Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function

Butts, Kelly A.; Weinberg, Joanne; Young, Allan H.; Phillips, Anthony G.

doi:10.1073/pnas.1111746108

Cited by 158 publications

(134 citation statements)

References 54 publications

(61 reference statements)

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“…As a result, the complex effects of increased circulating corticosterone on cognition while GRs are blocked make interpretation of the effects of systemically administered RU38486 on reversal learning difficult. It should be noted that a single systemic [13] or local intracerebral administration of RU38486 [6] is effective for assessing the mechanisms underlying stress-induced changes in cognition. Future studies using targeted local intracranial infusions of RU38486 may clarify the role of GRs in the stress-induced facilitation of reversal learning without confounds related to response latencies or alterations in levels of circulating corticosterone.…”

Section: Discussionmentioning

confidence: 99%

“…This design enabled assessment of the immediate effects of restraint stress and GR activation on early reversal learning [10], as well as the long-term effects on late reversal learning in a manner similar to that reported previously [11,12]. We hypothesized that blocking GRs would prevent the immediate influence of stress on reversal learning as GRs become saturated by elevated CORT levels following stress and blocking GRs reverses the effect of acute stress on cognitive functioning in previous studies [6,13].…”

Section: Introductionmentioning

confidence: 89%

“…However, the influence of acute stress on forms of cognition dependent on prefrontal cortex (PFC) is less well defined [1]. Research regarding the influence of acute stress on PFC-dependent executive processing and cognitive/behavioral flexibility have been inconsistent, with some studies showing impaired performance [6][7][8][9] while others show facilitated performance [10][11][12][13][14], depending on the specific task and stressor.…”

Section: Introductionmentioning

confidence: 99%

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Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

Bryce

Howland

2015

Behavioural Brain Research

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The stress response is essential to the survival of all species as it maintains internal equilibrium and allows organisms to respond to threats in the environment. Most stress research has focused on the detrimental impacts of stress on cognition and behavior. Reversal learning, which requires a change in response strategy based on one dimension of the stimuli, is one type of behavioral flexibility that is facilitated following some brief stress procedures. The current study investigated a potential mechanism underlying this facilitation by blocking glucocorticoid receptors (GRs) during stress. Thirty-seven male Long Evans rats learned to discriminate between two images on a touchscreen, one of which was rewarded. Once a criterion was reached, rats received stress (30 min of restraint stress or no stress) and drug (GR antagonist RU38486 or vehicle) administration prior to each of the first 3 days of reversal learning. We expected that stress would facilitate reversal learning and RU38486 (10 mg/kg) would prevent this facilitation in both early (<50% correct in one session) and late (>50% correct in one session) stages of reversal learning. Results showed that stressed rats performed better than unstressed rats (fewer days for late reversal, fewer correction trials, and fewer errors) in the late but not early stage of reversal learning. RU38486 did not block the facilitation of RL by stress, although it dramatically increased response, but not reward, latencies. These results confirm the facilitation of late reversal by stress in a touchscreenbased operant task in rats and further our understanding of how stress affects higher level cognitive functioning and behavior.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

Bryce

Howland

2015

Behavioural Brain Research

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“…Alterations in both stress/emotion systems and cognitive functioning attributable to early adverse experiences have pointed to interconnections between these systems across development. For instance, the PFC is rich in glucocorticoid receptors, and evidence from rodent models shows that blocking these receptors during acute stress prevents transient cognitive impairments in performance that are usually observed during these episodes (24). Although translational models face challenges attributable to species differences in developmental timing of neural maturation and differences in how adverse circumstances are modeled (25), there is incontrovertible evidence based on animal models that adverse care early in life disrupts the normal development of PFC-based cognitive systems.…”

Section: Animal Models Of the Effects Of Early Adversity On Cognitionmentioning

confidence: 99%

Associations between early life adversity and executive function in children adopted internationally from orphanages

