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

Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex MINI REVIEW ARTICLE published: 05 April 2013 HUMAN NEUROSCIENCE doi: 10.3389/fnhum.2013.00123 Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex Rebecca M. Shansky* and Jennifer Lipps Laboratory of Neuroanatomy and Behavior, Department of Psychology, Northeastern University, Boston, MA, USA Edited by: The mechanisms and neural circuits that drive emotion and cognition are inextricably Alexander J. Shackman, University linked. Activation of the hypothalamic-pituitary-adrenal (HPA) axis as a result of stress of Wisconsin-Madison, USA or other causes of arousal initiates a flood of hormone and neurotransmitter release Reviewed by: throughout the brain, affecting the way we think, decide, and behave. This review will Stephen Emrich, Brock University, focus on factors that influence the function of the prefrontal cortex (PFC), a brain region Canada Patrick H. Roseboom, University of that governs higher-level cognitive processes and executive function. The PFC becomes Wisconsin, USA markedly impaired by stress, producing measurable deficits in working memory. These *Correspondence: deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, Rebecca M. Shansky, Laboratory of catecholamines, and gonadal hormones; here we will discuss the non-human primate Neuroanatomy and Behavior, and rodent literature that has furthered our understanding of the circuitry, receptors, and Department of Psychology, signaling cascades responsible for stress-induced prefrontal dysfunction. Northeastern University, 360 Huntington Ave., 125 NI, Boston, MA 02115, USA. Keywords: working memory, stress, catecholamines, glucocorticoids, sex differences, estrogen e-mail: shansky@gmail.com INTRODUCTION it previously visited, and then visit the opposite arm on the sub- Our ability to manage, update, and act on information in the sequent trial. Both tasks involve dozens, or even hundreds of absence of external cues—executive functions collectively known trials, and thus during the delay the animal must not only keep as working memory—is critical to daily functioning (Arnsten the “signal” (i.e., correct choice) in mind, but also suppress the and Castellanos, 2002). These processes depend on the struc- “noise”—information from previous trials. Subsets of prefrontal tural and functional integrity of the prefrontal cortex (PFC) neurons fire exclusively during the delay (Funahashi et al., 1989), (Goldman-Rakic, 1996), a highly evolved brain region that guides suggesting a unique role for the PFC in this aspect of the task. emotion and behavior through projections to subcortical regions Moreover, lesions of the PFC disrupt accuracy only when the like the hypothalamus, amygdala, and brainstem nuclei (Price task involves a delay (Funahashi et al., 1993), demonstrating that et al., 1996). Under optimal, stress-free conditions, microcir- the PFC isnot involved inthe motorormotivational aspects cuits within the PFC work together to inhibit inappropriate of these tasks. Accurate performance on working memory tasks responses and allow nuanced decision-making (Goldman-Rakic, relies on the maintenance of a balanced neurochemical milieu in 1995). Exposure to stress, however, can disrupt PFC function, the PFC—one that is easily disrupted with exposure to stress. markedly impairing working memory (Arnsten, 2009; Arnsten Many kinds of mild stressors can impair working memory et al., 2012). From an ethological standpoint, this loss of com- in animals. The most common stressor for monkeys is a loud plex processing may have once allowed more primitive behaviors white noise, which also disrupts working memory in humans to take precedence in order to aid survival. But today, non-life- (Arnsten and Goldman-Rakic, 1998). Stressors in rodents include threatening stressors can activate these same circuits, eliciting brief restraint stress (Shansky et al., 2006), and administration of scattered thought, loss of focus, and judgment errors that can be the anxiogenic drug FG-7142, a benzodiazepine inverse agonist detrimental to daily life, and—in extreme cases—lead to mental (Shansky et al., 2004). Each of these manipulations activates the illness. Over the last few decades, animal research has helped elu- hypothalamic-pituitary-adrenal (HPA) axis, eliciting a cascade cidate the mechanisms that underlie these impairments, revealing of hormone and neurotransmitter release that alters cognitive a complex interaction between neurotransmitter signaling and and emotional processes throughout the brain (Cordero et al., hormone actions. 2003; Mikkelsen et al., 2005). In this review, we will focus on the Working memory in animals is assessed using delay-based contributions of the catecholamines dopamine (DA) and nore- tasks, which require an animal to keep a piece of information pinephrine (NE), and their interactions with glucocorticoids and in mind over the course of a delay period, in order to make an estrogen. accurate choice when the delay ends. Monkeys performing the Delayed Response task must remember the location of a briefly DOPAMINE AND NOREPINEPHRINE presented stimulus on a screen, and then move their eyes to The primary sources of DA and NE input to the PFC are the focus on that location. In rodents, the Delayed Alternation task ventral tegmental area (VTA) and locus coeruleus (LC), respec- requires the animal to remember which arm of a T-shaped maze tively (Thierry et al., 1992). Selective lesions of these afferents Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 1 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC impair working memory in monkeys, suggesting that base- basis of D1-driven information loss. Pharmacological blockade of line catecholamine signaling is required for optimal PFC func- HCN channels restores working memory performance and PFC tion (Brozoski et al., 1979). Investigations into the downstream network tuning during stress or after administration of a D1 ago- mechanisms by which these neurotransmitters mediate work- nist, demonstrating a functional link between these channels and ing memory—in both stress and non-stress conditions—indicate upstream changes in DA signaling (Arnsten, 2011b). critical roles for the DA D1 receptor, and noradrenergic alpha-1 HCN channel activity is also modulated by the noradrenergic and alpha-2 receptors (Arnsten, 1998a). alpha-2 receptor. This receptor is coupled to Gi, the activation The D1 receptor is coupled to the Gs protein, whose stimula- of which results in a decrease in cAMP. This causes a slowing tion triggers a signaling cascade that involves increases in cyclic- of HCN channel conductance, thus preserving incoming excita- AMP (cAMP) and protein kinase A (PKA), the effects of which are tory input. In this way, the alpha-2 receptor acts to strengthen discussed below (Arnsten, 2011a,b). Pharmacological blockade of PFC network activity, enhancing the “signal” for relevant infor- D1 receptors in both monkeys and rodents impairs performance mation, while as noted above, the D1 receptor suppresses “noise” on working memory tasks (Sawaguchi and Goldman-Rakic, 1991; (Wang et al., 2007). Thus, under optimal conditions, the D1 Izquierdo et al., 1998), indicating a key role for D1 signaling and alpha-2 receptors work together to fine-tune PFC neuronal in normal PFC function. Electron micrographs show that D1 firing. Pharmacological stimulation of the alpha-2 receptor can receptors co-localize with glutamate receptors on dendritic spines increase firing in PFC neurons that code for relevant infor- (Pickel et al., 2006,and see Figure 1), making them strategi- mation, enhancing working memory in monkeys and rodents cally positioned to modulate incoming excitatory information. (Wang et al., 2007). Additionally, alpha-2 agonists reverse work- Single unit physiological studies in monkeys performing a delayed ing memory impairments that occur during stress (Birnbaum response task have revealed that D1 activity plays an integral et al., 2000). role in filtering out “noise”—suppressing firing in PFC neurons Alpha-2 receptors have a high affinity for NE, and are pri- that code for information irrelevant to the immediate task, thus marily bound and active during non-stress conditions (O’Rourke increasing the likelihood of a correct response (Vijayraghavan et al., 1994). Under stress, however, the LC releases NE through- et al., 2007). Without D1 stimulation, PFC neurons become gen- out the brain and excess NE in the PFC binds instead to the lower- erally overactive, rendering the animal vulnerable to distractions affinity alpha-1 receptor (Mohell et al., 