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Client Article | Zixuan He & Xiaojuan Zhu’s Team at Northeast Normal University | A medial habenula neural circuit controlling anxiety-like behaviors in response to acute stress

Release time：2025-09-19 15:36:56
Anxiety refers to a negative emotional state in response to external stimuli and is often comorbid with other psychiatric disorders such as obsessive-compulsive disorder and post-traumatic stress disorder (PTSD). The medial habenula (MHb), a subregion of the habenula, plays an important regulatory role in addiction, anhedonia, fear, and anxiety. However, the precise mechanisms by which the MHb participates in emotion-related behaviors remain unclear.

On July 14, 2025, the team of Zixuan He and Xiaojuan Zhu from Northeast Normal University published a paper in Molecular Psychiatry titled “A medial habenula neural circuit controlling anxiety-like behaviors in response to acute stress”. This study reveals the neural circuit mechanism by which the MHb regulates anxiety-like behaviors induced by acute stress.

MHbTac1 Neurons Regulate Anxiety-Like Behaviors in Mice

In the study, male C57BL/6J mice were subjected to a 5-minute forced swim test, followed by a 1-hour rest, and then tested in open field, elevated plus maze, and light-dark box paradigms. Results showed that stressed mice exhibited significantly increased anxiety-like behaviors compared with control mice.

Further experiments involved injecting AAV-DIO-mCherry virus into the MHb of Tac1-Cre mice. The mCherry-positive neurons expressed the excitatory neuronal marker VGLUT2. Electrophysiological recordings revealed that acute stress suppressed the activity of MHb Tac1 neurons. This suggests that MHb neurons may play a key role in regulating anxiety-like behaviors induced by acute stress in mice.

Figure 1: Activity of MHbTac1 neurons decreases during the acute stress response.
 

MHbTac1 Neurons Modulate Anxiety-Like Behaviors Under Acute Stress

To further explore the causal role of MHbTac1 neurons, the researchers injected chemogenetic viruses (AAV-DIO-hM3Dq-mCherry for activation and AAV-DIO-hM4Di-mCherry for inhibition) into the MHb of Tac1-Cre mice. Combined with behavioral tests (open field, elevated plus maze, light-dark box), they found that activation of MHbTac1 neurons alleviated anxiety-like behaviors induced by acute stress, whereas inhibition of these neurons induced anxiety-like behaviors. This demonstrates that MHbTac1 neuronal activity plays a critical role in shaping anxiety-like responses to acute stress in mice.

Figure 2: MHbTac1 neurons regulate anxiety-like behaviors in mice under acute stress.
 

IFVGLUT→MHbTac1 Circuit Regulates Anxiety-Like Behaviors in Mice

To investigate whether upstream excitatory inputs to MHb neurons are altered under acute stress, the researchers injected AAV-DIO-mCherry into the MHb of Tac1-Cre mice. Four weeks later, the mice underwent a forced swim test, and excitatory inputs to MHbTac1 neurons were recorded. Results showed that, compared with control mice, stressed mice exhibited a significant reduction in the frequency—but not amplitude—of spontaneous excitatory postsynaptic currents (sEPSCs), indicating that relevant upstream excitatory projections were altered under acute stress.

Previous retrograde monosynaptic viral tracing and immunofluorescence experiments revealed that glutamatergic neurons in the IF region project to MHb neurons and may participate in the regulation of anxiety-like behaviors. To test this, AAV-fDIO-hM3Dq-mCherry or a control virus was injected into the MHb of Tac1-Cre mice, while AAV1-DIO-Flpo was injected into the IF region. Four weeks later, behavioral tests (open field, elevated plus maze, light-dark box) showed that activation of the IFVGLUT→MHbTac1 projection alleviated acute stress–induced anxiety-like behaviors.

Figure 3: IFVGLUT→MHbTac1 circuit regulates anxiety-like behaviors in mice.
 

MHbTac1→IPLVGLUT Circuit Regulates Anxiety-Like Behaviors in Mice

To examine the downstream projections of MHb neurons and their role in acute stress–induced anxiety-like behaviors, prior experiments injected AAV-DIO-mCherry into the MHb of Tac1-Cre mice, revealing long-range projections from MHbTac1 neurons to the IPL region. Further anterograde trans-synaptic viral tracing with AAV-CAG-DIO-mWGA-mCherry showed that excitatory neurons in the IPL receive inputs from MHbTac1 neurons.

Electrophysiological recordings demonstrated that, under acute stress, the excitability of IPL neurons receiving MHbTac1 projections decreased, along with reduced spontaneous excitatory postsynaptic currents. This suggests that acute stress may suppress MHb neuron activity, thereby reducing glutamate release to the IPL, decreasing IPL neuron excitability, and ultimately modulating anxiety-like behaviors.

To test this, AAV-fDIO-hM3Dq-mCherry or a control virus was bilaterally injected into the MHb of Tac1-Cre mice, while a retrograde AAV-FLEX-Flpo virus was injected into the IPL. Four weeks later, behavioral tests (open field, elevated plus maze, light-dark box) showed that inhibition of the MHbTac1→IPLVGLUT circuit induced acute stress–related anxiety-like behaviors. This indicates that the MHbTac1→IPLVGLUT circuit plays a key role in regulating anxiety-like behaviors induced by acute stress.

Figure 4: MHbTac1→IPLVGLUT circuit regulates anxiety-like behaviors in mice.

 

Conclusion

In summary, this study found that Tac1-expressing neurons play a role in the regulation of anxiety behaviors under acute stress and identified a novel neural circuit, IFVGLUT→MHbTac1→IPLVGLUT, which exerts a key regulatory effect on anxiety. These findings deepen our understanding of the mechanisms by which acute stress induces anxiety and provide new insights for the treatment of anxiety-related disorders.


The viral vectors used in this study are available from Brain Case Biotech

 

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