Journal article
A new insight into the role of CART peptide in serotonergic function and anxiety
The Journal of neuroscience, Vol.45(6), e0467242024
02/05/2025
DOI: 10.1523/JNEUROSCI.0467-24.2024
PMCID: PMC11800755
PMID: 39909575
Abstract
Cocaine- and amphetamine-regulated transcript (CART) peptide has been implicated in stress-related behaviors that are regulated by central serotonergic (5HT) systems in the dorsal raphe nucleus (DRN). Here, we aimed to investigate the interaction between CART and DRN-5HTergic systems after initially observing CART axonal terminals in the DRN. We found that microinfusion of CART peptide (55-102) into the DRN induced anxiogenic effects in male C57BL/6J mice, while central administration of CART reduced cfos in 5HT DRN neurons. This inhibitory effect of exogenous CART on 5HT DRN activity and local 5HT release was also demonstrated via in vivo fiber photometry coupled with calcium and 5HT biosensors. CART inputs to the DRN were observed in various subcortical nuclei, but only those in the Edinger-Westphal-centrally projecting nucleus (EWcp) were highly responsive to stress. Chemogenetic activation of these DRN-projecting CART EWcp neurons recapitulated the effects of intra-DRN CART infusion on anxiety-like behavior in males, but not in females, suggesting a sex-specific role for this pathway. Interestingly, CART EWcp projections to the DRN made direct synaptic contact primarily with non-5HT neurons, which were also found to express putative CART receptors. Furthermore, chemogenetic stimulation of this CART EWcp→DRN pathway inhibited 5HT neurons while increasing activity in local GABAergic neurons. In summary, this study establishes for the first time a neuromodulatroy role for CART EWcp neurons in 5HT DRN neurotransmission and suggests that CART may drive anxiety-like behavior by promoting feedforward inhibition of 5HT neurons.
Significance Statement Cocaine- and amphetamine-regulated transcript (CART) peptide is widely expressed in brain areas that are implicated in anxiety, stress, reward, and addiction. Genetic mutations in the CART gene have been linked to a heightened risk of developing anxiety/stress in adolescents, and particularly in the Edinger Westphal-centrally projecting nucleus (EWcp) upregulation of CART has been linked to depression in suicide victims. Here we report that CART EWcp signaling in the dorsal raphe nucleus (DRN) promotes anxiety-like behavior and inhibits serotonin (5HT) activity in a sex-specific manner.
Details
- Title: Subtitle
- A new insight into the role of CART peptide in serotonergic function and anxiety
- Creators
- Nagalakshmi Balasubramanian - University of IowaRuixiang Wang - University of IowaShafa Ismail - University of IowaBenjamin Hartman - University of IowaZeid Aboushaar - University of IowaCatherine A. Marcinkiewcz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.45(6), e0467242024
- DOI
- 10.1523/JNEUROSCI.0467-24.2024
- PMID
- 39909575
- PMCID
- PMC11800755
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- SOC NEUROSCIENCE
- Grant note
- Iowa Neuroscience InstituteDepartment of Neuroscience and Pharmacology at the University of Iowa
We thank Dr. Jeffrey Friedman (The Rockefeller University, New York, NY, USA) for donating the Cart-IRES2-Cre-D mice, Dr. Uchida Shusaku (Kyoto University, Kyoto, Japan) for providing the CART overexpression virus, and Dr. Yulong Li (Peking University, Beijing, China) for offering the g5-HT2h (GRAB5-HT3.5) biosensor. We acknowledge the University of Iowa Metabolomics Core Facility for performing LCMS analysis and the Viral Vector Core Facility for production of AAV particles. We thank Yu Xu for maintaining mouse colonies and Thomas D. James for tech-nical assistance in fiber photometry. This work was supported by funds from the Iowa Neuroscience Institute and the Department of Neuroscience and Pharmacology at the University of Iowa to C.A.M.
- Language
- English
- Electronic publication date
- 12/30/2024
- Date published
- 02/05/2025
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984770792102771
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