Impact of chronic stress protocols in learning and memory in rodents: systematic review and meta-analysis

The idea that maladaptive stress impairs cognitive function has been a cornerstone of decades in basic and clinical research. However, disparate findings have reinforced the need to aggregate results from multiple sources in order to confirm the validity of such statement. In this work, a systematic review and meta-analyses were performed to aggregate results from rodent studies investigating the impact of chronic stress on learning and memory. Results obtained from the included studies revealed a significant effect of stress on global cognitive performance. In addition, stressed rodents presented worse consolidation of learned memories, although no significantly differences between groups at the acquisition phase were found. Despite the methodological heterogeneity across studies, these effects were independent of the type of stress, animals' strains or age. However, our findings suggest that stress yields a more detrimental effect on spatial navigation tests' performance. Surprisingly, the vast majority of the selected studies in this field did not report appropriate statistics and were excluded from the quantitative analysis. We have therefore purposed a set of guidelines termed PROBE (Preferred Reporting Orientations for Behavioral Experiments) to promote an adequate reporting of behavioral experiments.This work was funded by the European Commission (FP7) "SwitchBox" (Contract HEALTH-F2-2010-259772) project and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), and by Fundacao Calouste Gulbenkian (Portugal) (Contract grant number: P-139977; project "Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)"). PSM is supported by an FCT fellowship grant, from the PhD-iHES program, with the reference PDE/BDE/113601/2015.info:eu-repo/semantics/publishedVersio

Relevance of Stress and Female Sex Hormones for Emotion and Cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders

Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism

Previous reports suggest that the resistance of neuronal cytoskeleton to drug toxicity may vary with age and gender. The aim of the present study was to assess the impact of cytosine arabinoside (AraC) treatment on neurofilament (NF) levels and phosphorylation status in the developing cerebellum of male, female and testosterone propionate (1.25. mg/rat)-androgenized female rats. AraC (200. mg/kg bw) was administered from postnatal day (PND) 14-16 and changes in the level and phosphorylation of NFs were detected at PND 16 by Western blot analysis. The drug had no effect in male pups, while it increased the non-phosphorylated NF subunits of medium and low molecular weight in females. Androgenization of females prevented the AraC-induced increase in NF subunits. The levels of estrogen receptor beta (ER-β), known to mediate neuroprotective actions of estrogens in the brain, were significantly higher in the developing female cerebellum, as compared to males and androgenized females.These data show that the neurofilament cytoskeleton in the developing rat cerebellum exhibits resistance to AraC that appears sexually dimorphic. In young males the resistance is exemplified by a lack of responsiveness, whereas in juvenile females it is presented by an androgenization-sensitive NF upregulation. © 2014 The Authors

Neurofilament isoform alterations in the rat cerebellum following cytosine arabinoside administration

A number of neurotoxic agents could potentially exert their action by degrading or modifying cytoskeleton components like neurofilaments (NF). Cytosine arabinoside (AraC) is an anticancer drug commonly used in leukemia treatment. Its side effects include neuronal cell death in the cerebellum and severe motor coordination deficits. We have previously shown that AraC administration (400 mg/kg bw) in adult rats reduced NF immunostaining in cerebellar neurons. To further delineate the susceptibility of individual NF isoforms (NF-H, NF-M, NF-L) to AraC, in the present study we used Western blot analysis to quantify their level. A significant and selective reduction of NF-H isoform was observed in the cerebellum of AraC-treated animals, compared to the controls. Administration of the antioxidant N-acetylcysteine (NAC) for a period of 14 days (prior to and during AraC treatment), which was previously shown to ameliorate the AraC-induced motor deficits in these animals, largely prevented the reduction in NF-H isoform. Given the significant role of NF proteins and particularly NF-H in maintaining structural integrity and synaptic transport, the observed loss of this isoform may be a key-target of AraC action in cerebellar neurons. Moreover, this study provides further data on the neuroprophylactic role of NAC in vivo against chemotherapy-induced toxicity. © 2009 Elsevier Ireland Ltd. All rights reserved

