Chronic stress effects on memory: sex differences in performance and monoaminergic activity

Increasing evidence suggests that the time course of advantageous versus deleterious effects of stress on physiologic function is also apparent in some brain functions, including learning and memory. This article reviews the effects of chronic stress on behavioral performance and, more importantly, shows that sex of the subject, as well as duration and intensity of stress, is an important determinant of the functional/behavioral, neurochemical, and anatomical consequences of the stress. Following chronic stress (7-28 days of restraint, 6 h/day), male and female rats were tested on a visual memory task (object recognition) and two spatial memory tasks (object placement and radial arm maze). At 21 days, stress impaired males on all tasks while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally, the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the sex-specific responses to stress is considered. Behavioral and neurochemical assessments following chronic stress in ovariectomized females, with and without estradiol, suggest that estrogen exerts both organizational and activational influences on the observed sex differences in response to stress. Furthermore, stress differentially affected central transmitter levels in the frontal cortex, hippocampus, and amygdala depending on sex. The possible role of these sex-specific changes in neurotransmitter levels in mediating behavioral differences in response to stress is discussed. While these results are thus far limited to a few studies and require both further investigation and verification, chronic stress appears to be associated with distinct, sex-differentiated behavioral/cognitive and neurochemical responses. We conclude that sex differences must be taken into account when investigating or describing stress and associated sequalae.     

Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster)

Various hormones, including sex steroids and neuropeptides, have been implicated in aggression. In this study we examined (1) sex differences in intrasexual aggression in na?ve prairie voles; (2) the effects of developmental manipulations of oxytocin on intrasexual aggression; and (3) changes in patterns of intrasexual aggression after brief exposure to an animal of the opposite sex. Within 24 h of birth, infants were randomly assigned to receive either an injection of oxytocin (OT) or oxytocin antagonist (OTA) or to one of two control (CTL) groups receiving either isotonic saline or handling without injection. As adults, animals were tested twice in a neutral arena; before (Test 1) and 24 h after (Test 2) a 4-h exposure to an animal of the opposite sex. In Test 1, CTL males were more likely to show aggressive and less likely to show social behavior than CTL females. No significant treatment differences were observed within either sex in Test 1. In Test 2, after brief exposure to a male, females treated with OT became more aggressive and less social than OTA or CTL females. Male aggressive behavior did not change after exposure to a female. An increase in aggression and decline in social behavior toward other females, seen here in OT-treated females, is typically observed only following several days of female-male cohabitation. These findings demonstrate a sex difference in intrasexual aggression and suggest that neonatal exposure to OT may facilitate the onset of the mate-guarding component of pair bonding in female prairie voles.     

Proximity to an edge affects search strategy in adults and children

When searching for a hidden goal, search patterns are often defined according to one of two main search strategies: an absolute strategy, which usually involves searching at a fixed learned distance and direction from a particular reference point, or a relational strategy, which involves searching at a point that maintains the relationship between two or more other points. Past research has shown that humans tend to prefer a relational strategy whereas most non-humans prefer an absolute strategy. However, recent research (Hartley et al., 2004) used a simulated 3D environment to demonstrate that proximity to a boundary affects strategy. In particular, when searching close to an edge, human participants were more likely to use an absolute strategy whereas when searching at a central location, participants were more likely to use a relational strategy. The current studies extend the findings of Hartley et al. Experiment 1 showed that adult humans use different strategies based on the goal's proximity to the edge of a search space, and that strategies differed between males and females. Experiment 2 suggested that children also use different strategies based on the goal's proximity to a boundary, and that some goal locations may be harder to learn than others. Taken together, our results show that search strategies are flexible and context-specific.     

