Loss of prefrontal cortical higher cognition with uncontrollable stress: molecular mechanisms, changes with age, and relevance to treatment
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The newly evolved prefrontal cortex (PFC) generates goals for "top-down" control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC "off-line." High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular "brakes" on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder.
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Stress impedes top-down regulation of subcortical structures such as the amygdala, leading to a reactive and reflexive state that could promote maladaptive cognitive processing and irrational behaviors.
“Indeed, stress impedes top-down regulation of subcortical structures such as the amygdala, leading to a reactive and reflexive state that could promote maladaptive cognitive processing and irrational behaviors (Datta & Arnsten, 2019).”
From Toward objective characterizations of suicide risk: A narrative review of laboratory-based cognitive and behavioral tasks (2023) · cites this paper as Datta & Arnsten, 2019
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Self-citationThe Catechol-O-Methyltransferase Gene
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Stress produces opioid-like effects on investigatory behavior
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Algaidi, S. A. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149461 · Cited by 40 · see citing works
Jakovljevic, K., Kober, K. M., Block, A., Cooper, B. A., Paul, S. M., Hammer, M. J., Cartwright, F., Conley, Y. P., Wright, F., Dunn, L. B., et al. (2021) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2020.07.019 · Cited by 32 · see citing works
Lamontagne, S. J., Zabala, P. K., Zarate, C. A., & Ballard, E. D. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105361 · Cited by 12 · see citing works
- Authors
- Datta, D., & Arnsten, A.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy
- Venue
- Brain Sciences
- Publisher
- MDPI AG
- Published
- 2019-05-17
- Volume
- 9
- Issue
- 5
- Pages
- 113
- ISSN
- 2076-3425 (ISSN-L)
- PMC
- PMC6562841
- OpenAlex
- W2946613615
- Cited by
- 78
- References
- 144
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 11 · 2023: 15 · 2022: 7 · 2021: 6 · 2020: 12 · 2019: 4
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Brain Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (AG061190-01)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- prefrontal cortex, uncontrollable stress, chronic stress, top-down control, norepinephrine, dopamine, alpha1-adrenoceptors, dopamine D1 receptor, potassium channels, dendritic atrophy, synaptic spines, adolescence, aging, phosphodiesterase, guanfacine, childhood trauma, prazosin, post-traumatic stress disorder, stress-related disorders
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