1983). Stimulation of this (Vijayraghavan et al., 2007). receptor—either pharmacologically or because of stress-induced While a lack of D1 activity can impair working memory NE release—leads to working memory impairment and a silenc- performance, high levels of D1 stimulation also produce cogni- ing of PFC network activity (Arnsten et al., 1999). Conversely, tive deficits—the classic “inverted-U” relationship. During stress, administration of an alpha-1 antagonist can restore PFC func- HPA axis activation leads to stimulation of the VTA, causing tion and neuronal firing during stress (Birnbaum et al., 1999). excess DA release into the PFC (Murphy et al., 1996). When The impairing effects of alpha-1 stimulation are due in part to this DA binds to the D1 receptor, its downstream signaling cas- downstream activation of protein kinase C (PKC), the inhibi- cades lead to working memory impairment (Taylor et al., 1999). tion of which also reverses stress-related impairments on working Accordingly, these impairments can be reversed by intra-PFC memory tasks in monkeys and rodents (Birnbaum et al., 2004). infusions of a D1 antagonist (Zahrt et al., 1997), as well as by The PKC pathway inhibits neuronal firing through the cleav- infusions of cAMP and PKA inhibitors (Taylor et al., 1999). age of membrane phoshoplipase C (PLC), which initiates phos- Physiologically, elevated D1 signaling leads to a suppression of phatidylinositol signaling (Birnbaum et al., 2004). Downstream, 2+ not only “noise”-related neurons, but of “signal” neurons as intracellular stores of Ca travel to the soma and inhibit neu- well (Vijayraghavan et al., 2007)—the information is lost, and ronal firing through opening of local K channels (Hagenston the PFC is unable to accurately guide behavior. Moreover, this et al., 2008). general silencing of neuronal activity loosens the PFC’s regula- In summary, stress disrupts working memory by eliciting cate- tory influence over subcortical structures, allowing amplified and cholamine release into the PFC, moving both DA and NE levels to protracted emotional responses (Arnsten, 1998b). the far end of their respective inverted U curves. Through DA D1 How does this switch take place on a cellular level? Recent work and NE alpha-1 receptor signaling, delay-related neuronal activity has revealed a critical role for hyperpolarization-activated/cyclic in the PFC is suppressed, and information critical to accurate task nucleotide-gated (HCN) ion channels, which co-localize on performance is lost (Figure 1). Because the PFC also helps to shut dendritic spines with D1 receptors (Paspalas et al., 2012). down the stress response, this loss of PFC function can lead to Traditionally, HCN channels serve to normalize neuronal mem- prolonged glucocorticoid release, which can exacerbate working brane potential, opening to allow positive ions into the cell memory impairments. to combat post-firing hyperpolarization (Wahl-Schott and Biel, GLUCOCORTICOIDS 2009). But as their name implies, HCN channels are also sen- sitive to changes in cAMP levels, and when cAMP increases (as During emotional and stressful situations, activation of the HPA happens when D1 receptors are over-activated), HCN channels axis causes the adrenal cortex to release glucocorticoids, which + + open, letting Na and K flow out of the cell (Chen et al., travel through the bloodstream and cross the blood-brain bar- 2007). The net effect of this efflux is a lessening of the likeli- rier to activate glucocorticoid receptors (GRs) throughout the hood that an incoming stimulus will be sufficiently excitatory brain (De Kloet et al., 2005). While this release is critical to the to propagate an action potential, thus forming the physiological enhancement of long term memories associated with the event Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 2 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC FIGURE 1 | Model for catecholamine modulation and stress-induced of NE alpha-1 receptors activates a PLC signaling cascade that causes impairment of working memory. Under stress-free conditions (top), further loss of excitation through K channels in the soma. This leads the noradrenergic alpha-2 receptor drives activity in the prefrontal to a loss of information, and working memory failure. Adapted from cortex by suppressing cAMP levels and strengthening the signal from Arnsten (2009) and Arnsten et al. (2012). Abbreviations: Glu, glutamate; incoming information. Under stress (bottom), overstimulation of the NMDA, N-methyl D-aspartic acid receptors; NE, norepinephrine; DA, dopamine D1 receptor activates cAMP, causing HCN channels to open, dopamine; HCN, hyperpolarization nucleotide-gated channels; PLC, resulting in a shunting of incoming excitation. Additionally, stimulation phospholipase C. (Rodrigues et al., 2009), glucocorticoid actions in the PFC impair the GR antagonist RU 38486 reverses stress-induced impairments working memory. Systemic injection of corticosterone in rats sig- on the delayed spatial win-shift (DSWS) task, another test of nificantly reduces Delayed Alternation accuracy, and infusion of prefrontal-dependent executive function (Butts et al., 2011). the GR agonist RU 28362 into the PFC similarly impairs working These findings suggest that glucocorticoids can impair PFC func- memory (Roozendaal et al., 2004). Finally, intra-PFC infusion of tion through direct actions at GRs, but glucocorticoids may Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 3 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC also indirectly exacerbate working memory impairments through the effect, and providing evidence against a simple hormone-drug interactions with the catecholamine systems described above. interaction. One mechanism of interaction between glucocorticoids and Further support for the idea that high estrogen levels con- catecholamines is the extraneuronal catecholamine transport sys- fer sensitivity to stress comes from studies in ovariectomized tem. These transporters are located on glia, and remove excess (OVX) female rats. OVX surgery removes circulating estrogen DA and NE from the synapse, helping to keep balanced and opti- and progesterone, hormones that can be re-introduced via a sub- mal stimulation of dopaminergic and noradrenergic receptors. cutaneous time-release silastic capsule. After administration of Corticosterone blocks catecholamine transporters in the PFC low doses of FG7142, OVX rats with long-term estrogen replace- (Gründemann et al., 1998), resulting in increased extracellular ment (OVX + E) demonstrate working memory impairments catecholamine levels. In this way, stress-induced glucocorticoid that are similar to those of females in proestrus, while OVX release in the PFC could lead to overstimulation of the both females with a blank capsule perform more like males—impaired dopamine D1 and α1 noradrenergic receptors, thus producing only at higher doses (Shansky et al., 2009). In all of the above PFC dysfunction. studies, high- and low-estrogen groups did not differ in baseline Glucocorticoids also modulate dopaminergic transmission in working memory performance, suggesting that estrogen does not the PFC. Dopaminergic cells in the VTA and PFC express GRs directly mediate PFC function, but instead modulates the factors that become saturated during stress (Ahima and Harlan, 1990), that contribute to stress-induced impairments. The mechanisms altering the firing of dopaminergic projections. Interestingly, glu- by which estrogen does this are not known, but several intriguing cocorticoid effects on DA release in the PFC appear to be locally possibilities exist. driven, rather than a result of actions in the VTA itself. In vivo First, estrogen may exacerbate the effects of stress-induced microdialysis experiments show that an infusion of GR antago- glucocorticoid release. Female rats in proestrus have higher nist RU-38486 into the PFC suppresses stress-induced DA release, baseline serum corticosterone levels than males or females in but infusions into the VTA have no effect (Butts et al., 2011). diestrus, and females have a more robust corticosterone response Therefore, GRs play a role specific to the PFC in modulating the to acute stress than males do (Mitsushima et al., 2003). Thus, magnitude of stress-induced DA efflux. females with high estrogen levels may be primed for an ampli- Finally, glucocorticoids may further exacerbate catecholamine fied corticosterone surge after exposure to lower levels of stress, effects by activating some of the same intracellular signaling eliciting working memory impairments through the mecha- pathways. As described above, α noradrenergic receptor