Functionally altered neurocircuits in a rat model of treatment-resistant depression show prominent role of the habenula
Abstract
Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. To investigate disease-related alterations of brain function we used a genetic animal model of TRD, congenital learned helplessness (cLH), and functional magnetic resonance imaging as a translational tool. High-resolution regional cerebral blood volume (rCBV) and resting-state functional connectivity measurements were acquired at 9.4T to determine regional dysfunction and interactions that could serve as vulnerability markers for TRD. Effects of cLH on rCBV were determined by statistical parametric mapping using 35 atlas-based regions of interest. Effects of cLH on functional connectivity were assessed by seed region analyses. Significant bilateral rCBV reductions were observed in the lateral habenula, dentate gyrus and subiculum of cLH rats. In contrast, focal bilateral increase in rCBV was observed in the bed nucleus of stria terminalis (BNST), a component of the habenular neurocircuitry. Functional connectivity was primarily enhanced in cLH rats, most notably with respect to serotonergic projections from the dorsal raphe nucleus to the forebrain, within the hippocampal-prefrontal network and between the BNST and lateral frontal regions. Dysregulation of neurocircuitry similar to that observed in depressed patients was detected in cLH rats, supporting the validity of the TRD model and suitability of high-field fMRI as a translational technology to detect and monitor vulnerability markers. Our findings also define neurocircuits that can be studied for TRD treatment in patients, and could be employed for translational research in rodent models.
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In the same animal model, significant differences in functional connectivity were found between the DRN and the OFC.
“In the same study, significant differences in functional connectivity were found within regions with major relevance to serotonergic transmission such as between the dorsal raphe nucleus (DRN) and the OFC (Gass et al., 2014).”
From Circuit Mechanisms of Reward, Anhedonia, and Depression (2019) · cites this paper as Gass et al., 2014
In an animal model of TRD (cLH), rats suffering from cLH showed significant differences in relative cerebral blood flow within the LHb compared with non-cLH rats.
“With relevance to reward processing, a translational study in an animal model of TRD (congenital learned helplessness [cLH]) showed significant differences in relative cerebral blood flow within the LHb in rats suffering from cLH compared with non-cLH rats.”
From Circuit Mechanisms of Reward, Anhedonia, and Depression (2019) · cites this paper as Gass et al., 2014
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Circuit Mechanisms of Reward, Anhedonia, and Depression
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- Authors
- Gass, N., Cleppien, D., Zheng, L., Schwarz, A. J., Meyer-Lindenberg, A., Vollmayr, B., Weber-Fahr, W., & Sartorius, A.
- Affiliations
- Heidelberg University (DE)
- Eli Lilly (United States) (US)
- Corresponding author
- Sartorius, Alexander
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 24
- Issue
- 3
- Pages
- 381-390
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W2094411987
- Cited by
- 36
- References
- 56
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 7
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Seventh Framework Programme
- Bundesministerium für Bildung und Forschung (01EW1110, 115008)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- treatment-resistant depression, habenula, bed nucleus of the stria terminalis, regional cerebral blood volume, resting-state functional connectivity, dorsal raphe nucleus, serotonergic projections, dentate gyrus, subiculum, neurocircuitry, vulnerability indicators, rat model
- MeSH terms
- Animals, Brain, Brain Mapping, Cerebrovascular Circulation, Helplessness, Learned, Magnetic Resonance Imaging, Male, Neural Pathways, Signal Processing, Computer-Assisted, Rats, Sprague-Dawley, Habenula, Rats, Depressive Disorder, Treatment-Resistant
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