Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function
Open accessAbstract
Glucocorticoid hormones are important in the maintenance of many brain functions. Although their receptors are distributed abundantly throughout the brain, including the prefrontal cortex (PFC), it is not clear how glucocorticoid functions, particularly with regard to cognitive processing in the PFC. There is evidence of PFC cognitive deficits such as working memory impairment in several stress-related neuropsychiatric disorders, including depression, schizophrenia, and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA) system, which is characterized by attenuated glucocorticoid negative feedback, is also observed. In rats, chronic stress induces working memory impairment as a result of decreased dopaminergic transmission in the PFC. These chronically stressed rats also show HPA disruption; this is caused in part by a reduced glucocorticoid response in the PFC. These findings implicate reduced glucocorticoid actions in working memory impairment. In the present study, we examined the effects of the suppression of endogenous glucocorticoids by adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC dopaminergic activities in memory. The ADX impaired working memory, decreased dopamine release, and upregulated D 1 receptors in the PFC. These dysfunctions were prevented by corticosterone replacement that reproduced normal physiological plasma levels, indicating that suppression of glucocorticoids causes these dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated by intra-PFC infusions of a D 1 receptor agonist, SKF 81297. Thus, suppression of glucocorticoids impaired working memory through a D 1 receptor-mediated hypodopaminergic mechanism in the PFC. This finding indicates that endogenous glucocorticoids are essential for maintaining PFC cognitive function and suggests that HPA disruption contributes to PFC cognitive deficits.
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Decreased GR expression and dopamine transmission in the prefrontal cortex in rats exposed to chronic stress are associated with working memory deficits.
“Likewise, decreased GR expression and dopamine transmission in the prefrontal cortex in rats exposed to chronic stress are associated with working memory deficits [126,127] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [127]
The associated downregulation of prefrontal GRs may contribute to decreased prefrontal dopamine transmission after chronic stress.
“Contributing to this effect may be the associated downregulation of prefrontal GRs [127] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [127]
The association between executive functions and stress physiology partly reflects modulation of synaptic activity in prefrontal cortex circuitry by stress hormones.
“The association between executive functions and stress physiology in part reflects the fact that stress hormone levels modulate synaptic activity in the neural circuitry of PFC that underlies executive functions (Arnsten & Li, 2005; Mizoguchi, Ishige, Takeda, Aburada, & Tabira, 2004).”
From Salivary cortisol mediates effects of poverty and parenting on executive functions in early childhood (2011) · cites this paper as Mizoguchi, Ishige, Takeda, Aburada, & Tabira, 2004
In human and animal studies, glucocorticoid and catecholamine levels have an inverted-U relation with executive functions: very high or very low levels are linked to deficits, while moderate increases are linked to higher executive function.
“In both human and animal studies, glucocorticoid and catecholamine (dopamine, norepinephrine) levels demonstrate an inverted U shaped relation with EFs. Very high or very low levels of glucocorticoids and catecholamines are associated with deficits in EFs, whereas moderate increases are associated with higher level of EFs (Arnsten & Li, 2005; Lupien, Gillin, & Hauger, 1999; Mizoguchi, et al., 2004”
From Stress and the development of self-regulation in context (2010) · cites this paper as Mizoguchi, et al., 2004
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References 57 · Cited by 192
- Authors
- Mizoguchi, K., Ishige, A., Takeda, S., Aburada, M., & Tabira, T.
- Affiliations
- Tsumura (Japan) (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-06-16
- Volume
- 24
- Issue
- 24
- Pages
- 5492-5499
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729338
- OpenAlex
- W2129097378
- Cited by
- 192
- References
- 57
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 10 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 14 · 2015: 14 · 2014: 9 · 2013: 11 · 2012: 8
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Health Sciences Foundation
- 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
- endogenous glucocorticoids, prefrontal cortex, working memory, adrenalectomy, corticosterone replacement, dopamine release, dopamine D1 receptor, hypothalamic-pituitary-adrenal axis, chronic stress, glucocorticoid negative feedback, stress-related neuropsychiatric disorders, SKF 81297
- MeSH terms
- Adrenalectomy, Animals, Benzazepines, Cognition, Corticosterone, Dopamine, Glucocorticoids, Male, Memory, Neurons, Radioligand Assay, Rats, Wistar, Prefrontal Cortex, Receptors, Dopamine D1, Microdialysis, Rats
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