Review Article | Published:

Stress signalling pathways that impair prefrontal cortex structure and function

Nature Reviews Neuroscience volume 10, pages 410422 (2009) | Download Citation

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Abstract

The prefrontal cortex (PFC) — the most evolved brain region — subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.

Key points

  • The prefrontal cortex (PFC) provides 'top-down', higher-order guidance of thought, attention, behaviour and emotion, with dorsolateral regions regulating cognition, and ventromedial regions regulating emotion.

  • The ability of the PFC to represent information in working memory requires interconnected neuronal networks. For example, spatial working memory requires spatially tuned, persistent firing while information is held 'in mind'; this persistent firing arises from recurrent excitation in a network of similarly tuned prefrontal neurons.

  • Prefrontal networks are very sensitive to their neurochemical environment. Either too little or too much noradrenaline or dopamine markedly impairs prefrontal spatial working memory function.

  • Exposure to even quite mild uncontrollable stress causes a rapid impairment in prefrontal function in animals and humans. This might have survival value when we are in danger but be maladaptive when the situation requires higher order or complex responses.

  • Stress impairs prefrontal working memory abilities through high levels of monoamine and glucocorticoid release. These neurochemical events involve powerful intracellular signalling events that reduce prefrontal firing and impair performance: high levels of cyclic AMP–hyperpolarization-activated cyclic nucleotide-gated (HCN) channel signalling weaken prefrontal network connectivity, and high levels of phosphatidylinositol–protein kinase C signalling suppress prefrontal firing.

  • The same neurochemical events that impair prefrontal working memory abilities actually strengthen the emotional operations of the amygdala. Thus, uncontrollable stress switches control of behaviour from the thoughtful PFC to the more primitive conditioned responses of the amygdala.

  • With chronic stress or glucocorticoid exposure the dendrites and dendritic spines of prefrontal pyramidal cells retract, whereas dendrites in the amygdala expand. Loss of dendritic material from prefrontal pyramidal cells correlates with loss of prefrontal cognitive abilities.

  • Many mental illnesses are worsened by stress exposure and are associated with impaired prefrontal function and reduced prefrontal grey matter. Recent genetic studies show that many of the molecules that inhibit intracellular stress signalling pathways can be altered in families with mental illness, which might increase susceptibility to prefrontal dysfunction.

  • Environmental insults can also erode prefrontal function by activating stress pathways. For example, lead poisoning may impair prefrontal function by potently activating protein kinase C.

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Acknowledgements

Much of the research cited in this Review has been supported by MERIT Award AG06036, and by P50MH068789, PO1AG030004 and RL1AA017536 as part of U54RR024350, as well as by the Kavli Neuroscience Institute at Yale and a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award to A.F.T.A.

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  1. Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.  amy.arnsten@yale.edu

    • Amy F. T. Arnsten

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Competing interests

Amy F. T. Arnsten

Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience 10, 410–422 (2009); doi:10.1038/nrn2648

Amy F. T. Arnsten and Yale University have licence agreements with Shire Pharmaceuticals for the development of guanfacine for the treatment of attention-deficit hyperactivity disorder and related disorders, and a licence under negotiation for the development of chelerythrine for the treatment of bipolar disorder, post-traumatic stress disorder and related conditions.

Glossary

Attentional set

A predisposition to attend to one dimension of a stimulus while inhibiting other dimensions — for example, attending to colour rather than shape.

Trier social stress test

A test in which subjects have to give a speech and perform calculations in front of a panel of people they do not know. Blood or saliva samples and blood pressure measurements can be taken before, during and after the test to determine the physical response to the stressor.

Learned helplessness paradigm

A paradigm developed more than 30 years ago in which rats were exposed to inescapable shock, and supposedly learned that they were helpless to respond. Research has debunked this interpretation and instead determined that uncontrollable stress can cause cognitive deficits.

Y-maze task

A task in which rats must learn to escape from a Y-shaped maze by making the correct decision. Exposure to uncontrollable stress and the presence of task-irrelevant cues in the maze has been found to impair performance.

Spatial delayed alternation task

A test of spatial working memory for primates or rodents in which the subject is required to make alternate responses on successive trials, with a delay period interposed between trials.

Tuned persistent firing of neurons

The neuronal representation of a specific stimulus — for example, a cue in a specific spatial location. Owing to network connections, a cell can sustain firing without stimulation from the environment, but the sustained firing (in this example) occurs only following a cue to a specific location in space; thus the neuron is 'tuned' to that direction.

Phosphodiesterase

An enzyme that hydrolizes cAMP. Inhibition of phosphodiesterase leads to a build-up in cAMP concentrations.

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https://doi.org/10.1038/nrn2648

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