The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress
Open accessAbstract
The prefrontal cortex r regulates behavior, cognition, and emotion by using working memory. Prefrontal functions are impaired by stress exposure. Acute, stress-induced deficits arise from excessive protein kinase C (PKC) signaling, which diminishes prefrontal neuronal firing. Chronic stress additionally produces architectural changes, reducing dendritic complexity and spine density of cortico-cortical pyramidal neurons, thereby disrupting excitatory working memory networks. In vitro studies have found that sustained PKC activity leads to spine loss from hippocampal-cultured neurons, suggesting that PKC may contribute to spine loss during chronic stress exposure. The present study tested whether inhibition of PKC with chelerythrine before daily stress would protect prefrontal spines and working memory. We found that inhibition of PKC rescued working memory impairments and reversed distal apical dendritic spine loss in layer II/III pyramidal neurons of rat prelimbic cortex. Greater spine density predicted better cognitive performance, the first direct correlation between pyramidal cell structure and working memory abilities. These findings suggest that PKC inhibitors may be neuroprotective in disorders with dysregulated PKC signaling such as bipolar disorder, schizophrenia, post-traumatic stress disorder, and lead poisoning—conditions characterized by impoverished prefrontal structural and functional integrity.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion.”
From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“stress increases, while guanfacine inhibits, the feedforward Ca2+-cAMP-PKA-K+ actions that weaken PFC network connectivity, neuronal firing and function.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“stress increases, while guanfacine inhibits, the feedforward Ca2+-cAMP-PKA-K+ actions that weaken PFC network connectivity, neuronal firing and function.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2009
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Loss of dendritic spines and/or dendrites is accompanied by, and often correlates with, the loss of PFC cognitive functioning.”
From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“With chronic stress exposure, dendritic spines are lost from layer II/III pyramidal cells in rat mPFC”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“Research in rats by Avis Hains has shown that inhibition of PKC or PKA signaling can prevent the loss of mPFC dendritic spines and working memory abilities during chronic stress exposure (Hains et al., 2009, Hains et al., 2015), suggesting that the sustained weakening of synaptic connectivity via K+ channel opening contributes to spine loss.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“With chronic stress exposure, there is architectural loss of mPFC spines and dendrites (Moda-Sava et al., 2019, Radley et al., 2006) that correlates with impaired PFC cognitive functioning (Hains et al., 2009, Hains et al., 2015, Liston et al., 2006).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“Dendritic spine loss from layer II/III pyramidal cells in the prelimbic medial PFC correlates with impaired working memory on the delayed alternation task75.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [75]
The cited source says what the claim attributes to it.
In the citing paper
“The protection of dendritic spines correlates with preserved working memory function75.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [75]
The cited source says what the claim attributes to it.
In the citing paper
“Inhibition of PKC signaling before daily stress exposure in rats prevents the loss of spines from layer II/III PFC pyramidal cells normally observed with chronic stress75.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [75]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cellular basis of working memory
Goldman-Rakic, P. S. (1995) · Neuron · doi:10.1016/0896-6273(95)90304-6 · Cited by 2,663
MCEWEN, B. S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1314.001 · Cited by 1,638
Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia
Glantz, L. A., & Lewis, D. A. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.1.65 · Cited by 1,636
Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS
Green, M. F., Kern, R. S., & Heaton, R. K. (2004) · Schizophrenia Research · doi:10.1016/j.schres.2004.09.009 · Cited by 1,422
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Dalley, J. W., Cardinal, R. N., & Robbins, T. W. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.09.006 · Cited by 1,329
Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V., & Arnsten, A. F. T. (2007) · Nature Neuroscience · doi:10.1038/nn1846 · Cited by 1,013
Self-citationListon, C., Miller, M. M., Goldwater, D. S., Radley, J. J., Rocher, A. B., Hof, P. R., Morrison, J. H., & McEwen, B. S. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1184-06.2006 · Cited by 968
Psychosocial stress reversibly disrupts prefrontal processing and attentional control
Liston, C., McEwen, B. S., & Casey, B. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807041106 · Cited by 859
Repeated Stress Induces Dendritic Spine Loss in the Rat Medial Prefrontal Cortex
Radley, J. J., Rocher, A. B., Miller, M., Janssen, W. G. M., Liston, C., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhi104 · Cited by 820
