Control of goal-directed and inflexible actions by dorsal striatal melanocortin systems, in coordination with the central nucleus of the amygdala
Open accessAbstract
The dorsomedial striatum (DMS) is associated with flexible goal seeking, as opposed to routinized habits. Whether local mechanisms brake this function, for instance when habits may be adaptive, is incompletely understood. We find that a sub-population of dopamine D1 receptor-containing striatal neurons express the melanocortin-4 receptor (MC4R) for α-melanocyte stimulating hormone. These neurons within the DMS are necessary and sufficient for controlling the capacity of mice to flexibly adjust actions based on the likelihood that they will be rewarded. In investigating MC4R function, we found that it suppresses immediate-early gene levels in the DMS and concurrently, flexible goal seeking. MC4R+ neurons receive input from the central nucleus of the amygdala, and behavioral experiments indicate that they are functionally integrated into an amygdalo-striatal circuit that suppresses action flexibility in favor of routine. Publicly available spatial transcriptomics datasets were analyzed for gene transcript correlates of Mc4r expression across the striatal subregions, revealing considerable co-variation in dorsal structures. This insight led to the discovery that the function of MC4R in the dorsolateral striatum complements that in the DMS, in this case suppressing habit-like behavior. Altogether, our findings suggest that striatal MC4R controls the capacity for goal-directed and inflexible actions alike.
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CeA→DMS projections oppose flexible adjustment of behavior when an action is no longer rewarded.
“that CeA→DMS projections oppose flexible adjustment of behavior when an action is no longer rewarded35.”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [35]
The CeA sends a direct, likely inhibitory projection to the striatum.
“It sends a direct, likely inhibitory33, projection to the striatum30,34,35 and is, thus, poised to oppose striatal activity.”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [35]
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A dual-pathway architecture for stress to disrupt agency and promote habit
Giovanniello, J. R., Paredes, N., Wiener, A., Ramírez-Armenta, K., Oragwam, C., Uwadia, H. O., Yu, A. L., Lim, K., Pimenta, J. S., Vilchez, G. E., et al. (2025) · Nature · doi:10.1038/s41586-024-08580-w · Cited by 30 · see citing works
- Authors
- Heaton, E. C., Seo, E. H., Butkovich, L. M., Yount, S. T., & Gourley, S. L.
- Affiliations
- Emory University (US)
- Corresponding author
- Gourley, Shannon L.
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2024-07
- Volume
- 238
- Pages
- 102629
- ISSN
- 0301-0082 (ISSN-L)
- PMC
- PMC11198735
- OpenAlex
- W4397024056
- Cited by
- 8
- References
- 65
- Citations by year
- 2026: 4 · 2025: 3 · 2023: 1
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 325 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Progress in Neurobiology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Marcus Foundation
- National Institutes of Health (DA044297, MH117103, DA055447, OD P51 011132)
- 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
- dorsomedial striatum, dorsolateral striatum, melanocortin-4 receptor, dopamine D1 receptor, central amygdala, goal-directed behavior, habit formation, alpha-melanocyte-stimulating hormone, immediate early gene expression, spatial transcriptomics, striatal subregions
- MeSH terms
- Animals, Corpus Striatum, Goals, Male, Mice, Inbred C57BL, Neural Pathways, Receptors, Dopamine D1, Receptor, Melanocortin, Type 4, Mice, Melanocortins, Central Amygdaloid Nucleus
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