of-dopamine-release-by-GPCR-D2R-autoreceptor-is-dependent-on-the-frequency-of_Q320.jpg)
![The modulation of AP‐evoked DA release and ICa are frequency‐dependent in WT but not D2R‐KO striatal slices. A) Diagram of real‐time DA recording in striatal slice. Coronary slices (300‐µm thick) were cut from the caudate putamen (CPu) or striatum region of the mouse brain and are bathed in 1 × 10⁻⁶ m DHβE to block the CTDT pathway (for details see Figure S9, Supporting Information). A stimulating electrode is used to generate different AP patterns and trigger DA release. The evoked DA signals are recorded by the CFE (200‐µm long). Drugs are delivered to the slices via a puffing system. B,C) In WT mice, representative traces of evoked DA release before and after D2R agonist QP (0.5 × 10⁻⁶ m) treatment with E‐stim patterns of 6 pulses at 2 Hz versus 6 pulses at 100 Hz. The enlarged insets show details of DA signals by 6 pulses (P1–P6) of E‐stim. D,E) Same as (B) and (C) but in D2R‐KO mice. F,G) Typical traces of QP inhibition on ICa with or without a prepulse depolarization effect in WT and D2R‐KO DA neurons. H) Statistics of (B) and (C) showing the effect of QP on total DA release (sum of IP1 + IP2 +…+ IP6) at two E‐stim frequencies: [2 Hz 6 P] versus [100 Hz 6 P] (paired Student's t‐test, ***p < 0.001, n = 11 slices from 5 mice). I) Statistics showing that a prepulse depolarization (100 mV, 100 ms) mostly removed the blockade effect of QP on ICa in WT DA neurons (QP inhibition on ICa ratio, P−: 25.54% ± 2.70% vs P+: 11.36% ± 1.18%, paired Student's t‐test, p < 0.001, n = 14 cells). J) Statistics of (D) and (E). QP does not alter DA release at both AP frequencies, indicating that the AP frequency‐dependence of the D2R modulation of DA release is abolished in D2R‐KO slices (paired Student's t‐test, p = 0.31, n.s., not significant, n = 10 slices from 4 mice). K) Statistics showed no effect of prepulse depolarization on ICa in D2R‐KO DA neurons (QP inhibition on ICa ratio, P−: 1.64% ± 1.28% vs P+: 1.78% ± 1.16%, paired Student's t‐test, p = 0.9120, n = 14 cells). Data are presented as the mean ± SEM. ***p < 0.001; p > 0.05, n.s., not significant.](https://www.researchgate.net/publication/387483320/figure/fig2/AS:11431281300249237@1735372263349/The-modulation-of-AP-evoked-DA-release-and-ICa-are-frequency-dependent-in-WT-but-not_Q320.jpg)
![The voltage dependence of D2R is validated in native secretary adrenal chromaffin cells (ACCs) overexpressing D2R. A) Diagram of combined patch‐clamp and CFE recordings in an ACC over‐expressing D2R. ACCs were bathed in 2 × 10⁻⁶ m QP and 0 Ca²⁺ extracellular solution, and whole‐cell dialysis with 1 × 10⁻³ m intracellular Ca²⁺ in the patch pipette was used to trigger quantal release, which can be real‐time recorded by a CFE as Iamp current. Simultaneously, through the whole‐cell patch‐clamp, two AP frequencies (1 Hz vs 20 Hz) stimulus were used to depolarize the ACCs during quantal vesicular release. Dashed boxes show a single AP waveform (left) and an averaged quantal spike signal (right), respectively. B) A representative amperometric recording of vesicle quantal release (Iamp, lower trace) evoked by the stimulation protocol shown in panel A in ACCs transfected with GFP control plasmid (ACC‐Ctrl). Insets show the averaged quantal size (QS) corresponding to three periods of stimulation at [1 Hz 30 s] (gray) versus [20 Hz 30 s] (blue). C) Same as (B) but in ACCs transfected with D2R plasmid (ACC‐D2R). D) Statistics of normalized QS. For ACC‐Ctrl, statistics show that QS does not change significantly during 1 Hz versus 20 Hz stimulation. For ACC‐D2R, statistics