Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex

“During emotional and stressful situations, activation of the HPA axis causes the adrenal cortex to release glucocorticoids, which travel through the bloodstream and cross the blood-brain barrier to activate glucocorticoid receptors (GRs) throughout the brain (De Kloet et al., 2005).”

“Adapted from Arnsten (2009) and Arnsten et al. (2012).”

“Subsets of prefrontal neurons fire exclusively during the delay (Funahashi et al., 1989), suggesting a unique role for the PFC in this aspect of the task.”

“Under optimal, stress-free conditions, microcircuits within the PFC work together to inhibit inappropriate responses and allow nuanced decision-making (Goldman-Rakic, 1995).”

“Selective lesions of these afferents Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 1 HUMAN NEUROSCIENCE impair working memory in monkeys, suggesting that baseline catecholamine signaling is required for optimal PFC function (Brozoski et al., 1979).”

“Pharmacological blockade of D1 receptors in both monkeys and rodents impairs performance on working memory tasks (Sawaguchi and Goldman-Rakic, 1991; Izquierdo et al., 1998), indicating a key role for D1 signaling in normal PFC function.”

“These processes depend on the structural and functional integrity of the prefrontal cortex (PFC) (Goldman-Rakic, 1996), a highly evolved brain region that guides emotion and behavior through projections to subcortical regions like the hypothalamus, amygdala, and brainstem nuclei (Price et al.”

“Accordingly, these impairments can be reversed by intra-PFC infusions of a D1 antagonist (Zahrt et al., 1997), as well as by infusions of cAMP and PKA inhibitors (Taylor et al.”

“Moreover, this general silencing of neuronal activity loosens the PFC’s regulatory influence over subcortical structures, allowing amplified and protracted emotional responses (Arnsten, 1998b).”

“During stress, HPA axis activation leads to stimulation of the VTA, causing excess DA release into the PFC (Murphy et al., 1996).”

“Moreover, lesions of the PFC disrupt accuracy only when the task involves a delay (Funahashi et al., 1993), demonstrating that the PFC is not involved in the motor or motivational aspects of these tasks.”

“(Rodrigues et al., 2009), glucocorticoid actions in the PFC impair working memory.”

“Adapted from Arnsten (2009) and Arnsten et al. (2012).”

“Pharmacological blockade of HCN channels restores working memory performance and PFC network tuning during stress or after administration of a D1 agonist, demonstrating a functional link between these channels and upstream changes in DA signaling (Arnsten, 2011b).”

“Traditionally, HCN channels serve to normalize neuronal membrane potential, opening to allow positive ions into the cell to combat post-firing hyperpolarization (Wahl-Schott and Biel, 2009).”

“Corticosterone blocks catecholamine transporters in the PFC (Gründemann et al., 1998), resulting in increased extracellular catecholamine levels.”

“Dopaminergic cells in the VTA and PFC express GRs that become saturated during stress (Ahima and Harlan, 1990), altering the firing of dopaminergic projections.”

“From a translational standpoint, this is problematic; stressrelated mental illnesses like post-traumatic stress disorder (PTSD) and major depressive disorder are twice as prevalent in women (Becker et al., 2007), suggesting a distinct neurobiology may underlie the stress response in female brains.”

“Systemic injection of corticosterone in rats significantly reduces Delayed Alternation accuracy, and infusion of the GR agonist RU 28362 into the PFC similarly impairs working memory (Roozendaal et al., 2004).”

“The impairing effects of alpha-1 stimulation are due in part to downstream activation of protein kinase C (PKC), the inhibition of which also reverses stress-related impairments on working memory tasks in monkeys and rodents (Birnbaum et al., 2004).”

“As described above, α1 noradrenergic receptor stimulation during stress impairs PFC working memory through PKC intracellular signaling pathways (Birnbaum et al., 1999).”

“Stimulation of this receptor—either pharmacologically or because of stress-induced NE release—leads to working memory impairment and a silencing of PFC network activity (Arnsten et al., 1999).”

“These processes depend on the structural and functional integrity of the prefrontal cortex (PFC) (Goldman-Rakic, 1996), a highly evolved brain region that guides emotion and behavior through projections to subcortical regions like the hypothalamus, amygdala, and brainstem nuclei (Price et al., 1996).”

“Estrogen increases the physical number of dopaminergic projections from the VTA to the PFC (Kritzer and Creutz, 2008) and enhances extracellular DA concentrations (Xiao and Becker, 1994), putting it in a powerful position to modulate working memory.”

“One of the first studies to investigate sex differences in stressinduced working memory impairments used the anxiogenic drug FG7142 to generate dose-response curves in male and female rats (Shansky et al., 2004).”

