Personal Profile

Li Boxing, Professor and Doctoral Supervisor, recipient of the National Outstanding Youth Science Fund and the National Excellent Youth Science Fund. Selected for the Young Talent Program of the National "High-level Talent Introduction Plan"; a leading talent in scientific and technological innovation under the "Pearl River Talent Plan", Outstanding Young Scientist in Guangdong Province, and a talent introduced under the "Hundred Talents Program" of Sun Yat-sen University. Executive Director and Secretary-General of the Academic Committee of the Chinese Neuroscience Society.

Dr. Li Boxing graduated with a Bachelor's degree in Clinical Medicine from the former First Military Medical University. Later, he obtained his Master's and Doctoral degrees in Neurobiology under the guidance of Academician Gao Tianming, a renowned neurobiologist in China. From 2012 to 2017, he completed postdoctoral training at New York University in the United States, with Academician Richard Tsien (Qian Yongchao), an internationally renowned neuroscientist, as his co-supervisor.

Professor Li Boxing's research group is dedicated to revealing the encoding mechanisms of higher-order neural functions such as cognition and emotion, and exploring the molecular mechanisms of neuro/psychiatric diseases such as autism. Research directions include: 1) The role of ion channels and downstream signaling pathways in cognitive functions; 2) The neural mechanisms of autism and cognitive dysfunction; 3) Development of new technologies in neuroscience. Research findings have been published as corresponding or first author in journals such as Cell, Science, Neuron, Nature Neuroscience, and Current Biology.

Our laboratory is recruiting full-time research staff (distinguished research fellows/senior research fellows, postdoctoral fellows), doctoral and master's students. For details, please visit /article/8090

Academic Achievements

Important Academic Research Achievements and Contributions

1. Discovery of the Neural Mechanism Underlying Gender Differences in Empathic Behavior

To adapt to group living, individuals need to promptly recognize the emotional states of others and respond appropriately. The ability to feel, recognize, understand, and imagine the emotional states of others and generate appropriate behaviors is known as empathy. When witnessing a companion experiencing pain, an individual may experience emotional changes such as anxiety, unease, and fear due to affective empathy, and may also exhibit prosocial behaviors such as comforting and rescuing due to cognitive empathy. For individuals, empathy helps to acquire environmental information, develop social relationships, better integrate into groups, and improve survival rates. For groups, empathy promotes altruistic behaviors, enhances cohesion, develops morality, and maintains the survival and reproduction of the species. Conversely, abnormal empathy can not only lead to extreme egoism but also result in extreme antisocial behaviors. In addition, abnormal empathy is also a common feature of various neuro/psychiatric diseases such as autism, depression, and schizophrenia.

We found that there are gender differences in empathic behavior. When facing a painful companion, female mice exhibit social approach behaviors (social preference) similar to comforting the other party, while male mice show self-grooming behaviors (self-grooming) similar to anxiety and self-comfort. We further analyzed the sensory modalities, neural circuits, and potential molecular mechanisms mediating empathic behavior. When witnessing a companion experiencing pain, the body fluid odor of the companion activates different neural circuits in male and female mice. In female mice, the piriform cortex → prefrontal cortex circuit mediates empathic social approach behaviors; in male mice, the piriform cortex → medial amygdala circuit mediates empathic self-grooming behaviors. The difference in the activation levels of the two circuits is due to gender differences in their gene expression patterns.

This work was published in Neuron (Fang, et al. Neuron 2024, 112(9):1498-1517).

For a detailed introduction, please visit https://mp.weixin.qq.com/s/tzCuEsf61LwC9N-Wz28S4w

2. Discovery of the Neural Circuit Mediating the Aversive Emotion Induced by Itching

Itching caused by mosquito bites, allergies, and chronic diseases can lead to aversive emotions, severely affecting the quality of life. However, the neural mechanism underlying the aversive emotion induced by itching remains unclear. We found that the anterior insular cortex (AIC) can be activated by pruritogens, and the activation of AIC mediates the aversive emotion induced by itching. At the neural circuit level, we discovered that the neural circuit from excitatory neurons in the AIC (AICExt) projecting to GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNSTGABA) (the AICExt → dBNSTGABA circuit) mediates itching and the resulting aversive emotion. Activating this circuit exacerbates itching and aversive emotions, while inhibiting it alleviates them.

This work was published in Current Biology (Zheng, et al. Current Biology 2024, 8;34(7):1453-1468).

