Stress weakens prefrontal networks: molecular insults to higher cognition

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Abstract

A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium-protein kinase C and cyclic AMP-protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer's degeneration.

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Most cited references 121

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Sex modifies the APOE-related risk of developing Alzheimer disease.

André Altmann, Lu Tian, Victor W Henderson … (2014)

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women). APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. © 2014 American Neurological Association.

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The stressed hippocampus, synaptic plasticity and lost memories.

Jeansok Kim, David M Diamond (2002)

Stress is a biologically significant factor that, by altering brain cell properties, can disturb cognitive processes such as learning and memory, and consequently limit the quality of human life. Extensive rodent and human research has shown that the hippocampus is not only crucially involved in memory formation, but is also highly sensitive to stress. So, the study of stress-induced cognitive and neurobiological sequelae in animal models might provide valuable insight into the mnemonic mechanisms that are vulnerable to stress. Here, we provide an overview of the neurobiology of stress memory interactions, and present a neural endocrine model to explain how stress modifies hippocampal functioning.