A Distinct Hypothalamus–Habenula Circuit Governs Risk Preference

Neurology Psychiatry Medicine Life Sciences Bioengineering Biophysics Cell Biology
risk preference hypothalamus habenula decision-making neural circuits

Study on the Hypothalamus-Habenula Circuit Regulating Risk Preference

Academic Background

In complex and uncertain environments, animals need to assess risks to make survival-favorable decisions. When faced with safe and risky options, animals usually exhibit a strong preference for one option, which remains consistent over time. However, how this risk preference is encoded in the brain remains a mystery. The lateral habenula (lhb) is considered a key brain region involved in value-guided behavior, but its specific role in risk preference decision-making is still unclear. This study aims to uncover the neural circuits regulating risk preference, particularly the role of the hypothalamus-habenula circuit in this process.

Source of the Paper

This paper was collaboratively completed by a research team led by Dominik Groos, Anna Maria Reuss, Peter Rupprecht, and others from the University of Zurich and ETH Zurich in Switzerland. Published in February 2025 in the journal Nature Neuroscience, the paper is titled “A Distinct Hypothalamus–Habenula Circuit Governs Risk Preference.” The study received support from multiple institutions, including the Brain Research Institute at the University of Zurich and the Neuroscience Center Zurich.

Research Process and Results

1. Experimental Design and Animal Models

The research team first designed a balanced two-alternative choice task to test risk preference in mice. In this task, mice had to choose between two water spouts: one consistently delivered a 5 µL sucrose water reward (safe option), while the other offered a 25% chance of a 17 µL reward and a 75% chance of a 1 µL reward (risky option). Both options had the same expected value but differed in risk. The study used a total of 144 male mice and 22 female mice, divided into multiple experimental groups.

2. Behavioral Experiments

Through behavioral experiments, the research team found significant individual differences in risk preference among mice. Most mice tended to choose the safe option (risk-averse), a few preferred the risky option (risk-prone), and some frequently switched between the two options (risk-neutral). This risk preference remained stable over several weeks, even when the positions of the options were reversed. Additionally, the study found that risk-averse mice were more likely to return to the safe option after experiencing a loss, while risk-prone mice were more inclined to try the risky option again.

3. Neural Activity Recording

To investigate the role of the habenula in risk preference decision-making, the research team used fiber photometry and two-photon calcium imaging to record the activity of habenula neurons in mice. The results showed that the activity of habenula neurons before decision-making reflected the individual risk preferences of the mice. Specifically, habenula neurons exhibited significantly enhanced activity before the preferred option was chosen, regardless of whether it was the safe or risky option. This activity pattern was independent of past decision outcomes, indicating that the habenula encodes information about upcoming choices.

4. Single-Cell Level Analysis

At the single-cell level, the research team identified a class of “risk-preference-selective cells” (RPSCs) in the habenula. These cells exhibited specific responses to the preferred option before decision-making. Among these, 47.9% of RPSCs showed increased activity when the preferred option was chosen, while 37.2% showed increased activity when the non-preferred option was chosen. This selective activity was highly correlated with the individual risk preferences of the mice.

5. Functional Study of the Hypothalamus-Habenula Circuit

Using whole-brain anatomical tracing and multi-fiber photometry, the research team found that glutamatergic projections from the medial hypothalamus (mh) to the habenula played a critical role in risk preference decision-making. In contrast, projections from the lateral hypothalamus (lh) did not show significant behavioral relevance. Further optogenetic experiments demonstrated that inhibiting mh→lhb projections significantly reduced the decision confidence and risk preference levels of the mice.

6. Synaptic Mechanism Study

Through ex vivo electrophysiological experiments, the research team discovered that mh→lhb projections not only released glutamate but also GABA (γ-aminobutyric acid), while lh→lhb projections primarily released glutamate. This dual neurotransmitter release mechanism may provide fine-tuned regulation of habenula neuron activity.

Research Conclusions

This study reveals the critical role of the hypothalamus-habenula circuit in risk preference decision-making. Specifically, the medial hypothalamus regulates habenula neuron activity through a glutamate/GABA co-release mechanism, thereby influencing the risk preference behavior of mice. This finding not only enhances our understanding of the brain’s decision-making mechanisms but also provides new insights for research on related psychiatric disorders, such as depression.

Research Highlights

  1. Innovative Behavioral Task: The study designed a balanced two-alternative choice task that effectively distinguishes risk preference types in mice.
  2. Multi-Dimensional Neural Activity Recording: By combining fiber photometry, two-photon calcium imaging, and optogenetics, the study comprehensively revealed the role of the habenula in risk preference decision-making.
  3. New Discovery in Synaptic Mechanisms: For the first time, the study found that mh→lhb projections have a glutamate/GABA co-release function, offering a new perspective on the fine regulation of neural circuits.
  4. Evolutionary Conservation Across Species: The results suggest that the hypothalamus-habenula circuit is highly conserved in evolution and may play similar roles in various animals.

Research Significance

The scientific value of this study lies in uncovering the specific neural circuits regulating risk preference in the brain, providing a new neurobiological foundation for understanding complex decision-making behavior. Additionally, the findings may offer potential therapeutic targets for psychiatric disorders, such as improving decision-making impairments in depression patients by modulating the hypothalamus-habenula circuit. In summary, this research not only advances the field of neuroscience but also provides important theoretical support for clinical medicine.