Dorsal raphe neuroinflammation promotes dramatic behavioral stress dysregulation
Open accessAbstract
Impulsivity, risk-taking behavior, and elevated stress responsivity are prominent symptoms of mania, a behavioral state common to schizophrenia and bipolar disorder. Though inflammatory processes activated within the brain are involved in the pathophysiology of both disorders, the specific mechanisms by which neuroinflammation drives manic behavior are not well understood. Serotonin cell bodies originating within the dorsal raphe (DR) play a major role in the regulation of behavioral features characteristic of mania. Therefore, we hypothesized that the link between neuroinflammation and manic behavior may be mediated by actions on serotonergic neurocircuitry. To examine this, we induced local neuroinflammation in the DR by viral delivery of Cre recombinase into interleukin (IL)-1β(XAT) transgenic male and female mice, resulting in overexpressing of the proinflammatory cytokine, IL-1β. For assertion of brain-region specificity of these outcomes, the prefrontal cortex (PFC), as a downstream target of DR serotonergic projections, was also infused. Inflammation within the DR, but not the PFC, resulted in a profound display of manic-like behavior, characterized by increased stress-induced locomotion and responsivity, and reduced risk-aversion/fearfulness. Microarray analysis of the DR revealed a dramatic increase in immune-related genes, and dysregulation of genes important in GABAergic, glutamatergic, and serotonergic neurotransmission. Behavioral and physiological changes were driven by a loss of serotonergic neurons and reduced output as measured by high-performance liquid chromatography, demonstrating inflammation-induced serotonergic hypofunction. Behavioral changes were rescued by acute selective serotonin reuptake inhibitor treatment, supporting the hypothesis that serotonin dysregulation stemming from neuroinflammation in the DR underlies manic-like behaviors.
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Activation of Gi-coupled pathways on pvMΦs via 5-HT1B receptors is a potential mechanism for the regulation of macrophage polarization and inflammatory responses by tonic 5-HT release within the DRN.
“Activation of Gi-coupled pathways on pvMΦs via 5-HT1B receptors is also a potential mechanism for the regulation of macrophage polarization and inflammatory responses by tonic 5-HT release within the DRN, which may be relevant to the increasing importance of neuroinflammatory pathways in the etiology of psychiatric disorders (Brisch et al., 2017; Howerton et al., 2014; Watkins et al., 2014).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Howerton et al., 2014
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Takahashi, A., & Russo, S. J. (2023) · Springer eBooks · doi:10.1007/978-3-031-31547-3_146 · Cited by 1 · see citing works
Cytokines, Chemokines, and Inflammatory Indicators in Bipolar Disorder
Poletti, S., Dallaspezia, S., & Spadini, S. (2024) · Springer eBooks · doi:10.1007/978-3-031-32035-4_22-1
Cytokines, Chemokines, and Inflammatory Indicators in Bipolar Disorder
Poletti, S., Dallaspezia, S., & Spadini, S. (2025) · Springer eBooks · doi:10.1007/978-3-031-73368-0_22
Khan, K. M., Balasubramanian, N., Gaudencio, G., Wang, R., Selvakumar, G. P., Kolling, L. J., Pierson, S. R., Tadinada, S. M., Abel, T. G., Hefti, M. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22620608
Terhune, T. D., Ghafourian, T., Eshraghi, R. S., Eshraghi, A. A., & Deth, R. C. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05842-8
Huang, K. W. (2019) · Harvard Dataverse · doi:10.7910/dvn/qb5cc8
- Authors
- Howerton, A. R., Roland, A. V., & Bale, T. L.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-05-21
- Volume
- 34
- Issue
- 21
- Pages
- 7113-7123
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4028491
- OpenAlex
- W2071527161
- Cited by
- 33
- References
- 66
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 3 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 1
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- University of Rochester
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- National Institute of Mental Health (P50MH099910, R01MH073030, MH 073030)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK019525)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD026979, P-30-HD26979)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- dorsal raphe nucleus, neuroinflammation, mania, serotonin, serotonergic neurons, IL-1β, stress responsivity, risk-taking, prefrontal cortex, immune gene expression, selective serotonin reuptake inhibitors, bipolar disorder, schizophrenia
- MeSH terms
- Dependovirus, Animals, Disease Models, Animal, Encephalitis, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Mice, Transgenic, Raphe Nuclei, Stress, Psychological, Citalopram, Selective Serotonin Reuptake Inhibitors, Maze Learning, Mice, Interleukin-1beta, Serotonergic Neurons
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