SEROTONERGIC ANXIETY IS A STRESS INTENSITY-DEPENDENT STATE MEDIATED BY DOPAMINERGIC SIGNALING
- 1University of Copenhagen
Abstract
Despite the central role attributed to serotonin in anxiety, its involvement and therapeutic efficacy are inconsistent, raising the possibility that serotonergic recruitment depends on the stress history from which anxiety emerges. Using larval zebrafish, we combined graded glucocorticoid exposure with chemogenetic DRN manipulation, whole-brain activity mapping, and pharmacology to test whether stress intensity determines serotonergic involvement in anxiety.Increasing stress intensity did not simply increase anxiety severity but generated distinct anxiety phenotypes. Lower glucocorticoid exposure produced context-general anxiety that required the serotonergic DRN, whereas higher exposure produced context-dependent, DRN-independent anxiety. Whole-brain mapping identified a posterior tubercular/hypothalamic dopaminergic region associated with DRN-dependent anxiolysis, while D1, but not D2 receptor antagonism abolished the anxiolytic effect of DRN ablation. Finally, environmentally relevant nanomolar concentrations of methylphenidate reduced anxiety-like behavior, further supporting dopaminergic modulation of anxiety. Together, our findings identify stress intensity as a determinant of serotonergic recruitment during anxiety, reveal a downstream contribution of D1-dependent dopaminergic signaling, and provide a framework for understanding the mechanistic heterogeneity of anxiety and its variable response to serotonergic treatments.
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BibTeX
@misc{varga2026serotonergic,
title = {{SEROTONERGIC ANXIETY IS A STRESS INTENSITY-DEPENDENT STATE MEDIATED BY DOPAMINERGIC SIGNALING}},
author = {Z. K. Varga and J. V. Mieghem and L. Jimenez-Fernandez and A. Ujhelyi and F. Kermen},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747812},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747812v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - SEROTONERGIC ANXIETY IS A STRESS INTENSITY-DEPENDENT STATE MEDIATED BY DOPAMINERGIC SIGNALING
AU - Z. K. Varga
AU - J. V. Mieghem
AU - L. Jimenez-Fernandez
AU - A. Ujhelyi
AU - F. Kermen
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747812
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747812v1
AB - Despite the central role attributed to serotonin in anxiety, its involvement and therapeutic efficacy are inconsistent, raising the possibility that serotonergic recruitment depends on the stress history from which anxiety emerges. Using larval zebrafish, we combined graded glucocorticoid exposure with chemogenetic DRN manipulation, whole-brain activity mapping, and pharmacology to test whether stress intensity determines serotonergic involvement in anxiety.Increasing stress intensity did not simply increase anxiety severity but generated distinct anxiety phenotypes. Lower glucocorticoid exposure produced context-general anxiety that required the serotonergic DRN, whereas higher exposure produced context-dependent, DRN-independent anxiety. Whole-brain mapping identified a posterior tubercular/hypothalamic dopaminergic region associated with DRN-dependent anxiolysis, while D1, but not D2 receptor antagonism abolished the anxiolytic effect of DRN ablation. Finally, environmentally relevant nanomolar concentrations of methylphenidate reduced anxiety-like behavior, further supporting dopaminergic modulation of anxiety. Together, our findings identify stress intensity as a determinant of serotonergic recruitment during anxiety, reveal a downstream contribution of D1-dependent dopaminergic signaling, and provide a framework for understanding the mechanistic heterogeneity of anxiety and its variable response to serotonergic treatments.
ER -