stim- nisms described above—either through direct actions at GRs, or ulation during stress impairs PFC working memory through through blockade of extraneuronal catecholamine transporters. PKC intracellular signaling pathways (Birnbaum et al., 1999). To date, however, estrogen-glucocorticoid interactions have not Glucocorticoid release can also activate PKC signaling (ffrench- been investigated in the context of stress-induced working mem- Mullen, 1995), thus potentially amplifying the effects of alpha-1 ory impairments. stimulation. Another means by which estrogen may sensitize the PFC to the detrimental effects of stress is through the dopaminergic sys- SEX DIFFERENCES AND ESTROGEN EFFECTS tem. Estrogen increases the physical number of dopaminergic The vast majority of behavioral neuroscience research is con- projections from the VTA to the PFC (Kritzer and Creutz, 2008) ducted in male animals, and thus our general understanding and enhances extracellular DA concentrations (Xiao and Becker, of stress effects in the PFC is within the context of the male 1994), putting it in a powerful position to modulate working brain. From a translational standpoint, this is problematic; stress- memory. While these elevated DA levels may not have measur- related mental illnesses like post-traumatic stress disorder (PTSD) able behavioral outcomes on their own, they could indicate that and major depressive disorder are twice as prevalent in women high-estrogen females are “ahead of the curve” with respect to (Becker et al., 2007), suggesting a distinct neurobiology may the D1-PFC function inverted U. In this scenario, mild stress underlie the stress response in female brains. Though the exact merely pushes low-estrogen females just over the top of the U, mechanisms have not yet been fully identified, a growing body while bumping high-estrogen females into impairment ranges. of literature points to an important role for estrogen in modu- This hypothesis is illustrated in Figure 2. lating the neurotransmitter and glucocorticoid effects described The effects of elevated D1 signaling in high-estrogen females above. may be further exacerbated through estrogen’s interactions with One of the first studies to investigate sex differences in stress- noradrenergic alpha-2a receptors. As described in the first section induced working memory impairments used the anxiogenic drug of this review, alpha-2a activity leads to decreased cAMP pro- FG7142 to generate dose-response curves in male and female duction and a closing of HCN channels, resulting in enhanced rats (Shansky et al., 2004). WhileT-mazeperformance declined “signal” in PFC neurons coding for relevant information. This with increasing doses in both sexes, females became impaired could serve to combat excess D1 activity, which leads to an after lower doses of FG7142 than those required to impair males. opening of HCN channels, and a loss of information. Estrogen When the authors divided the females based on estrus cycle phase, uncouples the alpha-2a receptor from its G-protein (Ansonoff they found that this stress sensitivity was driven by females in and Etgen, 2001), thus potentially disrupting the delicate bal- proestrus, when estrogen levels are highest. Similar results were ance of D1 and alpha-2a activity that is required for optimal found after using increasing durations of restraint stress instead of PFC function. In support of this idea, a dose of guanfacine (an FG7142 (Shansky et al., 2006), demonstrating generalizability of alpha-2a agonist) that rescues stress-induced working memory Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 4 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC FIGURE 2 | Estrogen “ahead of the curve” hypothesis. Estrogen perform equally well at working memory tasks under no-stress may amplify the stress response in females by raising baseline conditions, but mild stress shifts high-estrogen animals down into the dopamine D1 signaling, thus making small shifts more apparent in far end of the D1 inverted U, while only pushing low-estrogen animals behavioral measures. In this model, high- and low-estrogen females slightly across the middle. impairments in males and OVX female rats has no effect in OVX mental illnesses—including Major Depressive Disorder, PTSD, rats with estrogen replacement (Shansky et al., 2009). Schizophrenia, and Attention Deficit/Hyperactivity Disorder [ADHD (Arnsten, 2007)]—are characterized by PFC dysfunc- CONCLUSIONS tion, and the pathways elucidated by the animal research Stressful events can lead to immediate and marked impairments described here are currently being targeted in pharmacological in working memory, an executive function that depends on therapies. For example, the NE alpha-1 antagonist prazosin has a balanced neurochemical state in the PFC. Research in non- been reported to be an effective treatment for PTSD (Berger et al., human primates and rodents has shown that this impairment 2009), and the alpha-2 agonist guanfacine is used as an alternative is driven by increased catecholamine signaling, which may be to psychostimulant treatment for ADHD (Bidwell et al., 2011). further modulated or exacerbated by changes in steroid hor- Continued investigation into the neuromodulators that influence mone levels. Beyond stress, this work has provided critical insight working memory—particularly in female populations—could into the mechanisms that underlie PFC function in general, and lead to more nuanced and effective treatments for disorders that the potential for clinical application is substantial. Numerous compromise prefrontal function. REFERENCES Arnsten, A. F. T. (2009). Stress sig- for a hyperdopaminergic mecha- disorder: a systematic review. Ahima, R. S., and Harlan, R. E. (1990). nalling pathways that impair nism. Arch. Gen. Psychiatry 55, Prog. Neuropsychopharmacol. Biol. Charting of type II glucocorti- prefrontal cortex structure and 362–369. Psychiatry 33, 169–180. coid receptor-like immunoreactivity function. Nat. Rev. Neurosci. 10, Arnsten, A. F. T., Mathew, R., Ubriani, Bidwell, L. C., McClernon, F. J., and in the rat central nervous system. 410–422. R.,Taylor, J. R.,and Li,B.-M. Kollins, S. H. (2011). Cognitive Neuroscience 39, 579–604. Arnsten, A. F. T. (2011a). (1999). Alpha-1 noradrenergic enhancers for the treatment of Ansonoff, M. A., and Etgen, A. M. Catecholamine influences on receptor stimulation impairs pre- ADHD. Pharmacol. Biochem. Behav. (2001). Receptor phosphorylation dorsolateral prefrontal cortical frontal cortical cognitive function. 99, 262–274. mediates estradiol reduction of networks. Biol. Psychiatry 69, Biol. Psychiatry 45, 26–31. Birnbaum, S., Gobeske, K. T., alpha2-adrenoceptor coupling e89–e99. Arnsten, A. F. T., Wang, M. J., Auerbach, J., Taylor, J. R., and to G protein in the hypothala- Arnsten, A. F. T. (2011b). Prefrontal and Paspalas, C. D. (2012). Arnsten, A. F. (1999). A role for mus of female rats. Endocrine 14, cortical network connections: key Neuromodulation of thought: norepinephrine in stress-induced 165–174. site of vulnerability in stress and flexibilities and vulnerabilities cognitive deficits: alpha-1- Arnsten, A. F. (2007). Catecholamine schizophrenia. Int. J. Dev. Neurosci. in prefrontal cortical network adrenoceptor mediation in the and second messenger influences on 29, 215–223. synapses. Neuron 76, 223–239. prefrontal cortex. Biol. Psychiatry prefrontal cortical networks of “rep- Arnsten, A. F. T., and Castellanos, F. Becker, J. B., Monteggia, L. M., Perrot- 46, 1266–1274. resentational knowledge”: a ratio- X. (2002). “Neurobiology of atten- Sinal, T. S., Romeo, R. D., Taylor, J. Birnbaum, S. G., Podell, D. M., nal bridge between genetics and the tion regulation and its disorders,” R., Yehuda, R., et al. (2007). Stress and Arnsten, A. F. T. (2000). symptoms of mental illness. Cereb. in Textbook of Child and Adolescent and disease: is being female a pre- Noradrenergic alpha-2 receptor Cortex 17(Suppl. 1), i6–i15. Psychopharmacology, eds A. Martin, disposing factor? J. Neurosci. 27, agonists reverse working memory Arnsten, A. F. T. (1998a). L. Scahill, D. Charney, and J. 11851–11855. deficits induced by the anxiogenic Catecholamine modulation of pre- Leckman (New York, NY: Oxford Berger,W., Mendlowicz,M. V., drug, FG7142, in rats. Pharmacol. frontal cortical cognitive function. University Press), 99–109. Marques-Portella, C., Kinrys, G., Biochem. Behav. 