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1.  Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex 
The mechanisms and neural circuits that drive emotion and cognition are inextricably linked. Activation of the hypothalamic-pituitary-adrenal (HPA) axis as a result of stress or other causes of arousal initiates a flood of hormone and neurotransmitter release throughout the brain, affecting the way we think, decide, and behave. This review will focus on factors that influence the function of the prefrontal cortex (PFC), a brain region that governs higher-level cognitive processes and executive function. The PFC becomes markedly impaired by stress, producing measurable deficits in working memory. These deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, catecholamines, and gonadal hormones; here we will discuss the non-human primate and rodent literature that has furthered our understanding of the circuitry, receptors, and signaling cascades responsible for stress-induced prefrontal dysfunction.
PMCID: PMC3617365  PMID: 23576971
working memory; stress; catecholamines; glucocorticoids; sex differences; estrogen
2.  Estrogen Promotes Stress Sensitivity in a Prefrontal Cortex–Amygdala Pathway 
Cerebral Cortex (New York, NY)  2010;20(11):2560-2567.
We have recently reported in male rats that medial prefrontal cortex (mPFC) neurons that project to the basolateral nucleus of the amygdala (BLA) are resilient to stress-induced dendritic remodeling. The present study investigated whether this also occurs in female rats. This pathway was identified using the retrograde tracer Fast Blue injected into the BLA of ovariectomized female rats with estrogen replacement (OVX + E) and without (OVX + veh). Animals were exposed for 10 days either to 2-h immobilization stress or to home cage rest, after which layer III mPFC neurons that were either retrogradely labeled by Fast Blue or unlabeled were filled with Lucifer Yellow and analyzed for apical dendritic length and spine density. No dendritic remodeling occurred in unlabeled neurons from OVX + veh or OVX + E animals. In BLA-projecting neurons, however, stress had no effect on length in OVX + veh animals, but stressed OVX + E females showed greater dendritic length than controls at intermediate branches. Stress also caused an increase in spine density in all neurons in OVX + veh animals and a spine density increase in BLA-projecting neurons in OVX + E females. Estrogen also increased spine density on BLA-projecting neurons in unstressed animals. These data demonstrate both independent effects of estrogen on pyramidal cell morphology and effects that are interactive with stress, with the BLA-projecting neurons being sensitive to both kinds of effects.
PMCID: PMC2951843  PMID: 20139149
connectivity; dendritic arborization; medial prefrontal cortex; neural plasticity; sex difference
3.  Stress-induced dendritic remodeling in the medial prefrontal cortex: effects of circuit, hormones and rest 
Brain research  2009;1293:108-113.
The medial prefrontal cortex (mPFC) has been implicated as a site of dysfunction and abnormal morphology in major depressive disorder and post-traumatic stress disorder, two illnesses that can be brought on by exposure to stress. In animal models, stress has long been shown to induce impairments in tasks known to be mediated by the mPFC, and recent work has demonstrated that chronic stress can lead to morphological changes in mPFC pyramidal cells. This review explores the current literature on stress-induced dendritic remodeling in the mPFC, with particular focus on new findings that illuminate modulators of these effects.
PMCID: PMC2748148  PMID: 19361488
4.  Stress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific 
Cerebral Cortex (New York, NY)  2009;19(10):2479-2484.
Chronic stress exposure has been reported to induce dendritic remodeling in several brain regions, but it is not known whether individual neural circuits show distinct patterns of remodeling. The current study tested the hypothesis that the projections from the infralimbic (IL) area of the medial prefrontal cortex (mPFC) to the basolateral nucleus of the amygdala (BLA), a pathway relevant to stress-related mental illnesses like depression and post-traumatic stress disorder, would have a unique pattern of remodeling in response to chronic stress. The retrograde tracer FastBlue was injected into male rats’ BLA or entorhinal cortex (EC) 1 week prior to 10 days of immobilization stress. After cessation of stress, FastBlue-labeled and unlabeled IL pyaramidal neurons were loaded with fluorescent dye Lucifer Yellow to visualize dendritic arborization and spine density. As has been previously reported, randomly selected (non-FastBlue-labeled) neurons showed stress-induced dendritic retraction in apical dendrites, an effect also seen in EC-projecting neurons. In contrast, BLA-projecting neurons showed no remodeling with stress, suggesting that this pathway may be particularly resilient against the effects of stress. No neurons showed stress-related changes in spine density, contrasting with reports that more dorsal areas of the mPFC show stress-induced decreases in spine density. Such region- and circuit-specificity in response to stress could contribute to the development of stress-related mental illnesses.