3. Discovery of the Molecular Mechanism of Neuronal Intrinsic Excitability Homeostatic Plasticity

Neuronal homeostatic plasticity refers to the phenomenon where cells compensateively induce synaptic transmission or excitability to adjust in the opposite direction of the original change when synaptic transmission or excitability changes continuously, thereby maintaining synaptic transmission or excitability at a relatively stable level to ensure normal information transmission in neurons and neural circuits. Neuronal homeostatic plasticity is involved in regulating various important physiological functions. For example, during the wake-sleep cycle, continuous changes in neuronal firing can regulate the structure and function of synapses through homeostatic plasticity. Abnormalities in homeostatic plasticity are present in neuro/psychiatric diseases such as autism and Alzheimer's disease and are considered one of the molecular mechanisms underlying these diseases.

We used the sodium channel blocker (TTX) to block action potentials to simulate the long-term reduction in neuronal excitability. After TTX washout, the duration of action potentials was significantly prolonged, and neuronal excitability increased compensatorily, indicating the occurrence of excitability homeostatic regulation in neurons. Mechanistic studies revealed that the above excitability homeostatic regulation was due to the reduced alternative splicing of potassium channel (BK channel) mRNA mediated by Nova-2.

This study provided complete evidence for the "homeostatic feedback loop" hypothesis proposed nearly 30 years ago. Multiple molecules in this signaling pathway (AMPA receptor, L-type calcium channel, calmodulin kinase family, Nova-2, BK channel) are closely related to neuro/psychiatric diseases such as autism, schizophrenia, and depression, suggesting that abnormalities in this pathway may be an important mechanism for the occurrence of these diseases.

The research findings were published as a cover article in Cell (Li, et al. Cell 2020, 181(7):1547-1565). For a detailed introduction, please visit https://www.scimall.org.cn/article/detail?id=1845269

4. Demonstration that L-type Calcium Channels Regulate Gene Expression through Voltage-dependent Conformational Signals

L-type calcium channels are voltage-dependent calcium channels and one of the most important ion channels mediating calcium influx across the cell membrane. Their opening can activate intracellular transcription factors and gene expression. The traditional view holds that L-type calcium channels regulate gene expression mainly by mediating calcium influx. The calcium ions entering the cell act as second messengers, activating intracellular signal transduction pathways and thus activating gene expression. However, as a voltage-dependent ion channel, voltage changes (depolarization) not only cause channel opening and calcium influx but also lead to conformational changes in the channel protein. Traditional research methods could not separate calcium signals from conformational signals, so it was impossible to know the function of conformational signals in gene expression, let alone study their role in neuro/psychiatric diseases. We innovatively constructed chimeric ion channels, successfully separated calcium signals and conformational signals, and discovered through pharmacological and molecular biological research methods: 1) The conformational signal of L-type calcium channels participates in the regulation of gene expression; only when both calcium signals and conformational signals are present can L-type calcium channels complete the regulation of gene expression. 2) Calcium signals and conformational signals have different functions. Calcium signals release CaMKII from F-actin, while conformational signals recruit the released CaMKII around the channel. 3) The conformational signal of the calcium channel can synergize with calcium signals from other channels (NMDA receptors). More importantly, 4) In Timothy syndrome (a type of autism) caused by point mutations in L-type calcium channels, the appearance of autistic symptoms is closely related to abnormal conformational signals.

The research findings were published in Science (Li, et al. Science 2016, 351(6275), 863-866).

Our above findings updated the traditional view that calcium channels regulate gene expression only through calcium signals, revealing a new form of signal for regulating gene expression - conformational signals. At the same time, our findings updated the traditional view that Timothy syndrome is caused by increased calcium influx, proposing a new mechanism for autism cognitive impairment - the abnormal conformational signal mechanism. More importantly, the new research method we established (chimeric channels) can be widely applied to the study of other types of ion channels, providing an important research tool for people to comprehensively understand ion channel functions.

5. Demonstration that BK Channels Exist on the Nuclear Membrane of Hippocampal Neurons and Regulate Autism-related Gene Expression through Controlling Nuclear Calcium Signals, Revealing a New Mechanism for Autism Pathogenesis - the Nuclear Membrane Mechanism

BK channels (large-conductance calcium-activated potassium channels) are a type of potassium channel and one of the most important ion channels regulating membrane potential. Mutations in their genes are closely related to autism. Previous domestic and international studies have mainly focused on the function of BK channels on the cell membrane, while their expression and function at the subcellular level remain unclear. Through gene knockout, electrophysiology, calcium imaging, voltage imaging, morphology, and other means, we first discovered: 1) BK channels exist on the nuclear membrane of hippocampal neurons (nBK channels), which have the same encoding gene as membrane BK channels, similar voltage dependence, calcium dependence, and single-channel conductance. 2) nBK channels can regulate the functions of multiple autism-related molecules such as Ryanodine receptors, nuclear calcium signaling pathways, and transcription factor CREB. 3) nBK channels can regulate the expression of autism-related genes such as Npas4 by controlling neuron excitation-transcription coupling. 4) Abnormal growth of neuronal processes is a typical morphological change in autism, and nBK channels can regulate this change through the autism-related gene Npas4.

