The DOI matches its Crossref record; 166 of the 168 references it cites were found in a registry or an index.
Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses
Open accessAbstract
This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-cAMP signaling by stimulating α2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing, whereas optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia.
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“Immunoelectron microscopy studies of human126 and rhesus monkey13,127 dlPFC show that DISC1 is located in layer III spines, where it anchors PDE4A next to the spine apparatus, critically positioned to regulate feedforward cAMP–Ca2+ stress signaling pathways13,127.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [13]
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“Exposure to stress, however, can disrupt PFC function, markedly impairing working memory (Arnsten, 2009; Arnsten et al., 2012).”
From Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex (2013) · cites this paper as Arnsten et al., 2012
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“In these circuits, cAMP-PKA signaling opens nearby potassium (K+) channels to rapidly weaken synaptic strength and reduce Delay cell firing (Fig. 3C; (Arnsten et al., 2012)).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 2012
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“Layer III dlPFC microcircuits that generate mental representations have unique molecular needs for both neurotransmission and neuromodulation that allow them to sustain long periods of neuronal firing without bottom-up sensory stimulation (Arnsten, 2015, Arnsten et al., 2012).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 2012
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In the citing paper
“These very rapid changes in synapse strength, called dynamic network connectivity13, are mediated by feedforward, cAMP–Ca2+ signaling, which opens K+ channels (HCN, KCNQ) near the synapse to weaken the connection.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [13]
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“Physiological, behavioral and immunoelectron microscopic evidence suggest that these pathways interact: feedforward Ca2+–cAMP signaling opens nearby HCN and KCNQ K+ channels to weaken the efficacy of nearby NMDAR synaptic connections13.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [13]
In the citing paper
“Pharmacological investigations indicate that this relationship depends upon the level of release of neuromodulators, such as dopamine and norepinephrine (Arnsten, 2009; Arnsten et al., 2012).”
From Waking state: rapid variations modulate neural and behavioral responses (2015) · cites this paper as Arnsten et al., 2012
In the citing paper
“Activation of receptors for these neuromodulators at intermediate levels may enhance performance on PFC dependent tasks, whereas further increases may result in a decrement in behavioral performance and reduced neural representation of that performance in the PFC (reviewed in (Arnsten, 2009; Arnsten et al., 2012)).”
From Waking state: rapid variations modulate neural and behavioral responses (2015) · cites this paper as Arnsten et al., 2012
In the citing paper
“In tasks that require prefrontal cortical (PFC) function, there is an inverted U relationship between stress and performance.”
From Waking state: rapid variations modulate neural and behavioral responses (2015) · cites this paper as Arnsten et al., 2012
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Citations
Cites
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Cited by
Sorted by citations
The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course
McEwen, B. S., & Morrison, J. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.028 · Cited by 1,079
SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse
Koopmans, F., van Nierop, P., Andres-Alonso, M., Byrnes, A., Cijsouw, T., Coba, M. P., Cornelisse, L. N., Farrell, R. J., Goldschmidt, H. L., Howrigan, D. P., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.002 · Cited by 938
Orienting and reorienting: the locus coeruleus mediates cognition through arousal
Sara, S. J., & Bouret, S. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.011 · Cited by 1,056
Dynamic adaptation of large-scale brain networks in response to acute stressors
Hermans, E. J., Henckens, M. J. A. G., Joëls, M., & Fernández, G. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.03.006 · Cited by 988
Waking state: rapid variations modulate neural and behavioral responses
McGinley, M. J., Vinck, M., Reimer, J., Batista-Brito, R., Zagha, E., Cadwell, C. R., Tolias, A. S., Cardin, J. A., & McCormick, D. A. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.012 · Cited by 801
“Pharmacological investigations indicate that this relationship depends upon the level of release of neuromodulators, such as dopamine and norepinephrine (Arnsten, 2009; Arnsten et al., 2012).”
Metadata
- Authors
- Arnsten, A. F. T., Wang, M. J., & Paspalas, C. D.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy F.T.
- ORCID
- Arnsten, Amy F.T.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 76
- Issue
- 1
- Pages
- 223-239
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3488343
- OpenAlex
- W2087809804
- Cited by
- 538
- References
- 168
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 27 · 2023: 56 · 2022: 30 · 2021: 47 · 2020: 39 · 2019: 28 · 2018: 39 · 2017: 32 · 2016: 41 · 2015: 58 · 2014: 42 · 2013: 38 · 2012: 3
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale University
- National Alliance for Research on Schizophrenia and Depression
- Zorginstituut Nederland
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
- National Institute on Aging (P01AG030004)
- National Institute of Mental Health (MH 09335401, R01MH093354)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- neuromodulation, working memory, prefrontal cortex, NMDA receptor, dendritic spines, alpha2A-adrenoceptor, dopamine D1 receptor, recurrent excitation, aging, schizophrenia, fatigue, stress
- MeSH terms
- Animals, Humans, Nerve Net, Synaptic Transmission, Synapses, Thinking, Prefrontal Cortex, Neurotransmitter Agents
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