Team of Professor Han Feng and Collaborative Team from School of Basic Medical Sciences Reveal a Nov

Time：2026-03-31 15:13:58 View:

The research team led by Professor Han Feng from the School of Pharmacy, in collaboration with Professor Lu Yingmei from the School of Basic Medical Sciences at Nanjing Medical University and Professor Xu Yujun from the University of Chicago, published a study titled 'Molecular brake on firing pattern transitions in MHbChAT neurons to mediate nicotine withdrawal-induced anxiety' in the journal Neuron. This study focuses on the medial habenula and systematically investigates the electrophysiological and molecular mechanisms underlying anxiety disorders. The research found a significant transition in the firing pattern of cholinergic neurons in the ventral medial habenula (vMHbChAT), which plays a critical role in the generation of
anxiety-like behaviors. Further mechanistic studies revealed that the RNA-binding protein Pum1 regulates the expression of the T-type calcium channel Cav3.1, thereby modulating neuronal firing patterns and mediating the onset of anxiety. This study deepens the understanding of anxiety mechanisms from the perspective of neuronal firing patterns and provides new theoretical foundations and potential targets for precise intervention strategies aimed at regulating neural electrical activity.



Anxiety disorders are a class of mental illnesses characterized by excessive, persistent anxiety, fear, and emotional dysregulation. Patients with anxiety disorders typically require long-term medication. However, existing drugs, such as benzodiazepines that act as GABA receptor agonists, have clinical limitations. Although these drugs have a rapid onset of action, their targets are widely distributed throughout the brain, inevitably activating receptors in other brain regions and leading to side effects such as ataxia. More critically, long-term use can lead to tolerance and drug dependence. Therefore, elucidating new pathological mechanisms underlying anxiety disorders, identifying and validating highly druggable new targets, and developing novel lead compounds are urgent tasks to meet clinical needs.

By combining in vivo electrophysiology and ex vivo patch-clamp recordings, the research team discovered that under physiological conditions, vMHbChAT neurons primarily exhibit tonic firing. In contrast, under anxiety states, burst firing in these neurons is significantly enhanced. Further optogenetic induction of burst firing markedly aggravated anxiety-like behaviors in mice. This suggests that the transition in the firing pattern of vMHbChAT neurons is a critical neural basis driving anxiety.

At the electrophysiological mechanism level, transcriptome sequencing combined with electrophysiological recordings revealed that under anxiety states, the expression of the T-type voltage-dependent calcium channel Cav3.1 is upregulated in the medial habenula, accompanied by enhanced T-type calcium channel currents, which promote the transition of neurons to burst firing. Targeted knockdown of Cav3.1 in vMHbChAT neurons effectively reduced burst firing and alleviated anxiety-like behaviors, demonstrating the key role of the T-type calcium channel Cav3.1 in this process. At the molecular mechanism level, further transcriptomic analysis suggested that the RNA-binding protein Pum1 may be involved in regulating Cav3.1-mediated anxiety-related processes. The study found that Pum1 recognizes and binds to the mRNA of Cav3.1 through its conserved Pumilio homology domain, promoting its degradation and thereby inhibiting Cav3.1 expression. Under anxiety states, the decrease in Pum1 relieves the inhibition of Cav3.1, leading to its increased expression, which in turn enhances burst firing and promotes the occurrence of anxiety-like behaviors. Conversely, overexpressing Pum1 specifically in vMHbChAT neurons under anxiety states reduced Cav3.1 levels, decreased abnormal burst firing, and significantly alleviated anxiety-like behaviors.

This study anchors the pathological mechanism of anxiety at the more fundamental neurodynamic level of 'neuronal firing patterns' and reveals, for the first time, the core regulatory role of the Pum1–Cav3.1 molecular axis. This original discovery not only breaks through the limitations of the traditional 'neurotransmitter imbalance' theory but also opens up a new target landscape for the development of novel anxiolytic drugs, shifting the focus from 'chemical signal modulation' to 'electrophysiological rhythm restoration.' In the future, novel targets represented by the Cav3.1 channel and the Pum1 protein are expected to lead to a new generation of anxiolytic drugs characterized by high efficacy and low toxicity, offering safer and more effective treatment options for patients and providing crucial target reserves for original innovations in the field of neuropsychiatric drugs in China.