Hostinar

Stellern

Schaefer

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

199

138

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Executive function (EF) abilities are increasingly recognized as an important protective factor for children experiencing adversity, promoting better stress and emotion regulation as well as social and academic adjustment. We provide evidence that early life adversity is associated with significant reductions in EF performance on a developmentally sensitive battery of laboratory EF tasks that measured cognitive flexibility, working memory, and inhibitory control. Animal models also suggest that early adversity has a negative impact on the development of prefrontal cortex-based cognitive functions. In this study, we report EF performance 1 y after adoption in 2.5-to 4-y-old children who had experienced institutional care in orphanages overseas compared with a group of age-matched nonadopted children. To our knowledge, this is the youngest age and the soonest after adoption that reduced EF performance has been shown using laboratory measures in this population. EF reductions in performance were significant above and beyond differences in intelligence quotient. Within the adopted sample, current EF was associated with measures of early deprivation after controlling for intelligence quotient, with less time spent in the birth family before placement in an institution and lower quality of physical/social care in institutions predicting poorer performance on the EF battery.I t has been argued that early experiences have an impact on neurobehavioral development, for good or ill, and thus influence lifelong health and disease (1). The search for protective processes in the individual that may reduce the impact of early adversity has begun to identify executive functions (EFs) as one candidate domain for intervention (2). EFs are a set of higher order cognitive processes that allow individuals to engage in planning and conscious, goal-directed problem solving (3). In children, EF is related to emotion regulation (4), conscience and moral development (5, 6), and math and literacy ability in kindergarten (7), and it is also predictive of later social and academic competence (8, 9). It is believed that EF may play an especially important role in adverse circumstances because of its role in balancing emotional arousal and cognitive processing (10). Thus, understanding the development of EF in children who experience early adversity may provide avenues for promoting their resilience.Unfortunately, this factor that could help buffer children living in adverse rearing environments has also been shown to be impaired in these children. For instance, there is accumulating evidence that psychosocial deprivation in the form of being raised in an institution is associated with reduced performance in a variety of EF domains assessed years after adoption into an enriched family environment (11-15). Studies of children experiencing early adversity cannot definitively attribute reduced EF performance to their early experiences because of their frequent coexposure to multiple other prenatal and postnatal risk factors that stunt physical g...

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“…Thus, EP1 is critical for the attenuation of the mesocortical dopaminergic pathway by repeated stress. Notably, receptors for other stress-related molecules, such as glucocorticoid and corticotropinreleasing hormone, are involved in the facilitation of prefrontal dopamine release upon acute stress (24,25). Therefore, distinct molecules could regulate prefrontal dopamine release under acute and chronic stress (Fig.…”

Section: A Role For Pge 2 -Ep1 Signaling In the Induction Of Behaviormentioning

confidence: 99%

Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress

Furuyashiki

2012

J Pharmacol Sci

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Abstract. Prolonged or intensive stress results in emotional and cognitive deficits and is a major risk factor for psychiatric disorders such as depression. Since the molecular mechanisms of how biological adaptations to stress go awry remains elusive, pharmaceutical development targeting stress has not been established. In rodents, repeated stress alters functions of multiple brain areas including the medial prefrontal cortex (mPFC) that confers stress resilience, thereby causing depression, anxiety, and working memory deficit. The mesocortical dopaminergic pathway that regulates such stress-coping functions is attenuated with repetition of stress via prostaglandin (PG) E 2 , a bioactive lipid derived from arachidonic acid, and its receptor EP1. Several findings suggest that microglia activated by repeated stress are involved in emotional and cognitive changes as a source of inflammation-related molecules such as PGE 2 and IL-1β. IL-1 signaling is critical not only for emotional changes but also for microglial activation induced by repeated stress. Furthermore, purinergic signaling via the P2X7 receptor that can trigger PGE 2 and IL-1β production in microglia has been implicated in the pro-depressive effect of repeated stress as well as depressive disorders. Collectively, inflammation-related molecules that link repeated stress to mPFC dysfunction are potential targets of pharmaceutical development for psychiatric disorders.

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Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function

Cited by 158 publications

References 54 publications

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

Associations between early life adversity and executive function in children adopted internationally from orphanages

Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress

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