Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Abstract

The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of α1 receptors impairs prefrontal function via phosphatidylinositol–protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)—the molecule most associated with bipolar disorder— normally serve to inhibit phosphatidylinositol–protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.

Effect of chronic stress during adolescence in prefrontal cortex structure and function

“…Chronic stress can be induced in the laboratory by continuously submitting animals to stressful situations, such as physical immobilization, and observing the effects on brain and/or behavior. For instance, several studies have used this approach to evaluate morphological changes caused by chronic stress on pyramidal neurons of the hippocampus, amygdala and prefrontal cortex [10,17,[62][63][64]. Other studies have shown effects on neurogenesis, synaptogenesis and myelination, as well as the availability of neurotransmitters and neurotrophic factors [65,66].…”

Differential effects of environmental enrichment and isolation housing on the hormonal and neurochemical responses to stress in the prefrontal cortex of the adult rat: relationship to working and emotional memories

“…Different acute stressors increase the release of dopamine and acetylcholine in the PFC (Thierry et al 1976;Abercrombie et al 1989;Mark et al 1996;Del Arco et al 2007). These neurotransmitters play a role in modulating working memory and attention (Sarter and Bruno 1997;Williams and Castner 2006), which have been suggested to be relevant to cope with stress (Sarter and Bruno 1997;Hains and Arnsten 2008). Animals reared in EC show a reduced response to acute handling (a mild stress challenge) of the dopaminergic but not the cholinergic systems in the PFC (Del .…”

Neuroscience: Rethinking rehab

“…Animal studies have supported the human ones by showing, for example, that monkeys given cocaine swiftly develop prefrontal impairments 4 . And other researchers have found that stress, which frequently triggers drug use and relapse in people with addiction, seems to do so at least in part by shutting down prefrontal functions 5 . "We're really starting to understand the molecular basis of why this cortex falls apart with drugs of abuse, and during stress, and how those two interact, " says Amy Arnsten at Yale University School of Medicine in New Haven, Connecticut.…”