Exposure to Uncontrollable Stress Impairs PFC Function

Exposure to even mild, uncontrollable stress causes a rapid loss of PFC function. Feedforward Ca2+-PKC and cAMP-PKA  signaling rapidly opens K+ channels to disconnect dlPFC networks and reduce neuronal firing, i.e. Going To Hell In A Handbasket.


 However, there are mechanisms that inhibit these stress reactions and restore PFC top-down control. Importantly, many of these restorative mechanisms are the target of genetic insults in mental illness.

If you are interested:

  • Arnsten (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 10: 410-22.
  • Birnbaum et al. (2004) Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306: 882-4.


Acute Stress Rapidly takes PFC Offline to Switch Control to more Primitive Circuits

When we are alert and feel in control, there are moderate amounts of release of neuromodulators such as norepinephrine and dopamine which optimize PFC top-down control. However, when we feel stressed and out of control, high levels of norepinephrine and dopamine release rapidly weaken PFC, while strengthening more primitive emotional responses and habits mediated by the amygdala and striatum. This can save our lives when we are in danger and rapid, reflexive responding is needed, but can be detrimental when more thoughtful solutions are needed.

Chronic Stress leads to Architectural Changes

Chronic exposure to uncontrollable stress induces loss of PFC pyramidal cell spines and atrophy of dendrites which correlate with impaired working memory performance. This phenomenon has also been seen in humans, where PFC gray matter decreases and weaker PFC connectivity correlate with exposure to adverse events. What causes this atrophy?

Our data suggest that at least one factor involves sustained activation of protein kinase C (PKC) signaling, as daily treatment with the PKC inhibitor, chelerythrine, prevented spine loss and cognitive impairment. PKC may contribute to spine loss via phosphorylation of MARCKS, which detaches actin from the spine membrane. PKC is of particular interest, because it is activated by very low levels of lead (Pb2+), and may explain the grave impairments in PFC funciton and loss of PFC gray matter that occurs with lead poisoning. PKC signaling is also overactive in bipolar disorder, another condition associated with impaired PFC function.

If you are interested: Hains et al (2009) Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci U S A. 106: 17957-62.