67, 397–403. Trends Cogn. Sci. 2, 436–447. Arnsten, A. F. T., and Goldman- Fontenelle, L. F., Marmar, C. R., Birnbaum, S. G., Yuan, P. X., Wang, Arnsten, A. F. T. (1998b). The biol- Rakic, P. S. (1998). Noise stress et al. (2009). Pharmacologic M.,Vijayraghavan,S., Bloom,A.K., ogy of feeling frazzled. Science 280, impairs prefrontal cortical cogni- alternatives to antidepres- Davis, D. J., et al. (2004). Protein 1711–1712. tive function in monkeys: evidence sants in posttraumatic stress kinase C overactivity impairs Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 5 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC prefrontal cortical regulation of Gründemann, D., Schechinger, B., of the primate prefrontal cortex: Differential influence of dopamin- working memory. Science 306, Rappold, G. A., and Schömig, E. potential substrate for working ergic and noradrenergic afferents on 882–884. (1998). Molecular identification memory deficits in schizophrenia. their target cells in the rat prefrontal Brozoski, T. J.,Brown,R.M., Rosvold, of the corticosterone-sensitive Cereb. Cortex. doi: 10.1093/cercor/ cortex. Clin. Neuropharmacol. H. E., and Goldman, P. S. (1979). extraneuronal catecholamine bhs152. [Epub ahead of print]. 15(Suppl. 1), 139A–140A. Cognitive deficit caused by regional transporter. Nat. Neurosci. 1, Pickel, V. M., Colago, E. E., Mania, I., Vijayraghavan,S., Wang,M., depletion of dopamine in prefrontal 349–351. Molosh, A. I., and Rainnie, D. G. Birnbaum, S. G., Williams, G. cortex of rhesus monkey. Science Hagenston, A. M., Fitzpatrick, J. S., (2006). Dopamine D1 receptors V., and Arnsten, A. F. T. (2007). 205, 929–932. and Yeckel, M. F. (2008). MGluR- co-distribute with N-methyl-D- Inverted-U dopamine D1 receptor Butts, K. A., Weinberg, J., Young, A. mediated calcium waves that invade aspartic acid type-1 subunits and actions on prefrontal neurons H., and Phillips, A. G. (2011). the soma regulate firing in layer V modulate synaptically-evoked engaged in working memory. Nat. Glucocorticoid receptors in the medial prefrontal cortical pyramidal N-methyl-D-aspartic acid cur- Neurosci. 10, 376–384. prefrontal cortex regulate stress- neurons. Cereb. Cortex 18, 407–423. rents in rat basolateral amygdala. Wahl-Schott, C., and Biel, M. (2009). evoked dopamine efflux and Izquierdo, I., Izquierdo, L. A., Barros, Neuroscience 142, 671–690. HCN channels: structure, cellu- aspects of executive function. D. M., Mello e Souza, T., De Souza, Price, J. L., Carmichael, S. T., and lar regulation and physiological Proc. Natl. Acad. Sci. U.S.A. 108, M. M., Quevedo, J., et al. (1998). Drevets, W. C. (1996). Networks function. Cell. Mol. Life Sci. 66, 18459–18464. Differential involvement of cortical related to the orbital and medial 470–494. Chen, S., Wang, J., Zhou, L., George, receptor mechanisms in working, prefrontal cortex; a substrate for Wang, M., Ramos, B. P., Paspalas, C. D., M. S., and Siegelbaum, S. A. short-term and long-term memory. emotional behavior? Prog. Brain Res. Shu, Y., Simen, A., Duque, A., et al. (2007). Voltage sensor movement Behav. Pharmacol. 9, 421–427. 107, 523–536. (2007). Alpha2A-adrenoceptors and cAMP binding allosterically Kritzer, M. F.,and Creutz, L.M. Rodrigues, S. M., LeDoux, J. E., and strengthen working memory net- regulate an inherently voltage- (2008). Region and sex differences Sapolsky, R. M. (2009). The influ- works by inhibiting cAMP-HCN independent closed-open transition in constituent dopamine neurons ence of stress hormones on fear channel signaling in prefrontal in HCN channels. J. Gen. Physiol. and immunoreactivity for intracel- circuitry. Annu. Rev. Neurosci. 32, cortex. Cell 129, 397–410. 129, 175–188. lular estrogen and androgen recep- 289–313. Xiao, L., and Becker, J. B. (1994). Cordero, M. I., Venero, C., Kruyt, N. D., tors in mesocortical projections in Roozendaal, B., McReynolds, J. R., Quantitative microdialysis deter- and Sandi, C. (2003). Prior exposure rats. J. Neurosci. 28, 9525–9535. and McGaugh, J. L. (2004). The mination of extracellular striatal to a single stress session facilitates Mikkelsen, J. D., Søderman, A., basolateral amygdala interacts with dopamine concentration in male subsequent contextual fear condi- Kiss, A., and Mirza, N. (2005). the medial prefrontal cortex in and female rats: effects of estrous tioning in rats. Evidence for a role Effects of benzodiazepines receptor regulating glucocorticoid effects cycle and gonadectomy. Neurosci. of corticosterone. Horm. Behav. 44, agonists on the hypothalamic- on working memory impairment. Lett. 180, 155–158. 338–345. pituitary-adrenocortical axis. Eur. J. Neurosci. 24, 1385–1392. Zahrt, J., Taylor, J. R., Mathew, R. De Kloet, E. R., Joëls, M., and Holsboer, J. Pharmacol. 519, 223–230. Sawaguchi, T., and Goldman-Rakic, P. G., and Arnsten, A. F. (1997). F. (2005). Stress and the brain: Mitsushima, D., Masuda, J., and S. (1991). D1 dopamine receptors Supranormal stimulation of D1 from adaptation to disease. Nat. Rev. Kimura, F. (2003). Sex differences in prefrontal cortex: involvement dopamine receptors in the rodent Neurosci. 6, 463–475. in the stress-induced release of in working memory. Science 251, prefrontal cortex impairs spatial ffrench-Mullen, J. M. (1995). Cortisol acetylcholine in the hippocampus 947–950. working memory performance. inhibition of calcium currents in and corticosterone from the adrenal Shansky, R. M., Bender, G., and J. Neurosci. 17, 8528–8535. guinea pig hippocampal CA1 neu- cortex in rats. Neuroendocrinology Arnsten, A. F. (2009). Estrogen rons via G-protein-coupled activa- 78, 234–240. prevents norepinephrine alpha-2a Conflict of Interest Statement: The tion of protein kinase C. J. Neurosci. Mohell, N., Svartengren, J., and receptor reversal of stress-induced authors declare that the research 15, 903–911. Cannon, B. (1983). Identification working memory impairment. was conducted in the absence of any Funahashi, S.,Bruce, C.J., and of [ H]prazosin binding sites in Stress 12, 457–463. commercial or financial relationships Goldman-Rakic, P. S. (1989). crude membranes and isolated Shansky, R. M., Glavis-Bloom, C., that could be construed as a potential Mnemonic coding of visual space in cells of brown adipose tissue as Lerman, D., McRae, P., Benson, conflict of interest. the monkey’s dorsolateral prefrontal alpha 1-adrenergic receptors. Eur. C., Miller, K., et al. (2004). cortex. J. Neurophysiol. 61, 331–349. J. Pharmacol. 92, 15–25. Estrogen mediates sex differences Received: 21 February 2013; accepted: 20 Funahashi, S.,Bruce, C.J., and Murphy, B. L., Arnsten, A. F., Goldman- in stress-induced prefrontal cortex March 2013; published online: 05 April Goldman-Rakic, P. S. (1993). Rakic, P. S., and Roth, R. H. (1996). dysfunction. Mol. Psychiatry 9, 2013. Dorsolateral prefrontal lesions and Increased dopamine turnover in 531–538. Citation: Shansky RM and Lipps J oculomotor delayed-response per- the prefrontal cortex impairs spatial Shansky, R. M., Rubinow, K., Brennan, (2013) Stress-induced cognitive dysfunc- formance: evidence for mnemonic working memory performance in A., and Arnsten, A. F. T. (2006). The tion: hormone-neurotransmitter interac- “scotomas”. J. Neurosci. 13, rats and monkeys. Proc. Natl. Acad. effects of sex and hormonal status tions in the prefrontal cortex. Front. 1479–1497. Sci. U.S.A. 93, 1325–1329. on restraint-stress-induced working Hum. Neurosci. 7:123. doi: 10.3389/ Goldman-Rakic, P. S. (1995). Cellular O’Rourke, M. F., Blaxall, H. S., Iversen, memory impairment. Behav. Brain fnhum.2013.00123 basis of working memory. Neuron L. J., and Bylund, D. B. (1994). Funct. 2, 8. Copyright © 2013 Shansky and Lipps. 14, 477–485. Characterization of [ H]RX821002 Taylor, J. R., Birnbaum, S., Ubriani, This is an open-access article dis- Goldman-Rakic, P. S. (1996). The pre- binding to alpha-2 adrenergic R., and Arnsten, A. F. (1999). tributed under the terms of the Creative frontal landscape: implications of receptor subtypes. J. Pharmacol. Activation of cAMP-dependent pro- Commons Attribution License,which functional architecture for under- Exp. Ther. 268, 1362–1367. tein kinase A in prefrontal cortex permits use, distribution and reproduc- standing human mentation and Paspalas, C. D., Wang, M., and Arnsten, impairs working memory perfor- tion in other forums, provided the origi- the central executive. Philos. Trans. A. F. T. (2012). Constellation of mance. J. Neurosci. 19, RC23. nal authors and source are credited and R. Soc. Lond. B Biol. Sci. 351, HCN channels and cAMP regu- Thierry, A. M., Godbout, R., Mantz, J., subject to any copyright notices concern- 1445–1453. lating proteins in dendritic spines Pirot, S., and Glowinski, J. (1992). ing any third-party graphics etc. Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 6 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Human Neuroscience Pubmed Central

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

