Layer-specific input to medial prefrontal cortex is linked to stress susceptibility
Open accessPublished version of a preprint
Abstract
Stress response is essential for adapting to an ever-changing environment. However, the mechanisms that render some individuals susceptible to stress are poorly understood. While chronic stress is known to induce dendritic atrophy and spine loss in medial prefrontal cortex (mPFC), its impact on synapses made by long-range projections terminating on the mPFC remains unknown. Here, we labeled synapses on male mouse mPFC dendrites formed by ventral hippocampus (VH), basolateral amygdala (BLA) and ventral tegmental area (VTA) long-range afferents using different-colored eGRASP constructs. We obtained multispectral 3D-images of the mPFC covering all cortical laminae, and automatically segmented the dendrites and synapses. In layer II/III, the relative abundances and spatial organizations of VH-mPFC and BLA-mPFC synapses changed similarly in stress resilient (SR) and stress susceptible (SS) mice when compared to stress naïve (SN) mice. In layers Vb and VI, on the other hand, the percentage of BLA-mPFC synapses increased and that of VH-mPFC decreased only in SS mice. Moreover, the distances of VH synapses to their corresponding closest BLA synapses decreased and the distances of BLA synapses to their corresponding closest VH synapses increased in the SS group. Consistently, the percentage of single dendritic segments receiving input from multiple brain regions increased in the SS group, suggesting that long-range synaptic inputs to deep layers of mPFC were disorganized in SS mice. Our findings demonstrate afferent- and lamina-specific differential reorganization of synapses between different stress phenotypes, suggesting specific roles for different long-range projections in mediating the stress response.
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Dysregulation of mPFC activity, particularly within L5 projection neurons, is implicated in the pathophysiology of depression through clinical imaging and preclinical models.
“Dysregulation of mPFC activity—particularly within layer 5 (L5) projection neurons—has been implicated in the pathophysiology of depression through both clinical imaging studies and preclinical models [12–14].”
From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [14]
The Introduction (page not available) links mPFC activity and layer V neuronal changes to stress and depression-like behavior in preclinical models. The Discussion (page not available) reports disrupted inputs to deep mPFC layers in stress-susceptible mice. The paper does not provide clinical imaging evidence or establish that the disruption is specifically within layer V projection neurons. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrior studies demonstrate layer-specific or region-specific excitation-inhibition imbalance in stress-related circuits.
“These studies demonstrate layer-specific or region-specific excitation–inhibition imbalance in stress-related circuits”
From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [14]
The Results (page not provided) report layer- and brain-region-specific changes in synaptic inputs in stress-susceptible mice. However, the Methods specify that the mapped projections were excitatory; the cited findings do not establish an excitation–inhibition imbalance. (LLM, conf=0.86)
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Zhao, X., Shah, P. T., Feng, L., Song, S., Feng, Y., Wu, C., Liu, R., Wang, Y., Zhang, S., & Wu, Z. (2025) · Neuroscience Letters · doi:10.1016/j.neulet.2025.138366 · Cited by 1 · see citing works
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- Authors
- Solakoğlu, S. T., Erdener, Ş. E., Gliko, O., Can, A., Sümbül, U., & Eren-Koçak, E.
- Affiliations
- Hacettepe University (TR)
- Allen Institute for Brain Science (US)
- Ankara University (TR)
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2025-04-09
- Volume
- 15
- Issue
- 1
- Pages
- 134-134
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC11982315
- OpenAlex
- W4409284422
- Cited by
- 5
- References
- 72
- Citations by year
- 2026: 4 · 2025: 1
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Hacettepe Üniversitesi (TSA-2020-18753)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- medial prefrontal cortex, stress vulnerability, chronic stress, ventral hippocampus, basolateral amygdala, ventral tegmental area, synaptic organization, cortical layers, dendritic spine loss, stress resilience
- MeSH terms
- Animals, Dendrites, Hippocampus, Male, Mice, Inbred C57BL, Stress, Psychological, Synapses, Prefrontal Cortex, Ventral Tegmental Area, Mice, Basolateral Nuclear Complex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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