Androgens and eye movements in women and men during a test of mental rotation ability

Eye movements were monitored in 16 women and 20 men during completion of a standard diagram-based test of mental rotation ability to provide measures of cognitive function not requiring conscious, decisional processes. Overall, women and men allocated visual attention during task performance in very similar, systematic ways. However, consistent with previous suggestions that sex differences in attentional processes during completion of the mental rotation task may exist, eye movements in men compared to women indicated greater discrimination and longer processing of correct alternatives during task performance. Other findings suggested that androgens may enhance cognitive processes that are recruited differentially by women and men as a function of the task. Specifically, smaller (i.e., more masculine) digit ratios were associated with men's shorter fixations on distracters, suggesting that perinatal androgen action may influence brain systems that facilitate the identification of relevant task stimuli. In women, higher circulating testosterone levels appeared to contribute to more general processes engaged during task performance, for example higher levels of visual persistence. It is possible that variability in the relative contribution of such hormone sensitive cognitive processes to accuracy scores as a function of different sample characteristics or assessment methods may partially account for the inconsistent findings of previous research on hormonal factors in mental rotation ability.     

工作记忆的负荷影响心理旋转任务中的性别差异

目的:探讨心理旋转任务中的性别差异是否受工作记忆的负荷的影响。方法:采用先后呈现提示刺激和目标刺激的范式,任务分为三种:1.无效提示的数字旋转;2.有效提示的数字旋转;3.有效提示的PMA图形旋转。结果:重复测量的方差分析表明:对无效提示的数字旋转任务,男性和女性之间的反应时和正确率都无差异;对有效提示的数字旋转任务,男性和女性之间的正确率无差异,而反应时的差异边缘显著;对有效提示的PMA图形旋转任务,男性和女性之间的正确率无差异,而反应时有显著差异。结论:工作记忆的负荷可能会影响心理旋转任务中的性别差异。     

Do hormonal changes that appear at the onset of puberty determine the strategies used by female rats when solving a navigation task?

The present set of experiments evaluated the possibility that the hormonal changes that appear at the onset of puberty might influence the strategies used by female rats to solve a spatial navigation task. In each experiment, rats were trained in a triangular shaped pool to find a hidden platform which maintained a constant relationship with two sources of information, one individual landmark and one corner of the pool with a distinctive geometry. Then, three test trials were conducted without the platform in counterbalanced order. In one, both the geometry and the landmark were simultaneously presented, although in different spatial positions, in order to measure the rats' preferences. In the remaining test trials what the rats had learned about the two sources of information was measured by presenting them individually. Experiment 1, with 60-day old rats, revealed a clear sex difference, thus replicating a previous finding (Rodríguez et al., 2010): females spent more time in an area of the pool that corresponded to the landmark, whereas males spent more time in the distinctive corner of the pool even though the remaining tests revealed that both sexes had learned about the two sources of information. In Experiment 2, 30-day old female rats, unlike adults, preferred to solve the task using the geometry information rather than the landmark (although juvenile males behaved in exactly the same way as adults). Experiment 3 directly compared the performance of 90- and 30-day old females and found that while the adult females preferred to solve the task using the landmark, the reverse was true in juvenile females. Experiment 4 compared ovariectomized and sham operated females and found that while sham operated females preferred to solve the task using the landmark, the reverse was true in ovariectomized females. Finally, Experiment 5 directly compared adult males and females, juvenile males and females, and ovariectomized females and found that adult males, juvenile males and females, and ovariectomized females did not differ among them in their preferred cue, but they all differed from adult females.     

Staurosporine Activates a 60,000 Mr Protein Kinase in Bovine Chromaffin Cells That Phosphorylates Myelin Basic Protein In Vitro

