Stress signalling pathways that impair prefrontal cortex structure and function

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Abstract
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.