Prefrontal cortex output circuits guide reward seeking through divergent cue encoding
Open accessAbstract
The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.
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Stimulation of PFC-to-NAc neurons promotes conditioned reward-seeking behaviour, while activation of PFC-to-thalamic neurons suppresses both acquisition and expression of conditioned reward seeking.
“Prefrontal circuitry can dynamically control reward-seeking behaviour through projection-specific cue encoding 16: stimulation of PFC to nucleus accumbens (NAc) neurons promotes conditioned reward-seeking behaviour, while activation of PFC to thalamic neurons suppresses both the acquisition and expression of conditioned reward seeking.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [16]
Activation of hippocampal and prefrontal inputs to the nucleus accumbens is rewarding and reinforces rewarding stimuli.
“Activation of inputs to the NAc from the hippocampus and PFC is rewarding and reinforcing of rewarding stimuli [227,228].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [228]
The study sheds light on a previously unrecognized role of mPFC->PVT projections in naturalistic (unconditioned) social processing in addition to their known function in Pavlovian conditioning and extinction.
“Our study sheds light on a previously unrecognized role of mPFC->PVT projections in naturalistic (unconditioned) social processing in addition to their known function in Pavlovian conditioning and extinction 15–18.”
From A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice (2020) · cites this paper as [15]
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“Prefrontal circuitry can dynamically control reward-seeking behavior through projection-speci fi c cue encoding [16]: stimulation of PFC to nucleus accumbens (NAc) neurons promotes conditioned reward-seeking behavior, while activation of PFC to thalamic neurons suppresses both the acquisition and…”
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- Authors
- Otis, J. M., Namboodiri, V. M. K., Matan, A. M., Voets, E. S., Mohorn, E. P., Kosyk, O., McHenry, J. A., Robinson, J. E., Resendez, S. L., Rossi, M. A., & Stuber, G. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Stuber, Garret D.
- ORCID
- Venue
- Nature
- Published
- 2017-02-22
- Volume
- 543
- Issue
- 7643
- Pages
- 103-107
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5772935
- OpenAlex
- W2590164153
- Cited by
- 412
- References
- 40
- Citations by year
- 2026: 40 · 2025: 44 · 2024: 28 · 2023: 48 · 2022: 45 · 2021: 57 · 2020: 50 · 2019: 39 · 2018: 35 · 2017: 26
- FWCI
- 20.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UNC Libraries
- Funders
- Foundation of Hope for Research and Treatment of Mental Illness
- National Institutes of Health (NS045892, DA038168, DA032750, HD079124)
- National Institute of Mental Health (MH093315, T32MH093315)
- National Institute on Drug Abuse (R01DA032750, DA038168, F32DA041184, DA032750, R01DA038168, R37DA032750)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056350)
- National Institute of Neurological Disorders and Stroke (P30NS045892, T32NS007431)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124, T32-HD079124)
- 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 › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- prefrontal cortex, reward seeking, corticostriatal neurons, corticothalamic neurons, nucleus accumbens, paraventricular thalamus, reward-predictive cues, optogenetic manipulation, motivated behavior
- MeSH terms
- Animals, Appetitive Behavior, Calcium, Conditioning, Classical, Cues, Male, Mice, Inbred C57BL, Neural Pathways, Neuronal Plasticity, Neurons, Nucleus Accumbens, Reward, Thalamus, Prefrontal Cortex, Microscopy, Fluorescence, Multiphoton, Mice, Molecular Imaging
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