Frontiers in Human Neuroscience , Volume 7 – Apr 5, 2013

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Abstract

MINI REVIEW ARTICLE published: 05 April 2013 HUMAN NEUROSCIENCE doi: 10.3389/fnhum.2013.00123 Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex Rebecca M. Shansky* and Jennifer Lipps Laboratory of Neuroanatomy and Behavior, Department of Psychology, Northeastern University, Boston, MA, USA Edited by: The mechanisms and neural circuits that drive emotion and cognition are inextricably Alexander J. Shackman, University linked. Activation of the hypothalamic-pituitary-adrenal (HPA) axis as a result of stress of Wisconsin-Madison, USA or other causes of arousal initiates a flood of hormone and neurotransmitter release Reviewed by: throughout the brain, affecting the way we think, decide, and behave. This review will Stephen Emrich, Brock University, focus on factors that influence the function of the prefrontal cortex (PFC), a brain region Canada Patrick H. Roseboom, University of that governs higher-level cognitive processes and executive function. The PFC becomes Wisconsin, USA markedly impaired by stress, producing measurable deficits in working memory. These *Correspondence: deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, Rebecca M. Shansky, Laboratory of catecholamines, and gonadal hormones; here we will discuss the non-human primate Neuroanatomy and Behavior, and rodent literature that has furthered our understanding of the circuitry, receptors, and Department of Psychology, signaling cascades responsible for stress-induced prefrontal dysfunction. Northeastern University, 360 Huntington Ave., 125 NI, Boston, MA 02115, USA. Keywords: working memory, stress, catecholamines, glucocorticoids, sex differences, estrogen e-mail: shansky@gmail.com INTRODUCTION it previously visited, and then visit the opposite arm on the sub- Our ability to manage, update, and act on information in the sequent trial. Both tasks involve dozens, or even hundreds of absence of external cues—executive functions collectively known trials, and thus during the delay the animal must not only keep as working memory—is critical to daily functioning (Arnsten the “signal” (i.e., correct choice) in mind, but also suppress the and Castellanos, 2002). These processes depend on the struc- “noise”—information from previous trials. Subsets of prefrontal tural and functional integrity of the prefrontal cortex (PFC) neurons fire exclusively during the delay (Funahashi et al., 1989), (Goldman-Rakic, 1996), a highly evolved brain region that guides suggesting a unique role for the PFC in this aspect of the task. emotion and behavior through projections to subcortical regions Moreover, lesions of the PFC disrupt accuracy only when the like the hypothalamus, amygdala, and brainstem nuclei (Price task involves a delay (Funahashi et al., 1993), demonstrating that et al., 1996). Under optimal, stress-free conditions, microcir- the PFC isnot involved inthe motorormotivational aspects cuits within the PFC work together to inhibit inappropriate of these tasks. Accurate performance on working memory tasks responses and allow nuanced decision-making (Goldman-Rakic, relies on the maintenance of a balanced neurochemical milieu in 1995). Exposure to stress, however, can disrupt PFC function, the PFC—one that is easily disrupted with exposure to stress. markedly impairing working memory (Arnsten, 2009; Arnsten Many kinds of mild stressors can impair working memory et al., 2012). From an ethological standpoint, this loss of com- in animals. The most common stressor for monkeys is a loud plex processing may have once allowed more primitive behaviors white noise, which also disrupts working memory in humans to take precedence in order to aid survival. But today, non-life- (Arnsten and Goldman-Rakic, 1998). Stressors in rodents include threatening stressors can activate these same circuits, eliciting brief restraint stress (Shansky et al., 2006), and administration of scattered thought, loss of focus, and judgment errors that can be the anxiogenic drug FG-7142, a benzodiazepine inverse agonist detrimental to daily life, and—in extreme cases—lead to mental (Shansky et al., 2004). Each of these manipulations activates the illness. Over the last few decades, animal research has helped elu- hypothalamic-pituitary-adrenal (HPA) axis, eliciting a cascade cidate the mechanisms that underlie these impairments, revealing of hormone and neurotransmitter release that alters cognitive a complex interaction between neurotransmitter signaling and and emotional processes throughout the brain (Cordero et al., hormone actions. 2003; Mikkelsen et al., 2005). In this review, we will focus on the Working memory in animals is assessed using delay-based contributions of the catecholamines dopamine (DA) and nore- tasks, which require an animal to keep a piece of information pinephrine (NE), and their interactions with glucocorticoids and in mind over the course of a delay period, in order to make an estrogen. accurate choice when the delay ends. Monkeys performing the Delayed Response task must remember the location of a briefly DOPAMINE AND NOREPINEPHRINE presented stimulus on a screen, and then move their eyes to The primary sources of DA and NE input to the PFC are the focus on that location. In rodents, the Delayed Alternation task ventral tegmental area (VTA) and locus coeruleus (LC), respec- requires the animal to remember which arm of a T-shaped maze tively (Thierry et al., 1992). Selective lesions of these afferents Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 1 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC impair working memory in monkeys, suggesting that base- basis of D1-driven information loss. Pharmacological blockade of line catecholamine signaling is required for optimal PFC func- HCN channels restores working memory performance and PFC tion (Brozoski et al., 1979). Investigations into the downstream network tuning during stress or after administration of a D1 ago- mechanisms by which these neurotransmitters mediate work- nist, demonstrating a functional link between these channels and ing memory—in both stress and non-stress conditions—indicate upstream changes in DA signaling (Arnsten, 2011b). critical roles for the DA D1 receptor, and noradrenergic alpha-1 HCN channel activity is also modulated by the noradrenergic and alpha-2 receptors (Arnsten, 1998a). alpha-2 receptor. This receptor is coupled to Gi, the activation The D1 receptor is coupled to the Gs protein, whose stimula- of which results in a decrease in cAMP. This causes a slowing tion triggers a signaling cascade that involves increases in cyclic- of HCN channel conductance, thus preserving incoming excita- AMP (cAMP) and protein kinase A (PKA), the effects of which are tory input. In this way, the alpha-2 receptor acts to strengthen discussed below (Arnsten, 2011a,b). Pharmacological blockade of PFC network activity, enhancing the “signal” for relevant infor- D1 receptors in both monkeys and rodents impairs performance mation, while as noted above, the D1 receptor suppresses “noise” on working memory tasks (Sawaguchi and Goldman-Rakic, 1991; (Wang et al., 2007). Thus, under optimal conditions, the D1 Izquierdo et al., 1998), indicating a key role for D1 signaling and alpha-2 receptors work together to fine-tune PFC neuronal in normal PFC function. Electron micrographs show that D1 firing. Pharmacological stimulation of the alpha-2 receptor can receptors co-localize with glutamate receptors on dendritic spines increase firing in PFC neurons that code for relevant infor- (Pickel et al., 2006,and see Figure 1), making them strategi- mation, enhancing working memory in monkeys and rodents cally positioned to modulate incoming excitatory information. (Wang et al., 2007). Additionally, alpha-2 agonists reverse work- Single unit physiological studies in monkeys performing a delayed ing memory impairments that occur during stress (Birnbaum response task have revealed that D1 activity plays an integral et al., 2000). role in filtering out “noise”—suppressing firing in PFC neurons Alpha-2 receptors have a high affinity for NE, and are pri- that code for information irrelevant to the immediate task, thus marily bound and active during non-stress conditions (O’Rourke increasing the likelihood of a correct response (Vijayraghavan et al., 1994). Under stress, however, the LC releases NE through- et al., 2007). Without D1 stimulation, PFC neurons become gen- out the brain and excess NE in the PFC binds instead to the lower- erally overactive, rendering the animal vulnerable to distractions affinity alpha-1 receptor (Mohell et al., 1983). Stimulation of this (Vijayraghavan et al., 2007). receptor—either pharmacologically or because of stress-induced While a lack of D1 activity can impair working memory NE release—leads to working memory impairment and a silenc- performance, high levels of D1 stimulation also produce cogni- ing of PFC network activity (Arnsten et al., 1999). Conversely, tive deficits—the classic “inverted-U” relationship. During stress, administration of an alpha-1 antagonist can restore PFC func- HPA axis activation leads to stimulation of the VTA, causing tion and neuronal firing during stress (Birnbaum et al., 1999). excess DA release into the PFC (Murphy et al., 1996). When The impairing effects of alpha-1 stimulation are due in part to this DA binds to the D1 receptor, its downstream signaling cas- downstream activation of protein kinase C (PKC), the inhibi- cades lead to working memory impairment (Taylor et al., 1999). tion of which also reverses stress-related impairments on working Accordingly, these impairments can be reversed by intra-PFC memory tasks in monkeys and rodents (Birnbaum et al., 2004). infusions of a D1 antagonist (Zahrt et al., 1997), as well as by The PKC pathway inhibits neuronal firing through the cleav- infusions of cAMP and PKA inhibitors (Taylor et al., 1999). age of membrane phoshoplipase C (PLC), which initiates phos- Physiologically, elevated D1 signaling leads to a suppression of phatidylinositol signaling (Birnbaum et al., 2004). Downstream, 2+ not only “noise”-related neurons, but of “signal” neurons as intracellular stores of Ca travel to the soma and inhibit neu- well (Vijayraghavan et al., 2007)—the information is lost, and ronal firing through opening of local K channels (Hagenston the PFC is unable to accurately guide behavior. Moreover, this et al., 2008). general silencing of neuronal activity loosens the PFC’s regula- In summary, stress disrupts working memory by eliciting cate- tory influence over subcortical structures, allowing amplified and cholamine release into the PFC, moving both DA and NE levels to protracted emotional responses (Arnsten, 1998b). the far end of their respective inverted U curves. Through DA D1 How does this switch take place on a cellular level? Recent work and NE alpha-1 receptor signaling, delay-related neuronal activity has revealed a critical role for hyperpolarization-activated/cyclic in the PFC is suppressed, and information critical to accurate task nucleotide-gated (HCN) ion channels, which co-localize on performance is lost (Figure 1). Because the PFC also helps to shut dendritic spines with D1 receptors (Paspalas et al., 2012). down the stress response, this loss of PFC function can lead to Traditionally, HCN channels serve to normalize neuronal mem- prolonged glucocorticoid release, which can exacerbate working brane potential, opening to allow positive ions into the cell memory impairments. to combat post-firing hyperpolarization (Wahl-Schott and Biel, GLUCOCORTICOIDS 2009). But as their name implies, HCN channels are also sen- sitive to changes in cAMP levels, and when cAMP increases (as During emotional and stressful situations, activation of the HPA happens when D1 receptors are over-activated), HCN channels axis causes the adrenal cortex to release glucocorticoids, which + + open, letting Na and K flow out of the cell (Chen et al., travel through the bloodstream and cross the blood-brain bar- 2007). The net effect of this efflux is a lessening of the likeli- rier to activate glucocorticoid receptors (GRs) throughout the hood that an incoming stimulus will be sufficiently excitatory brain (De Kloet et al., 2005). While this release is critical to the to propagate an action potential, thus forming the physiological enhancement of long term memories associated with the event Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 2 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC FIGURE 1 | Model for catecholamine modulation and stress-induced of NE alpha-1 receptors activates a PLC signaling cascade that causes impairment of working memory. Under stress-free conditions (top), further loss of excitation through K channels in the soma. This leads the noradrenergic alpha-2 receptor drives activity in the prefrontal to a loss of information, and working memory failure. Adapted from cortex by suppressing cAMP levels and strengthening the signal from Arnsten (2009) and Arnsten et al. (2012). Abbreviations: Glu, glutamate; incoming information. Under stress (bottom), overstimulation of the NMDA, N-methyl D-aspartic acid receptors; NE, norepinephrine; DA, dopamine D1 receptor activates cAMP, causing HCN channels to open, dopamine; HCN, hyperpolarization nucleotide-gated channels; PLC, resulting in a shunting of incoming excitation. Additionally, stimulation phospholipase C. (Rodrigues et al., 2009), glucocorticoid actions in the PFC impair the GR antagonist RU 38486 reverses stress-induced impairments working memory. Systemic injection of corticosterone in rats sig- on the delayed spatial win-shift (DSWS) task, another test of nificantly reduces Delayed Alternation accuracy, and infusion of prefrontal-dependent executive function (Butts et al., 2011). the GR agonist RU 28362 into the PFC similarly impairs working These findings suggest that glucocorticoids can impair PFC func- memory (Roozendaal et al., 2004). Finally, intra-PFC infusion of tion through direct actions at GRs, but glucocorticoids may Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 3 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC also indirectly exacerbate working memory impairments through the effect, and providing evidence against a simple hormone-drug interactions with the catecholamine systems described above. interaction. One mechanism of interaction between glucocorticoids and Further support for the idea that high estrogen levels con- catecholamines is the extraneuronal catecholamine transport sys- fer sensitivity to stress comes from studies in ovariectomized tem. These transporters are located on glia, and remove excess (OVX) female rats. OVX surgery removes circulating estrogen DA and NE from the synapse, helping to keep balanced and opti- and progesterone, hormones that can be re-introduced via a sub- mal stimulation of dopaminergic and noradrenergic receptors. cutaneous time-release silastic capsule. After administration of Corticosterone blocks catecholamine transporters in the PFC low doses of FG7142, OVX rats with long-term estrogen replace- (Gründemann et al., 1998), resulting in increased extracellular ment (OVX + E) demonstrate working memory impairments catecholamine levels. In this way, stress-induced glucocorticoid that are similar to those of females in proestrus, while OVX release in the PFC could lead to overstimulation of the both females with a blank capsule perform more like males—impaired dopamine D1 and α1 noradrenergic receptors, thus producing only at higher doses (Shansky et al., 2009). In all of the above PFC dysfunction. studies, high- and low-estrogen groups did not differ in baseline Glucocorticoids also modulate dopaminergic transmission in working memory performance, suggesting that estrogen does not the PFC. Dopaminergic cells in the VTA and PFC express GRs directly mediate PFC function, but instead modulates the factors that become saturated during stress (Ahima and Harlan, 1990), that contribute to stress-induced impairments. The mechanisms altering the firing of dopaminergic projections. Interestingly, glu- by which estrogen does this are not known, but several intriguing cocorticoid effects on DA release in the PFC appear to be locally possibilities exist. driven, rather than a result of actions in the VTA itself. In vivo First, estrogen may exacerbate the effects of stress-induced microdialysis experiments show that an infusion of GR antago- glucocorticoid release. Female rats in proestrus have higher nist RU-38486 into the PFC suppresses stress-induced DA release, baseline serum corticosterone levels than males or females in but infusions into the VTA have no effect (Butts et al., 2011). diestrus, and females have a more robust corticosterone response Therefore, GRs play a role specific to the PFC in modulating the to acute stress than males do (Mitsushima et al., 2003). Thus, magnitude of stress-induced DA efflux. females with high estrogen levels may be primed for an ampli- Finally, glucocorticoids may further exacerbate catecholamine fied corticosterone surge after exposure to lower levels of stress, effects by activating some of the same intracellular signaling eliciting working memory impairments through the mecha- pathways. As described above, α