show that high frequency (20 Hz) significantly increases QS compared to low frequency (1 Hz) (one‐way ANOVA test, post hoc Tukey's multiple comparisons test, p > 0.05, n.s.; **p < 0.01, n = 16 cells for ACC‐Ctrl and n = 12 cells for ACC‐D2R). e) Statistics of the quantal release amplitude during 1 Hz versus 20 Hz stimulation in ACCs transfected with control (ACC‐Ctrl) or D2R‐expressing (ACC‐D2R) plasmid. (One‐way ANOVA, post hoc Tukey's multiple comparisons test, p > 0.05, n.s., not significant, n = 16 cells for ACC‐Ctrl and n = 12 cells for ACC‐D2R). Data are presented as the mean ± SEM. **p < 0.01, ***p < 0.001; p > 0.05, n.s., not significant.](https://www.researchgate.net/publication/387483320/figure/fig3/AS:11431281300227885@1735372263555/The-voltage-dependence-of-D2R-is-validated-in-native-secretary-adrenal-chromaffin-cells_Q320.jpg)
![A D2R voltage‐sensing site (D131) as revealed with a reconstituted GIRK system overexpressing D2R. A) Left, cartoon illustration of the D2R‐Gi‐βγ‐GIRK current assay. GIRK1/4 and D2R plasmids are co‐expressed in HEK293A cells, and the D2R agonist QP activates the D2R‐Gi pathway to induce GIRK current (IGIRK) in 140 × 10⁻³ m KCl (140K) solution. Right, Whole‐cell recording of IGIRK following 10 and 500 × 10⁻⁹ m QP treatment (ΔI10 and ΔI500 are IGIRK induced by 10 and 500 × 10⁻⁹ m QP). Note, IGIRK is larger at 500 × 10⁻⁹ m that at 10 × 10⁻⁹ m QP. B) Left, IGIRK evoked by 10 or 500 × 10⁻⁹ m QP measured at a holding Vm of −40 or −100 mV in cells co‐expressing D2R‐WT and GIRK1/4. The IGIRK ratio is defined as γ(Vm) = ΔI10/ΔI500 = IGIRK (10 × 10⁻⁹ m)/IGIRK (500 × 10⁻⁹ m). Right, statistics of γ(Vm) at the two holding potentials. γ(Vm) is potentiated at −100 mV versus −40 mV (***p < 0.001, Wilcoxon test, n = 62 cells). C) Similar to panel (B), but here in cells with D2R‐D131N mutation and GIRK1/4 co‐expression. The γ(Vm) shows no significant difference at Vm of −40 and −100 mV (p = 0.19, n.s., not significant, Wilcoxon test, n = 43 cells). D) Log [QP] − normalized IGIRK curves for D2R‐WT (left) and D131N (right) at holding potentials of −40 and −100 mV; the EC50 of QP for WT and D131N are calculated by fitting from log [agonist] versus normalized IGIRK (normalized to IGIRK evoked by 1000 × 10⁻⁹ m QP) responses. The dose‐dependent curve of the WT at −40 mV is significantly right shifted than at −100 mV (n = 17 cells) but not D131N (n = 26 cells), indicating that D2R‐WT is Vm‐dependent, while D131N mutation abolishes the initial Vm‐dependence. Inset, cartoon showing the D2R topology and positions of those transmembrane, charged and conserved amino acids in D2R, including D80, D114, and DRY motif‐D131and R132. D131 is identified as the voltage‐sensor in D2R by the reconstituted GIRK system via screening. Data are presented as the mean ± SEM (B, C). ***p < 0.001; p > 0.05, n.s., not significant.](https://www.researchgate.net/publication/387483320/figure/fig4/AS:11431281300249238@1735372263735/A-D2R-voltage-sensing-site-D131-as-revealed-with-a-reconstituted-GIRK-system_Q320.jpg)
![Fig. 1 Stronger single pulse stimulus triggers the PSC signal faster in sensory system. A Model showing electrical field stimulus and patch clamp recording in sensory DRG-DH coculture system. B Image showing presynaptic DRG neurons and postsynaptic DH neuron with the patched glass electrode. Scale bar, 10 μm. C Definition showing the onset point and the amplitude of the PSC signal. To simplify the analysis, we analyzed and compared the delay time as the delta time from the onset of stimulus artifact to the peak of the PSC signal and then minus the duration of applied