Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes

Abstract

Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention.

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

“…With chronic stress exposure, there continues to be elevated catecholamine and glucocorticoid release, but there are additional architectural changes, with loss of layer III dendrites and spines ((61-63), reviewed in (64)). Much of this research has been done in rodent models, largely for ethical reasons.…”

“…As described above, psychological stress drives Ca 2+ -cAMP-K + signaling, and chronic stress exposure leads to spines loss. There is some evidence from rodents that psychological stress exposure can reduce the expression of the Ca 2+ binding protein, calbindin (127), which would further increase cytosolic Ca 2+ levels, leading to inflammation and spine removal (64).…”

“…Note that genetic alterations in schizophrenia may propel spine loss at multiple stages of this sequence. For more details on the mechanisms underlying spine removal, please see (64). MOAS = Mitochondria-On-A-String; ROS = reactive oxygen species.…”

The Mind After Midnight: Nocturnal Wakefulness, Behavioral Dysregulation, and Psychopathology

“…This may not only extend wakefulness but also adversely affect psychiatric symptoms associated with dopaminergic dysregulation (e.g., sensation seeking, impulsivity, delusional thinking). Nocturnal wakefulness may also produce a stress response with a surge in adrenergic signaling that further weakens prefrontal cortical activity, increases limbic/subcortical responsivity, and increases reflexive, impulsive decision-making ( Arnsten, 2015 ; Woo et al, 2021 ).…”

A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress

“…Animal studies provide ample evidence that stress exposure can result in functional and morphological changes of limbic brain areas ( McEwen et al, 2015 ). Pronounced stress-induced changes of neuronal morphology have been documented in the medial prefrontal cortex (mPFC) of rodents such as dendritic debranching, loss of dendritic spines and synaptic contacts ( Holmes and Wellman, 2009 ; Lucassen et al, 2014 ; Arnsten, 2015 ; Woo et al, 2021 ). The infralimbic cortex (IL), which is the most ventral part of the mPFC, has been implicated in several higher order executive functions and it plays a critical role in regulating the chronic stress response ( Flak et al, 2012 ).…”