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Stress weakens prefrontal networks: molecular insults to higher cognition

Nature Neuroscience volume 18, pages 1376–1385 (2015)Cite this article

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Abstract

A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium–protein kinase C and cyclic AMP–protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer's degeneration.

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Figure 1: Changes in brain systems controlling behavior under conditions of alert safety versus uncontrollable stress.
Figure 2: The cellular basis of working memory, as discovered by Goldman-Rakic.
Figure 3: Dynamic network connectivity (DNC) in the primate dlPFC.

Marina Corral Spence/Nature Publishing Group

Figure 4: Hypothetical interactions between the intracellular signaling pathways activated by stress exposure and pathways that regulate actin dynamics and inflammation.

Marina Corral Spence/Nature Publishing Group

Figure 5: The multiple, interacting, feedforward vicious cycles that may be disinhibited in the aging dlPFC, contributing to increased vulnerability to degeneration.

Marina Corral Spence/Nature Publishing Group

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Acknowledgements

Gratitude to S. Katrancha for discussions regarding spine dynamics. A.F.T.A. is supported by a US National Institutes of Health Director's Pioneer Award DP1AG047744-01, R01AG043430-01A1 and RO1MH100064-01A1.

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  1. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Amy F T Arnsten

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Correspondence to Amy F T Arnsten.

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A.F.T.A. and Yale University receive royalties from Shire Pharmaceuticals from the sales of Intuniv (extended release guanfacine) for the treatment of pediatric ADHD. They do not receive royalties from generic forms of Intuniv.

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Arnsten, A. Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci 18, 1376–1385 (2015). https://doi.org/10.1038/nn.4087

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