PMCID: PMC2742599  PMID: 19193712
amygdala; chronic stress; connectivity; infralimbic cortex; neural plasticity; spine density
5.  Estrogen prevents norepinephrine alpha-2a receptor reversal of stress-induced working memory impairment 
Stress (Amsterdam, Netherlands)  2009;12(5):457-463.
Understanding effects of estrogen on the medial prefrontal cortex (PFC) may help to elucidate the increased prevalence of depression and post-traumatic stress disorder in women of ovarian cycling age. Estrogen replacement in ovariectomized (OVX) young rats amplifies the detrimental effects of stress on working memory (a PFC-mediated task), but the mechanisms by which this occurs have yet to be identified. In male rats, stimulation of norepinephrine alpha-2 adrenoceptors protects working memory from stress-induced impairments. However, this effect has not been studied in females, and has not been examined for sensitivity to estrogen. The current study asked whether OVX females with estrogen replacement (OVX + Est) and without replacement (OVX + Veh) responded differently to stimulation of alpha-2 adrenoceptors after administration of the benzodiazepine inverse agonist FG7142, a pharmacological stressor. The alpha-2 agonist, guanfacine, protected working memory from the impairing effects of FG7142 in OVX + Veh, but not in OVX + Est rats. Western Blot analysis for alpha-2 receptors was performed on PFC tissue from each group, but no changes in expression were found, indicating that the behavioral effects observed were likely not due to changes in receptor expression. These findings point to possible mechanisms by which estrogen may enhance the stress response, and hold implications for the gender discrepancy in the prevalence of stress-related mental illness.
PMCID: PMC3143502  PMID: 19005873
Acute stress; estrogen; norepinephrine; prefrontal cortex; sex differences; working memory
6.  Estrogen enhances stress-induced prefrontal cortex dysfunction: relevance to Major Depressive Disorder in women 
It is well documented that exposure to stress can precipitate or exacerbate many mental illnesses,1,2 including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Women are twice as likely as men to develop these disorders,34 as well as most anxiety disorders and phobias,5 but the biological causes of this discrepancy are poorly understood. Interestingly, there is evidence that the increased prevalence of MDD in women occurs primarily during the childbearing years, when circulating estrogen is present.67 These observations raise questions as to whether men and women have distinct neurobiological responses to stress, and if so, how might estrogen mediate these differences? Attempts to answer these questions in animal models have generated a growing body of literature demonstrating that estrogen can, indeed, modulate the effects of stress in the brain. Moreover, these effects are demonstrable in brain regions relevant to MDD, and are consistent with the idea that estrogen might enhance the stress response, promoting a greater vulnerability to mental illness.
PMCID: PMC3181833
7.  The effects of sex and hormonal status on restraint-stress-induced working memory impairment 
Restraint stress has been shown to elicit numerous effects on hippocampal function and neuronal morphology, as well as to induce dendritic remodeling in the prefrontal cortex (PFC). However, the effects of acute restraint stress on PFC cognitive function have not been investigated, despite substantial evidence that the PFC malfunctions in many stress-related disorders.
The present study examined the effects of restraint stress on PFC function in both male rats and cycling female rats in either the proestrus (high estrogen) or estrus (low estrogen) phase of the estrus cycle. Animals were restrained for 60 or 120 minutes and then tested on spatial delayed alternation, a PFC-mediated task. Performance after stress was compared to performance on a different day under no-stress conditions, and analyzed using analysis of variance (ANOVA).
Sixty minutes of restraint impaired only females in proestrus, while 120 minutes of restraint produced significant impairments in all animals. Increases in task completion times did not affect performance.
These results demonstrate an interaction between hormonal status and cognitive response to stress in female rats, with high estrogen levels being associated with amplified sensitivity to stress. This effect has been previously observed after administration of a pharmacological stressor (the benzodiazepine inverse agonist FG7142), and results from both studies may be relevant to the increased prevalence of stress-related disorders, such as major depressive disorder, in cycling women. Overall, the results show that restraint stress has important effects on the cognitive functions of the PFC, and that hormonal influences in the PFC are an important area for future research.
PMCID: PMC1420310  PMID: 16522198

Results 1-7 (7)