Chronic stress alters dendritic morphology in rat medial prefrontal cortex
Cook, S. C., & Wellman, C. L. (2004) · Journal of Neurobiology · doi:10.1002/neu.20025 · Cited by 785
Cited by
Sorted by citations
Items 201–231 of 231
THE ROLE OF DENDRITIC BDNF TRANSCRIPTS ON ALTERED INHIBITORY CIRCUITRY IN AGING AND DEPRESSION
Oh, H. (2015) · D-Scholarship@Pitt (University of Pittsburgh)
Glucocorticoid modulation of the mesocortical dopamine system and aspects of executive function
Butts, K. A. (2013) · cIRcle (University of British Columbia) · doi:10.14288/1.0073693
Li, Z., Wang, S., & Xu, T. (2017) · International Conference on Photonics and Imaging in Biology and Medicine (PIBM) · doi:10.1364/pibm.2017.w3a.88
Efeitos comportamentais e neuroplásticos da combinação de escitalopram e canabinóides
Scarante, F. F. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.17.2018.tde-25072018-103829
Roedding, A. S. (2013) · TSpace (University of Toronto)
Fish Oil Supplementation for Depression
McNamara, R. K., Almeida, D. M., & Strawn, J. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811297-7.00029-9
Arnsten, A. F. T. (2020) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190069162.013.4
Self-citationАбрамец, И. И., Евдокимов, Д. В., Кузнецов, Ю. В., & Сидорова, Ю. В. (2020) · Университетская клиника · doi:10.26435/uc.v0i3(36).559
Stress Systems and Brain Maturation During Adolescence
Wong, A. P. (2018) · TSpace (University of Toronto)
Hen, R. (2011) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.7494957.7789055
Sportaktivität, Stress und das Gehirn
Ludyga, S. (2016) · Springer eBooks · doi:10.1007/978-3-662-49411-0_11-1
Vulnerability and resilience to stressful and traumatic events
Gruene, T. M. (2017) · Digital Repository Service (Northeastern University) · doi:10.17760/d20252694
Gould, E., & Leuner, B. (2010) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.5558963.5526066
Chemobrain: Mysteries and the importance of their revelation
Tuncer, M. (2022) · Hacettepe University Journal of the Faculty of Pharmacy · doi:10.52794/hujpharm.1100269
Modulação da plasticidade sináptica por TREK-1 e 5HT>sub<1A>/sub< no estresse crônico pós-natal.
de Oliveira, J. F. (2020) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2020.tde-23092021-134813
Bal, F. (2023) · Medicine International · doi:10.3892/mi.2023.115
Adaptation to intermittent hypoxia protects the brain in post-traumatic stress disorder
Manukhina, E. B., Цейликман, В. Э., Tseilikman, O. B., & Dauni, G. F. (2023) · Nauchno-prakticheskii zhurnal «Patogenez» · doi:10.25557/2310-0435.2023.04.4-12
Nesengani, L., Sherington, V. A., & Snaifer, C. (2024) · Medical Journal of Cell Biology · doi:10.2478/acb-2024-0003
The circuit mechanisms of working memory: Key roles of the dorsolateral prefrontal cortex
Arnsten, A. F. T., & Martínez-Trujillo, J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15754-7.00038-9
Self-citationAdditional file 4 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853519
Additional file 3 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853516
Additional file 5 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853522
Additional file 7 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853528
Additional file 9 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853534
Additional file 1 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853510
Additional file 2 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853513
Additional file 8 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853531
Additional file 6 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853525
Cabré, L. R. (2012) · Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona)
Metadata
- Authors
- Hains, A. B., Vu, M. A. T., Maciejewski, P. K., van Dyck, C. H., Gottron, M., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy F. T.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-10-20
- Volume
- 106
- Issue
- 42
- Pages
- 17957-17962
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2742406
- OpenAlex
- W1996838710
- Cited by
- 234
- References
- 66
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 12 · 2022: 15 · 2021: 23 · 2020: 13 · 2019: 15 · 2018: 13 · 2017: 19 · 2016: 14 · 2015: 20 · 2014: 15 · 2013: 17 · 2012: 12
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- U.S. Public Health Service
- National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
- National Institute on Aging (R37AG006036)
- National Institute of Mental Health (P50MH068789)
- National Institute of Neurological Disorders and Stroke (K25NS044316)
- National Center for Research Resources (U54RR024350)
- 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
- protein kinase C, chronic stress, dendritic spines, prefrontal cortex, working memory, chelerythrine, prelimbic cortex, pyramidal neurons, spine loss, neuroprotection, cognitive impairment, bipolar disorder, schizophrenia, post-traumatic stress disorder, lead poisoning
- MeSH terms
- Animals, Atrophy, Cognition, Disease Models, Animal, Humans, Male, Memory, Models, Neurological, Protein Kinase C, Stress, Physiological, Stress, Psychological, Signal Transduction, Rats, Sprague-Dawley, Prefrontal Cortex, Protein Kinase Inhibitors, Dendritic Spines, Rats, Benzophenanthridines
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 ›
Are you an author, or do you see a problem with this page? Request a review