Abstract: Bovine chromaffin cells contain a family of renaturable protein kinases. One of these, a 60,000 M_r kinase (PK60) that phosphorylated myelin basic protein in vitro, was activated fourfold when cells were treated with the protein kinase inhibitor Staurosporine. Because staurosporine inhibits protein kinase C, the role of this kinase in the regulation of PK60 activity was investigated. Fifty nanomolar Staurosporine produced half-maximal inhibition of protein kinase C activity in chromaffin cells, whereas ∼225 n M Staurosporine was required to induce half-maximal activation of PK60. Other protein kinase C inhibitors, H-7 and K-252a, did not mimic the effect of Staurosporine on PK60 activity. Chromaffin cells have three protein kinase C isoforms: α, ε, and ζ. Prolonged treatment with phorbol esters depleted the cells of protein kinase C α and ε, but not ζ. Neither activation nor depletion of protein kinase C affected the basal activity of PK60. Moreover, Staurosporine activated PK60 in cells depleted of protein kinase C α and e; thus, Staurosporine appeared to activate PK60 by a mechanism that does not require these protein kinase C isoforms. Incubation of cell extracts with Staurosporine in vitro did not activate PK60. Incubation of these extracts with adenosine 5'-O-(3-thiotriphosphate), however, caused a twofold activation of PK60. Although this suggests that PK60 activity is regulated by phosphorylation, the mechanism by which Staurosporine activates PK60 is not known. Staurosporine has been reported to promote neurite outgrowth from chromaffin cells. The role of PK60 in mediating the effects of Staurosporine on chromaffin cell function remains to be determined.     

Identification of Two Distinct Populations of Protein Kinase C in Rat Brain Membranes

The regulatory enzyme protein kinase C (PKC) is proposed to be activated on its translocation from the cytosol to the membrane. However, a portion of the native activity is always associated with the membrane fraction. Using a noninvasive procedure to extract this endogenous activity from rat brain membranes, it has been possible to characterize the activity in a partially purified reconstituted system bearing resemblance to the in vivo system. Two subpopulations of membrane-associated PKC were identified and characterized at the level of activation, inhibition, and isozyme immunologic characteristics and chromatographic properties. One peak had properties similar to those of cytosolic PKC, whereas the second population, extracted as protein-lipid complexes, had considerable constitutive activity that could be stimulated further on addition of PKC activators. This latter activity was relatively resistant to staurosporine inhibition and phorbol ester treatment, but it phosphorylated the exogenous PKC substrates, histone 1 and the epidermal growth factor receptor peptide KTRLRR. The constitutive activity was totally dependent on its endogenous associated lipids coextracted by the solubilization procedure. The ratio between these two populations was ontogenetically regulated and modulated by phorbol ester treatment, suggesting that different PKC populations may serve unique functions in the rat brain regulated by the lipid environment. Analyses of the phospholipids extracted in these protein-lipid complexes showed differences in the major classes correlating to age. However, apart from a markedly lower cholesterol content in these complexes, no direct relationship between a specific lipid composition and the amount of constitutive PKC activity was evident.     

Phorbol Myristate Acetate and 8-Bromo-Cyclic AMP-Induced Phosphorylation of Glial Fibrillary Acidic Protein and Vimentin in Astrocytes: Comparison of Phosphorylation Sites

Both the protein kinase C (PK-C) activator, phorbol 12-myristate 13-acetate (PMA), and the cyclic AMP-dependent protein kinase (PK-A) activator, 8-bromo-cyclic AMP (8-BR), have been shown to increase 32P incorporation into glial fibrillary acidic protein (GFAP) and vimentin in cultured astrocytes. Also, treatment of astrocytes with PMA or 8-BR results in the morphological transformation of flat, polygonal-shaped cells into stellate, process-bearing cells, suggesting the possibility that signals mediated by these two kinase systems converge at the level of protein phosphorylation to elicit similar changes in cell morphology. Therefore, studies were conducted to determine whether treatment with PMA and 8-BR results in the phosphorylation of the same tryptic peptide fragments on GFAP and vimentin in astrocytes. Treatment with PMA increased 32P incorporation into all the peptide fragments that were phosphorylated by 8-BR on both vimentin and GFAP; however, PMA also stimulated phosphorylation of additional fragments of both proteins. The phosphorylation of vimentin and GFAP resulting from PMA or 8-BR treatment was restricted to serine residues in the N-terminal domain of these proteins. Studies were also conducted to compare the two-dimensional tryptic phosphopeptide maps of GFAP and vimentin from intact cells treated with PMA and 8-BR with those produced when the proteins were phosphorylated with purified PK-C or PK-A. PK-C phosphorylated the same fragments of GFAP and vimentin that were phosphorylated by PMA treatment. Additionally, PK-C phosphorylated some tryptic peptide fragments of these proteins that were not observed with PMA treatment in intact cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterizing spatial extinction in an abbreviated version of the Barnes maze