noradrenergic receptor stim- nisms described above—either through direct actions at GRs, or ulation during stress impairs PFC working memory through through blockade of extraneuronal catecholamine transporters. PKC intracellular signaling pathways (Birnbaum et al., 1999). To date, however, estrogen-glucocorticoid interactions have not Glucocorticoid release can also activate PKC signaling (ffrench- been investigated in the context of stress-induced working mem- Mullen, 1995), thus potentially amplifying the effects of alpha-1 ory impairments. stimulation. Another means by which estrogen may sensitize the PFC to the detrimental effects of stress is through the dopaminergic sys- SEX DIFFERENCES AND ESTROGEN EFFECTS tem. Estrogen increases the physical number of dopaminergic The vast majority of behavioral neuroscience research is con- projections from the VTA to the PFC (Kritzer and Creutz, 2008) ducted in male animals, and thus our general understanding and enhances extracellular DA concentrations (Xiao and Becker, of stress effects in the PFC is within the context of the male 1994), putting it in a powerful position to modulate working brain. From a translational standpoint, this is problematic; stress- memory. While these elevated DA levels may not have measur- related mental illnesses like post-traumatic stress disorder (PTSD) able behavioral outcomes on their own, they could indicate that and major depressive disorder are twice as prevalent in women high-estrogen females are “ahead of the curve” with respect to (Becker et al., 2007), suggesting a distinct neurobiology may the D1-PFC function inverted U. In this scenario, mild stress underlie the stress response in female brains. Though the exact merely pushes low-estrogen females just over the top of the U, mechanisms have not yet been fully identified, a growing body while bumping high-estrogen females into impairment ranges. of literature points to an important role for estrogen in modu- This hypothesis is illustrated in Figure 2. lating the neurotransmitter and glucocorticoid effects described The effects of elevated D1 signaling in high-estrogen females above. may be further exacerbated through estrogen’s interactions with One of the first studies to investigate sex differences in stress- noradrenergic alpha-2a receptors. As described in the first section induced working memory impairments used the anxiogenic drug of this review, alpha-2a activity leads to decreased cAMP pro- FG7142 to generate dose-response curves in male and female duction and a closing of HCN channels, resulting in enhanced rats (Shansky et al., 2004). WhileT-mazeperformance declined “signal” in PFC neurons coding for relevant information. This with increasing doses in both sexes, females became impaired could serve to combat excess D1 activity, which leads to an after lower doses of FG7142 than those required to impair males. opening of HCN channels, and a loss of information. Estrogen When the authors divided the females based on estrus cycle phase, uncouples the alpha-2a receptor from its G-protein (Ansonoff they found that this stress sensitivity was driven by females in and Etgen, 2001), thus potentially disrupting the delicate bal- proestrus, when estrogen levels are highest. Similar results were ance of D1 and alpha-2a activity that is required for optimal found after using increasing durations of restraint stress instead of PFC function. In support of this idea, a dose of guanfacine (an FG7142 (Shansky et al., 2006), demonstrating generalizability of alpha-2a agonist) that rescues stress-induced working memory Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 4 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC FIGURE 2 | Estrogen “ahead of the curve” hypothesis. Estrogen perform equally well at working memory tasks under no-stress may amplify the stress response in females by raising baseline conditions, but mild stress shifts high-estrogen animals down into the dopamine D1 signaling, thus making small shifts more apparent in far end of the D1 inverted U, while only pushing low-estrogen animals behavioral measures. In this model, high- and low-estrogen females slightly across the middle. impairments in males and OVX female rats has no effect in OVX mental illnesses—including Major Depressive Disorder, PTSD, rats with estrogen replacement (Shansky et al., 2009). Schizophrenia, and Attention Deficit/Hyperactivity Disorder [ADHD (Arnsten, 2007)]—are characterized by PFC dysfunc- CONCLUSIONS tion, and the pathways elucidated by the animal research Stressful events can lead to immediate and marked impairments described here are currently being targeted in pharmacological in working memory, an executive function that depends on therapies. For example, the NE alpha-1 antagonist prazosin has a balanced neurochemical state in the PFC. Research in non- been reported to be an effective treatment for PTSD (Berger et al., human primates and rodents has shown that this impairment 2009), and the alpha-2 agonist guanfacine is used as an alternative is driven by increased catecholamine signaling, which may be to psychostimulant treatment for ADHD (Bidwell et al., 2011). further modulated or exacerbated by changes in steroid hor- Continued investigation into the neuromodulators that influence mone levels. Beyond stress, this work has provided critical insight working memory—particularly in female populations—could into the mechanisms that underlie PFC function in general, and lead to more nuanced and effective treatments for disorders that the potential for clinical application is substantial. Numerous compromise prefrontal function. REFERENCES Arnsten, A. F. T. (2009). Stress sig- for a hyperdopaminergic mecha- disorder: a systematic review. Ahima, R. S., and Harlan, R. E. (1990). nalling pathways that impair nism. Arch. Gen. Psychiatry 55, Prog. Neuropsychopharmacol. Biol. Charting of type II glucocorti- prefrontal cortex structure and 362–369. Psychiatry 33, 169–180. coid receptor-like immunoreactivity function. Nat. Rev. Neurosci. 10, Arnsten, A. F. T., Mathew, R., Ubriani, Bidwell, L. C., McClernon, F. J., and in the rat central nervous system. 410–422. R.,Taylor, J. R.,and Li,B.-M. Kollins, S. H. (2011). Cognitive Neuroscience 39, 579–604. Arnsten, A. F. T. (2011a). (1999). Alpha-1 noradrenergic enhancers for the treatment of Ansonoff, M. A., and Etgen, A. M. Catecholamine influences on receptor stimulation impairs pre- ADHD. Pharmacol. Biochem. Behav. (2001). Receptor phosphorylation dorsolateral prefrontal cortical frontal cortical cognitive function. 99, 262–274. mediates estradiol reduction of networks. Biol. Psychiatry 69, Biol. Psychiatry 45, 26–31. Birnbaum, S., Gobeske, K. T., alpha2-adrenoceptor coupling e89–e99. Arnsten, A. F. T., Wang, M. J., Auerbach, J., Taylor, J. R., and to G protein in the hypothala- Arnsten, A. F. T. (2011b). Prefrontal and Paspalas, C. D. (2012). Arnsten, A. F. (1999). A role for mus of female rats. Endocrine 14, cortical network connections: key Neuromodulation of thought: norepinephrine in stress-induced 165–174. site of vulnerability in stress and flexibilities and vulnerabilities cognitive deficits: alpha-1- Arnsten, A. F. (2007). Catecholamine schizophrenia. Int. J. Dev. Neurosci. in prefrontal cortical network adrenoceptor mediation in the and second messenger influences on 29, 215–223. synapses. Neuron 76, 223–239. prefrontal cortex. Biol. Psychiatry prefrontal cortical networks of “rep- Arnsten, A. F. T., and Castellanos, F. Becker, J. B., Monteggia, L. M., Perrot- 46, 1266–1274. resentational knowledge”: a ratio- X. (2002). “Neurobiology of atten- Sinal, T. S., Romeo, R. D., Taylor, J. Birnbaum, S. G., Podell, D. M., nal bridge between genetics and the tion regulation and its disorders,” R., Yehuda, R., et al. (2007). Stress and Arnsten, A. F. T. (2000). symptoms of mental illness. Cereb. in Textbook of Child and Adolescent and disease: is being female a pre- Noradrenergic alpha-2 receptor Cortex 17(Suppl. 1), i6–i15. Psychopharmacology, eds A. Martin, disposing factor? J. Neurosci. 27, agonists reverse working memory Arnsten, A. F. T. (1998a). L. Scahill, D. Charney, and J. 11851–11855. deficits induced by the anxiogenic Catecholamine modulation of pre- Leckman (New York, NY: Oxford Berger,W., Mendlowicz,M. V., drug, FG7142, in rats. Pharmacol. frontal cortical cognitive function. University Press), 99–109. Marques-Portella, C., Kinrys, G., Biochem. Behav. 