The research findings were published in Nature Neuroscience (Li, et al. Nature Neuroscience 2014, 17(8):1055-63).

Our above findings revealed a new mechanism for autism pathogenesis - the nuclear membrane mechanism, opening up a new field for studying and treating autism from the perspective of the nuclear membrane. At the same time, our study updated the traditional view that BK channels only exist on the cell membrane and mitochondria, emphasizing the new direction of research on neuronal nuclear membrane ion channels and broadening people's understanding of ion channel functions.

Ten Representative Papers

1. Shunchang Fang, Zhengyi Luo, Zicheng Wei, Yuxin Qin, Jieyan Zheng, Hongyang Zhang, Jianhua Jin, Jiali Li, Chenjian Miao, Shana Yang, Yonglin Li, Zirui Liang, Xiao-Dan Yu, Xiao Min Zhang, Wei Xiong, Hongying Zhu, Wen-Biao Gan, Lianyan Huang*, Boxing Li* Sexually dimorphic control of affective state processing and empathic behaviors. Neuron 2024, 112(9):1498-1517 (*correspondence author, F1000 recommendation).

2. Jieyan Zheng#, Xiao Min Zhang#, Wenting Tang#, Yonglin Li, Pei Wang, Jianhua Jin, Zhengyi Luo, Shunchang Fang, Shana Yang, Zicheng Wei, Kexin Song, Zihan Huang, Zihao Wang, Ziyu Zhu, Naizhen Shi, Diyun Xiao, Linyu Yuan, Hualin Shen, Lianyan Huang*, Boxing Li* An insular cortical circuit required for itch sensation and aversion. Current Biology 2024, 8;34(7):1453-1468 (*correspondence author).

3. Boxing Li*, Benjamin S. Suutari, Simon D. Sun, Zhengyi Luo, Chuanchuan Wei, Nicolas Chenouard, Natanial J. Mandelberg, Guoan Zhang, Brie Wamsley, Guoling Tian, Sandrine Sanchez, Sikun You, Lianyan Huang, Thomas A. Neubert, Gordon Fishell, Richard W. Tsien* Neuronal inactivity co-opts LTP machinery to drive potassium channel splicing and homeostatic spike widening. Cell 2020, 181(7):1547-1565 (*correspondence author,Cover Story, highlighted in Nature Reviews Neuroscience, 2020,21,398–399: Splicing resets spikes).

4. Boxing Li#, Michael R. Tadross#*, Richard W. Tsien. Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 2016, 351(6275), 863-86. (# equal contribution) (F1000 Recommendation, Editor's Choice in Science Signaling; Paper of Note in Science).

5. Boxing Li, Wei Jie, Lianyan Huang, Peng Wei, Shuji Li, Zhengyi Luo, Allyson K. Friedman, Andrea L. Meredith, Ming-Hu Han, Xin-Hong Zhu, Tian-Ming Gao*. Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling. Nature Neuroscience 2014, 17(8):1055-63. 

6. Shana Yang#, Song Zhang#, Wenting Tang, Shunchang Fang, Hongyang Zhang, Jieyan Zheng, Xia Liu, Liang Zhao, Ying Zhang, Lianyan Huang*, Boxing Li*. Enriched environment prevents surgery-induced persistent neural inhibition and cognitive dysfunction Frontiers in Aging Neuroscience 2021,1(13):744719 (*correspondence author).

7. Yuchong Luo#, Xiao Chen1#, Chunren Wei, Hongyang Zhang, Lingyi Zhang, Lu Han, Ke Sun*, Boxing Li*, Shenglin Wen* BDNF alleviates microglial inhibition and stereotypic behaviors in a mouse model of obsessive-compulsive disorder Frontiers in Molecular Neuroscience 2022;15:926572 (*correspondence author).

8. Zicheng Wei, Yuxin Qin, Gordon Fishell, Boxing Li*. FACS-Based Neuronal Cell Type-Specific RNA Isolation and Alternative Splicing Analysis. Methods Mol Biol. 2022;2537:51-62 (*correspondence author).

9. Shunchang Fang, Yuxin Qin, Shana Yang, Hongyang Z, Jieyan Zheng, Songhai Wen, Weimin Li, Zirui Liang, Xiao Min Zhang, Boxing Li*, Lianyan Huang*. Differences in the neural basis and transcriptomic patterns in acute and persistent pain-related anxiety-like behaviors. Frontiers in Molecular Neuroscience 2023,26;16:1185243 (*correspondence author).

10. Boxing Li, Tian-Ming Gao* Functional Role of Mitochondrial and Nuclear BK channels. In: Big on Bk: Current Insights into the Function of Large Conductance Voltage- and Ca2+- Activated K+ Channels at the Molecular, Cellular and Systemic Levels. International Review of Neurobiology. 2016;128:163-91.