Neuroscientists have identified specific neural circuits in the midbrain that control whether animals persist with current activities, explore new options, or disengage entirely – findings with potential implications for various psychiatric conditions.
A groundbreaking study published in Nature on 5 March 2025 has revealed how a small brain region acts as a central switchboard for controlling fundamental behavioural strategies. Researchers at the Sainsbury Wellcome Centre at UCL have identified specific neural circuits in the midbrain that determine whether animals persevere with current goals, seek alternatives, or disengage completely.
The median raphe’s triple role
The research team, led by Professor Sonja Hofer, focused on the median raphe nucleus (MRN) in mice, investigating how this brain region controls decision-making processes across both instinctive and learned behaviours.
Using sophisticated techniques including optogenetic manipulations, calcium imaging, and neural circuit tracing, the scientists discovered three distinct cell types within the MRN, each controlling a different behavioural strategy.
“We found that suppression of GABAergic neurons causes perseverance in a current or familiar goal; activation of glutamatergic neurons drives exploration of alternative options; and suppression of serotonergic neurons in the median raphe nucleus causes the animal to disengage,” explained Mehran Ahmadlou, Senior Research Fellow and first author of the study.
The researchers observed these effects consistently across both innate and learned tasks, suggesting these neural mechanisms represent fundamental behavioural control systems.
Input signals shape decisions
Further investigation revealed that the median raphe receives crucial information from two additional brain regions – the lateral hypothalamus and the lateral habenula – which signal whether an experience is positive or negative. These inputs, in turn, influence whether an animal persists with its current goal or disengages.
“We were really surprised to find that the three main cell types in this small brain structure had three fundamentally different but complementary functions with such strong control over the animals’ behaviour,” said Professor Hofer.
Implications for psychiatric conditions
The discovery of these neural circuits may enhance understanding of several neuropsychiatric conditions. For instance, excessive perseverance and repetitive behaviours characterise both obsessive-compulsive disorder (OCD) and autism spectrum disorders, while pathological disengagement is a hallmark of major depressive disorder.
The research suggests that abnormal firing rates of specific median raphe cell types could contribute to certain aspects of these conditions. Professor Hofer noted: “It is possible that in some mental disorders specific median raphe neurons could have pathological firing rates. For example, very low activity of serotonergic neurons specifically in the median raphe nucleus could contribute to a depressive phenotype.”
This insight is particularly relevant given that many effective treatments for depression target serotonin, though current medications are often non-specific and don’t work for all patients.
Evolutionary conservation
The researchers emphasised that the need to balance perseverance, exploration, and disengagement is common across species, suggesting these neural circuits are likely evolutionarily conserved and subcortical.
This work could potentially lead to more targeted treatments for psychiatric disorders by providing a deeper understanding of the neural mechanisms underlying both healthy and pathological behavioural patterns.
The research was funded by the Sainsbury Wellcome Centre Core Grant from the Gatsby Charity Foundation and Well-come, along with a European Research Council Starting Grant.
Reference:
Ahmadlou, M., et al. (2025). A subcortical switchboard for perseverative, exploratory, and disengaged states. Nature. https://doi.org/10.1038/s41586-025-08672-1