Adult male Wistar rats were trained to find an escape box in the Barnes maze in order to characterize the extinction process of a learned spatial preference. To do so, once they had fully acquired the spatial task, they were repeatedly exposed to the maze without the escape box. Multiple behavioral measurements (grouped into motor skill and spatial preference indicators) were followed up throughout the complete training process. Animals gained efficiency in finding the escape box during acquisition, as indicated by the reduction in the time spent escaping from the maze, the number of errors, the length of the traveled path, and by the increase in exploration accuracy and execution speed. When their retention and preference were tested 24 h later, all the subjects retained their enhanced performance efficiency and accuracy and displayed a clear-cut preference for the escape hole and its adjacent holes. Almost all motor skill indicators followed an inverse, though not monotonic, pattern during the extinction training, returning to basal levels after three trials without escape box, displaying a transient relapse during the fifth extinction trial. Preference indicators also followed a reverse pattern; however, it took seven trials for them to return to basal levels, relapsing during the eighth extinction trial. The abbreviated Barnes maze acquisition, evaluation, and extinction procedures described herein are useful tools for evaluating the effects of behavioral and/or pharmacological treatment on different stages of spatial memory, and could also be used for studying the neurophysiological and neurobiological underpinnings of this kind of memory.     

PKC、PKA和TPK在血小板激活中的作用

利用~（３２）Ｐ－ＮａＨ_２ＰＯ_４标记猪血小板,然后以ＰＭＡ、凝血酶、ＰＧＥ_１、腺苷等处理,结果表明,随着ＰＭＡ激活ＰＫＣ,血小板发生聚集。３５μｍｏｌ／ＬＰＧＥ_１或１ｍｍｏｌ／ＬｄｂｃＡＭＰ不能抑制５０ｎｍｏｌ／ＬＰＭＡ诱导的血小板聚集,腺苷却能抑制ＰＭＡ诱导的血小板聚集（ＥＣ_（５０）＝０．１ｍｍｏｌ／Ｌ）,ｄｂ－ｃＡＭＰ、腺苷都不能抑制１００ｎｍｏｌ／ＬＰＭＡ诱导的４０ｋＤ蛋白磷酸化。ＰＫＡ激活不能抑制ＰＭＡ激活的ＰＫＣ。在ＰＭＡ、凝血酶激活的血小板中,ＰＫＣ、ＴＰＫ都发生激活,４０ｋＤ底物既是ＰＫＣ的底物又是ＴＰＫ的底物,ＰＫＣ和ＴＰＫ在血小板聚集中起着重要的调节作用。     

TPA-induced activation of MAP kinase

Threonine and tyrosine residue phosphorylation of a 42 kDa protein identified as mitogen-activated protein kinase (MAP kinase) was stimulated in extracts from TPA-pretreated cells. It is further shown that TPA pretreatment leads to the enhancement of an activity that will induce reactivation of dephosphorylated/inactivated MAP kinase. This TPA-induced activity induces the threonine and tyrosine phosphorylation of p42 in extracts from unstimulated cells.     

钙调素高表达对NRK细胞中DG-PKC和cAMP-PKA水平的影响

钙调素（ＣａＭ）作为Ｃａ２＋的主要受体,对细胞增殖起重要调节作用,而且在转化细胞中ＣａＭ的水平明显高于正常细胞．ｃＡＭＰ作为一种第二信使,起着将细胞外刺激信号转化为细胞内各种生理活动的媒介作用．蛋白激酶Ａ（ＰＫＡ）则是这种转化过程中的关键激酶．蛋白激...