A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge
Open accessAbstract
The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.
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DRN serotonergic neurons are controlled by glutamatergic projections from the PFC.
“In addition, DRN serotonergic neurons are controlled by glutamatergic projections from the PFC [152, 207–209].”
From Development of prefrontal cortex (2022) · cites this paper as [207]
The supplied Abstract passages describe excitatory mPFC projections to the DRN and report that glutamate receptor antagonists block an effect of stimulating those projections. They also say the mPFC controls DRN activity and extracellular serotonin levels, but do not establish that the glutamatergic projections control serotonergic neurons specifically; the paper notes that the DRN also contains GABA neurons. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOptogenetic stimulation of medial PFC neurons projecting to the dorsal raphe nucleus decreased immobility in the forced swim test.
“Deisseroth et al. later found that optogenetic stimulation of medial PFC neurons projecting to the dorsal raphe nucleus (DRN) decreased immobility in the forced swim test (175).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [175]
DRSert→OFC neurons and frontal cortex→DRSert neurons may form a reciprocal loop that promotes active coping under challenge.
“Thus, DRSert→OFC neurons and frontal cortex→DRSert neurons may constitute a reciprocal loop to promote active coping in the face of challenge.”
From Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems (2018) · cites this paper as Warden et al., 2012
Optogenetic activation of prefrontal cortical neuron terminals in the DR promotes active coping.
“Optogenetic activation of prefrontal cortical neuron terminals in the DR has previously been shown to promote active coping (Warden et al., 2012).”
From Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems (2018) · cites this paper as Warden et al., 2012
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- Authors
- Warden, M. R., Selimbeyoglu, A., Mirzabekov, J. J., Lo, M., Thompson, K. R., Kim, S.-Y., Adhikari, A., Tye, K. M., Frank, L. M., & Deisseroth, K.
- Affiliations
- Stanford University (US)
- Massachusetts Institute of Technology (US)
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Warden, Melissa R.
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2012-11-18
- Volume
- 492
- Issue
- 7429
- Pages
- 428-432
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5929119
- OpenAlex
- W2042404539
- Cited by
- 645
- References
- 28
- Citations by year
- 2026: 27 · 2025: 39 · 2024: 52 · 2023: 34 · 2022: 49 · 2021: 53 · 2020: 55 · 2019: 52 · 2018: 45 · 2017: 70 · 2016: 40 · 2015: 45 · 2014: 53 · 2013: 28 · 2012: 2
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (F32MH088010, R01MH075957)
- National Institute on Drug Abuse (R01DA020794)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- medial prefrontal cortex, dorsal raphe nucleus, brainstem, neuronal projections, forced swim test, escape behavior, motivation, action selection, serotonergic neurons, depression, optogenetic stimulation, single-unit recording, rats, neural circuits, amotivation, impulsivity, high-speed tracking
- MeSH terms
- Action Potentials, Animals, Axons, Behavior, Animal, Depression, Electrophysiology, Locomotion, Male, Motivation, Neurons, Raphe Nuclei, Swimming, Synapses, Time Factors, Prefrontal Cortex, Rats, Long-Evans, Rats, Optogenetics
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