stimulus impulse. D Typical traces showing the onset point move according to the intensity of local stimulus [keep stimulus duration constant (100 μs), only change the amplitude (~10 V or 50 V)]. First weak stimulus (black), then strong stimulus (blue), last recover to weak stimulus (red). E Typical traces showing the onset point move according to the intensity of local stimulus [keep stimulus amplitude constant (~35 V), only change the duration]. First short-duration stimulus (50 μs, black), then intermediate-duration stimulus (100 μs, red), last long-duration stimulus (200 μs, blue). F Quantification of (E). 10 cells for 50 μs, 100 μs and 200 μs stimulation, respectively. All recordings in each panel were performed in the same one cell and aligned based on the onset of the stimulus. The time interval between different stimulus is at least one min. Data are shown as mean + s.e.m; paired Student's t test for panel F; *p < 0.05; **p < 0.01; ***p < 0.001](https://www.researchgate.net/publication/377371560/figure/fig1/AS:11431281217380455@1705205321933/Stronger-single-pulse-stimulus-triggers-the-PSC-signal-faster-in-sensory-system-A-Model_Q320.jpg)
![Fig. 2 Stronger single pulse stimulus triggers the AP signal faster in sensory system. A Definition showing the delay time and the amplitude of the AP signal. We analyzed the delay time as the delta time from the onset of stimulus artifact to the peak of the AP and then minus the duration of applied stimulus pulse.B Typical traces showing the delay time move according to the intensity of local stimulus [keep stimulus amplitude constant (~35 V), change the duration]. First short-duration stimulus (50 μs, black), then intermediate-duration stimulus (100 μs, red), last long-duration stimulus (200 μs, blue). All recordings were performed in the same one cell and aligned based on the onset of the stimulus. The time interval between different stimulus is at least one min. C Quantification of (B). 9 cells for 50 μs, 100 μs and 200 μs, respectively. Data are shown as mean + s.e.m; paired Student's t test for panel C; *p < 0.05; **p < 0.01; ns, not significant](https://www.researchgate.net/publication/377371560/figure/fig2/AS:11431281217391241@1705205322146/Stronger-single-pulse-stimulus-triggers-the-AP-signal-faster-in-sensory-system-A_Q320.jpg)
![Fig. 3 Stronger single pulse stimulus triggers the PSC and AP signal faster in hippocampal system. A Image showing patch clamp recording in cultured hippocampus neurons. Scale bar, 10 μm. B Typical traces showing the delay time of PSCs change according to the intensity of local stimulus [keep stimulus amplitude constant (~35 V), change the duration]. First short-duration stimulus (50 μs, black), then long-duration stimulus (100 μs, red). C Quantification of (B). 16 cells for 50 μs and 100 μs, respectively. D Typical traces showing the delay time of APs change according to the intensity of local stimulus [keep stimulus amplitude constant (~35 V), change the duration]. First short-duration stimulus (50 μs, black), then long-duration stimulus (100 μs, red). E Quantification of (D). 14 cells for 50 μs and 100 μs, respectively. All recordings in each panel were performed in the same one cell and aligned based on the onset of the stimulus. The time interval between different stimulus is at least one min. Data are shown as mean + s.e.m; paired Student's t test for panel C and E; **p < 0.01; ns, not significant](https://www.researchgate.net/publication/377371560/figure/fig3/AS:11431281217436785@1705205322297/Stronger-single-pulse-stimulus-triggers-the-PSC-and-AP-signal-faster-in-hippocampal_Q320.jpg)