67, 397–403. Trends Cogn. Sci. 2, 436–447. Arnsten, A. F. T., and Goldman- Fontenelle, L. F., Marmar, C. R., Birnbaum, S. G., Yuan, P. X., Wang, Arnsten, A. F. T. (1998b). The biol- Rakic, P. S. (1998). Noise stress et al. (2009). Pharmacologic M.,Vijayraghavan,S., Bloom,A.K., ogy of feeling frazzled. Science 280, impairs prefrontal cortical cogni- alternatives to antidepres- Davis, D. J., et al. (2004). Protein 1711–1712. tive function in monkeys: evidence sants in posttraumatic stress kinase C overactivity impairs Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 5 Shansky and Lipps Stress, hormone, and catecholamine interactions in the PFC prefrontal cortical regulation of Gründemann, D., Schechinger, B., of the primate prefrontal cortex: Differential influence of dopamin- working memory. Science 306, Rappold, G. A., and Schömig, E. potential substrate for working ergic and noradrenergic afferents on 882–884. (1998). Molecular identification memory deficits in schizophrenia. their target cells in the rat prefrontal Brozoski, T. J.,Brown,R.M., Rosvold, of the corticosterone-sensitive Cereb. Cortex. doi: 10.1093/cercor/ cortex. Clin. Neuropharmacol. H. E., and Goldman, P. S. (1979). extraneuronal catecholamine bhs152. [Epub ahead of print]. 15(Suppl. 1), 139A–140A. Cognitive deficit caused by regional transporter. Nat. Neurosci. 1, Pickel, V. M., Colago, E. E., Mania, I., Vijayraghavan,S., Wang,M., depletion of dopamine in prefrontal 349–351. Molosh, A. I., and Rainnie, D. G. Birnbaum, S. G., Williams, G. cortex of rhesus monkey. Science Hagenston, A. M., Fitzpatrick, J. S., (2006). Dopamine D1 receptors V., and Arnsten, A. F. T. (2007). 205, 929–932. and Yeckel, M. F. (2008). MGluR- co-distribute with N-methyl-D- Inverted-U dopamine D1 receptor Butts, K. A., Weinberg, J., Young, A. mediated calcium waves that invade aspartic acid type-1 subunits and actions on prefrontal neurons H., and Phillips, A. G. (2011). the soma regulate firing in layer V modulate synaptically-evoked engaged in working memory. Nat. Glucocorticoid receptors in the medial prefrontal cortical pyramidal N-methyl-D-aspartic acid cur- Neurosci. 10, 376–384. prefrontal cortex regulate stress- neurons. Cereb. Cortex 18, 407–423. rents in rat basolateral amygdala. Wahl-Schott, C., and Biel, M. (2009). evoked dopamine efflux and Izquierdo, I., Izquierdo, L. A., Barros, Neuroscience 142, 671–690. HCN channels: structure, cellu- aspects of executive function. D. M., Mello e Souza, T., De Souza, Price, J. L., Carmichael, S. T., and lar regulation and physiological Proc. Natl. Acad. Sci. U.S.A. 108, M. M., Quevedo, J., et al. (1998). Drevets, W. C. (1996). Networks function. Cell. Mol. Life Sci. 66, 18459–18464. Differential involvement of cortical related to the orbital and medial 470–494. Chen, S., Wang, J., Zhou, L., George, receptor mechanisms in working, prefrontal cortex; a substrate for Wang, M., Ramos, B. P., Paspalas, C. D., M. S., and Siegelbaum, S. A. short-term and long-term memory. emotional behavior? Prog. Brain Res. Shu, Y., Simen, A., Duque, A., et al. (2007). Voltage sensor movement Behav. Pharmacol. 9, 421–427. 107, 523–536. (2007). Alpha2A-adrenoceptors and cAMP binding allosterically Kritzer, M. F.,and Creutz, L.M. Rodrigues, S. M., LeDoux, J. E., and strengthen working memory net- regulate an inherently voltage- (2008). Region and sex differences Sapolsky, R. M. (2009). The influ- works by inhibiting cAMP-HCN independent closed-open transition in constituent dopamine neurons ence of stress hormones on fear channel signaling in prefrontal in HCN channels. J. Gen. Physiol. and immunoreactivity for intracel- circuitry. Annu. Rev. Neurosci. 32, cortex. Cell 129, 397–410. 129, 175–188. lular estrogen and androgen recep- 289–313. Xiao, L., and Becker, J. B. (1994). Cordero, M. I., Venero, C., Kruyt, N. D., tors in mesocortical projections in Roozendaal, B., McReynolds, J. R., Quantitative microdialysis deter- and Sandi, C. (2003). Prior exposure rats. J. Neurosci. 28, 9525–9535. and McGaugh, J. L. (2004). The mination of extracellular striatal to a single stress session facilitates Mikkelsen, J. D., Søderman, A., basolateral amygdala interacts with dopamine concentration in male subsequent contextual fear condi- Kiss, A., and Mirza, N. (2005). the medial prefrontal cortex in and female rats: effects of estrous tioning in rats. Evidence for a role Effects of benzodiazepines receptor regulating glucocorticoid effects cycle and gonadectomy. Neurosci. of corticosterone. Horm. Behav. 44, agonists on the hypothalamic- on working memory impairment. Lett. 180, 155–158. 338–345. pituitary-adrenocortical axis. Eur. J. Neurosci. 24, 1385–1392. Zahrt, J., Taylor, J. R., Mathew, R. De Kloet, E. R., Joëls, M., and Holsboer, J. Pharmacol. 519, 223–230. Sawaguchi, T., and Goldman-Rakic, P. G., and Arnsten, A. F. (1997). F. (2005). Stress and the brain: Mitsushima, D., Masuda, J., and S. (1991). D1 dopamine receptors Supranormal stimulation of D1 from adaptation to disease. Nat. Rev. Kimura, F. (2003). Sex differences in prefrontal cortex: involvement dopamine receptors in the rodent Neurosci. 6, 463–475. in the stress-induced release of in working memory. Science 251, prefrontal cortex impairs spatial ffrench-Mullen, J. M. (1995). Cortisol acetylcholine in the hippocampus 947–950. working memory performance. inhibition of calcium currents in and corticosterone from the adrenal Shansky, R. M., Bender, G., and J. Neurosci. 17, 8528–8535. guinea pig hippocampal CA1 neu- cortex in rats. Neuroendocrinology Arnsten, A. F. (2009). Estrogen rons via G-protein-coupled activa- 78, 234–240. prevents norepinephrine alpha-2a Conflict of Interest Statement: The tion of protein kinase C. J. Neurosci. Mohell, N., Svartengren, J., and receptor reversal of stress-induced authors declare that the research 15, 903–911. Cannon, B. (1983). Identification working memory impairment. was conducted in the absence of any Funahashi, S.,Bruce, C.J., and of [ H]prazosin binding sites in Stress 12, 457–463. commercial or financial relationships Goldman-Rakic, P. S. (1989). crude membranes and isolated Shansky, R. M., Glavis-Bloom, C., that could be construed as a potential Mnemonic coding of visual space in cells of brown adipose tissue as Lerman, D., McRae, P., Benson, conflict of interest. the monkey’s dorsolateral prefrontal alpha 1-adrenergic receptors. Eur. C., Miller, K., et al. (2004). cortex. J. Neurophysiol. 61, 331–349. J. Pharmacol. 92, 15–25. Estrogen mediates sex differences Received: 21 February 2013; accepted: 20 Funahashi, S.,Bruce, C.J., and Murphy, B. L., Arnsten, A. F., Goldman- in stress-induced prefrontal cortex March 2013; published online: 05 April Goldman-Rakic, P. S. (1993). Rakic, P. S., and Roth, R. H. (1996). dysfunction. Mol. Psychiatry 9, 2013. Dorsolateral prefrontal lesions and Increased dopamine turnover in 531–538. Citation: Shansky RM and Lipps J oculomotor delayed-response per- the prefrontal cortex impairs spatial Shansky, R. M., Rubinow, K., Brennan, (2013) Stress-induced cognitive dysfunc- formance: evidence for mnemonic working memory performance in A., and Arnsten, A. F. T. (2006). The tion: hormone-neurotransmitter interac- “scotomas”. J. Neurosci. 13, rats and monkeys. Proc. Natl. Acad. effects of sex and hormonal status tions in the prefrontal cortex. Front. 1479–1497. Sci. U.S.A. 93, 1325–1329. on restraint-stress-induced working Hum. Neurosci. 7:123. doi: 10.3389/ Goldman-Rakic, P. S. (1995). Cellular O’Rourke, M. F., Blaxall, H. S., Iversen, memory impairment. Behav. Brain fnhum.2013.00123 basis of working memory. Neuron L. J., and Bylund, D. B. (1994). Funct. 2, 8. Copyright © 2013 Shansky and Lipps. 14, 477–485. Characterization of [ H]RX821002 Taylor, J. R., Birnbaum, S., Ubriani, This is an open-access article dis- Goldman-Rakic, P. S. (1996). The pre- binding to alpha-2 adrenergic R., and Arnsten, A. F. (1999). tributed under the terms of the Creative frontal landscape: implications of receptor subtypes. J. Pharmacol. Activation of cAMP-dependent pro- Commons Attribution License,which functional architecture for under- Exp. Ther. 268, 1362–1367. tein kinase A in prefrontal cortex permits use, distribution and reproduc- standing human mentation and Paspalas, C. D., Wang, M., and Arnsten, impairs working memory perfor- tion in other forums, provided the origi- the central executive. Philos. Trans. A. F. T. (2012). Constellation of mance. J. Neurosci. 19, RC23. nal authors and source are credited and R. Soc. Lond. B Biol. Sci. 351, HCN channels and cAMP regu- Thierry, A. M., Godbout, R., Mantz, J., subject to any copyright notices concern- 1445–1453. lating proteins in dendritic spines Pirot, S., and Glowinski, J. (1992). ing any third-party graphics etc. Frontiers in Human Neuroscience www.frontiersin.org April 2013 | Volume 7 | Article 123 | 6

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