A subcortical switchboard for perseverative, exploratory and disengaged states
Open accessAbstract
Abstract To survive in dynamic environments with uncertain resources, animals must adapt their behaviour flexibly, choosing strategies such as persevering with a current choice, exploring alternatives or disengaging altogether. Previous studies have mainly investigated how forebrain regions represent choice costs and values as well as optimal strategies during such decisions 1–5 . However, the neural mechanisms by which the brain implements alternative behavioural strategies such as persevering, exploring or disengaging remain poorly understood. Here we identify a neural hub that is critical for flexible switching between behavioural strategies, the median raphe nucleus (MRN). Using cell-type-specific optogenetic manipulations, fibre photometry and circuit tracing in mice performing diverse instinctive and learnt behaviours, we found that the main cell types of the MRN—GABAergic (γ-aminobutyric acid-expressing), glutamatergic (VGluT2 + ) and serotonergic neurons—have complementary functions and regulate perseverance, exploration and disengagement, respectively. Suppression of MRN GABAergic neurons—for instance, through inhibitory input from lateral hypothalamus, which conveys strong positive valence to the MRN—leads to perseverative behaviour. By contrast, activation of MRN VGluT2 + neurons drives exploration. Activity of serotonergic MRN neurons is necessary for general task engagement. Input from the lateral habenula that conveys negative valence suppresses serotonergic MRN neurons, leading to disengagement. These findings establish the MRN as a central behavioural switchboard that is uniquely positioned to flexibly control behavioural strategies. These circuits thus may also have an important role in the aetiology of major mental pathologies such as depressive or obsessive-compulsive disorders.
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fMRI recording cannot determine whether DRN signals arise from serotonergic, glutamatergic, or GABAergic neurons.
“Although DRN is strongly associated with serotonin, fMRI recording here cannot determine whether these signals arise from serotonergic, glutamatergic, or GABAergic neurons.84”
From Two prefrontal-subcortical circuits estimate controllability and reflect its impact on learning (2026) · cites this paper as [84]
The Main section (page unavailable) identifies the DRN as a main source of serotonin, supporting the sentence’s background point. But the paper discusses distinct serotonergic, glutamatergic and GABAergic cell classes in the MRN, not the DRN, and does not address whether fMRI can distinguish the source of DRN signals. (LLM, conf=0.82)
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- Authors
- Ahmadlou, M., Shirazi, M. Y., Zhang, P., Rogers, I. L. M., Dziubek, J., Young, M., & Hofer, S. B.
- Affiliations
- Sainsbury Wellcome Centre (GB)
- Corresponding author
- Ahmadlou, Mehran
- Hofer, Sonja B.
- ORCID
- Venue
- Nature
- Published
- 2025-03-05
- Volume
- 641
- Issue
- 8061
- Pages
- 151-161
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC12043504
- OpenAlex
- W4408221278
- Cited by
- 25
- References
- 74
- Citations by year
- 2026: 16 · 2025: 9
- FWCI
- 9.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- median raphe nucleus, behavioral flexibility, perseveration, exploration, disengagement, serotonergic neurons, GABAergic neurons, glutamatergic neurons, lateral hypothalamus, lateral habenula, valence, depression, obsessive-compulsive disorder
- MeSH terms
- Animals, Exploratory Behavior, Female, Hypothalamic Area, Lateral, Male, Mice, Inbred C57BL, Neural Pathways, Raphe Nuclei, Vesicular Glutamate Transport Protein 2, Mice, Serotonergic Neurons, GABAergic Neurons, Optogenetics
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