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Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment

Department Neuroscience, Yale Medical School, New Haven, CT 06510, USA
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Brain Sci. 2019, 9(5), 113; https://doi.org/10.3390/brainsci9050113
Received: 17 April 2019 / Revised: 13 May 2019 / Accepted: 13 May 2019 / Published: 17 May 2019
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Abstract

The newly evolved prefrontal cortex (PFC) generates goals for “top-down” control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC “off-line.” High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular “brakes” on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder. View Full-Text
Keywords: prefrontal cortex; stress adolescence; aging; calcium; cAMP; dopamine; norepinephrine prefrontal cortex; stress adolescence; aging; calcium; cAMP; dopamine; norepinephrine
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Datta, D.; Arnsten, A.F.T. Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment. Brain Sci. 2019, 9, 113.

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