“Numerous mental illnesses—including Major Depressive Disorder, PTSD, Schizophrenia, and Attention Deficit/Hyperactivity Disorder [ADHD (Arnsten, 2007)]—are characterized by PFC dysfunction, and the pathways elucidated by the animal research described here are currently being targeted in pharmacological therapies.”

“Each of these manipulations activates the hypothalamic-pituitary-adrenal (HPA) axis, eliciting a cascade of hormone and neurotransmitter release that alters cognitive and emotional processes throughout the brain (Cordero et al., 2003; Mikkelsen et al., 2005).”

“In vivo microdialysis experiments show that an infusion of GR antagonist RU-38486 into the PFC suppresses stress-induced DA release, but infusions into the VTA have no effect (Butts et al., 2011).”

“Pharmacological blockade of HCN channels restores working memory performance and PFC network tuning during stress or after administration of a D1 agonist, demonstrating a functional link between these channels and upstream changes in DA signaling (Arnsten, 2011b).”

“Estrogen increases the physical number of dopaminergic projections from the VTA to the PFC (Kritzer and Creutz, 2008) and enhances extracellular DA concentrations (Xiao and Becker, 1994), putting it in a powerful position to modulate working memory.”

“From a translational standpoint, this is problematic; stressrelated mental illnesses like post-traumatic stress disorder (PTSD) and major depressive disorder are twice as prevalent in women (Becker et al., 2007), suggesting a distinct neurobiology may underlie the stress response in female brains.”

“Recent work has revealed a critical role for hyperpolarization-activated/cyclic nucleotide-gated (HCN) ion channels, which co-localize on dendritic spines with D1 receptors (Paspalas et al., 2012).”

“Accordingly, these impairments can be reversed by intra-PFC infusions of a D1 antagonist (Zahrt et al., 1997), as well as by infusions of cAMP and PKA inhibitors (Taylor et al., 1999).”

“Downstream, intracellular stores of Ca2+ travel to the soma and inhibit neuronal firing through opening of local K+ channels (Hagenston et al., 2008).”

“Numerous mental illnesses—including Major Depressive Disorder, PTSD, Schizophrenia, and Attention Deficit/Hyperactivity Disorder [ADHD (Arnsten, 2007)]—are characterized by PFC dysfunction, and the pathways elucidated by the animal research described here are currently being targeted in pharmacological therapies.”

“Pharmacological blockade of D1 receptors in both monkeys and rodents impairs performance on working memory tasks (Sawaguchi and Goldman-Rakic, 1991; Izquierdo et al., 1998), indicating a key role for D1 signaling in normal PFC function.”

“Additionally, alpha-2 agonists reverse working memory impairments that occur during stress (Birnbaum et al., 2000).”

“Female rats in proestrus have higher baseline serum corticosterone levels than males or females in diestrus, and females have a more robust corticosterone response to acute stress than males do (Mitsushima et al., 2003).”

“Under stress, however, the LC releases NE throughout the brain and excess NE in the PFC binds instead to the loweraffinity alpha-1 receptor (Mohell et al., 1983).”

“Electron micrographs show that D1 receptors co-localize with glutamate receptors on dendritic spines (Pickel et al., 2006, and see Figure 1), making them strategically positioned to modulate incoming excitatory information.”

“But as their name implies, HCN channels are also sensitive to changes in cAMP levels, and when cAMP increases (as happens when D1 receptors are over-activated), HCN channels open, letting Na+ and K+ flow out of the cell (Chen et al., 2007).”

“…no-stress conditions, but mild stress shifts high-estrogen animals down into the far end of the D1 inverted U, while only pushing low-estrogen animals slightly across the middle. impairments in males and OVX female rats has no effect in OVX rats with estrogen replacement (Shansky et al., 2009).”

“Estrogen uncouples the alpha-2a receptor from its G-protein (Ansonoff and Etgen, 2001), thus potentially disrupting the delicate balance of D1 and alpha-2a activity that is required for optimal PFC function.”

“INTRODUCTION Our ability to manage, update, and act on information in the absence of external cues—executive functions collectively known as working memory—is critical to daily functioning (Arnsten and Castellanos, 2002).”

“hormone-neurotransmitter interactions in the prefrontal cortex”

“For example, stress first exerts rapid effects in the brain by producing a surge in both dopaminergic and noradrenergic activity within the prefrontal cortex (Arnsten, 2009; Shansky & Lipps, 2013).”

“Moreover, the changes in glucocorticoids that arise following environmental perturbations can also impact numerous behaviors through actions at other brain regions (Weiser and Handa, 2009, for review see: (Shansky and Lipps, 2013)).”