Estrogens influence behavioral responses in a kainic acid model of neurotoxicity

The behavioral and neuroprotective effects of 17beta-estradiol (E2), on ovariectomized rats treated with a subconvulsive dose (7 mg/kg bw, ip) of kainic acid (KA), were examined. Estradiol was administered either acutely (150 mug/rat, ip) along with KA, 14 days post-ovariectomy, or chronically (sc capsules providing proestrus estrogen levels in serum) starting at ovariectomy. Exploratory behavior, as deduced by sniffing in the open field test, was reduced in KA-treated rats. Both hormonal schemes partially restored sniffing behavior in KA-lesioned subjects. Moreover, acute and chronic E2 administration in KA-treated rats resulted in increased vertical and horizontal activity of these animals in the open field test. Memory for object recognition was reduced following KA and was not restored by hormonal treatments. Acute, but not chronic, E2 coadministration with KA significantly impaired spatial performance in the water maze task, while KA alone had no effect. Both acute and chronic estradiol administration rescued hilar and CA1 neurons from KA-induced cell death. Chronic, but not acute, E2 increased neurofilament immunoreactivity in the mossy fibers of the dentate gyrus neurons, similarly to KA. Our results show that although estradiol administration in KA-treated rats has beneficial effects on cell survival, it has diverse effects on exploratory behavior, object, and spatial memory. Estradiol effects on KA-lesioned animals depended on the duration and timing of exposure to the hormone, implying different mechanisms of hormone actions.Horm Beha

Estrogens influence behavioral responses in a kainic acid model of neurotoxicity

The behavioral and neuroprotective effects of 17 beta-estradiol (E2), on ovariectomized rats treated with a subconvulsive dose (7 mg/kg bw, ip) of kainic acid (KA), were examined. Estradiol was administered either acutely (150 mu g/rat, ip) along with KA, 14 days post-ovariectomy, or chronically (sc capsules providing proestrus estrogen levels in serum) starting at ovariectomy. Exploratory behavior, as deduced by sniffing in the open field test, was reduced in KA-treated rats. Both hormonal schemes partially restored sniffing behavior in KA-lesioned subjects. Moreover, acute and chronic E2 administration in KA-treated rats resulted in increased vertical and horizontal activity of these animals in the open field test. Memory for object recognition was reduced following KA and was not restored by hormonal treatments. Acute, but not chronic, E2 coadministration with KA significantly impaired spatial performance in the water maze task, while KA alone had no effect. Both acute and chronic estradiol administration rescued hilar and CA1 neurons from KA-induced cell death. Chronic, but not acute, E2 increased neurofilament immunoreactivity in the mossy fibers of the dentate gyrus neurons, similarly to KA. Our results show that although estradiol administration in KA-treated rats has beneficial effects on cell survival, it has diverse effects on exploratory behavior, object, and spatial memory. Estradiol effects on KA-lesioned animals depended on the duration and timing of exposure to the hormone, implying different mechanisms of hormone actions. (c) 2005 Elsevier Inc. All rights reserved

Fat feeding of rats during pubertal growth leads to neuroendocrine alterations in adulthood

Juvenile obesity is a rising epidemic due largely to consumption of caloric dense, fat-enriched foods. Nevertheless, literature on fat-induced neuroendocrine and metabolic disturbances during adolescence, preceding obesity, is limited. This study aimed to examine early events induced by a fat diet (45% calories from saturated fat) in male rats fed the diet during the pre- and post-pubertal period. The neuroendocrine endpoints studied were the levels of circulating leptin, insulin and corticosterone, as well as their receptors in the hypothalamus and hippocampus. Hormonal levels were determined by radioimmunoassay and receptors' levels by western blot analysis. Leptinemia was increased in pubertal rats and in adult rats fed the fat diet from weaning to adulthood, but not in those fed from puberty to adulthood. Modifications in the developmental pattern from puberty to adulthood were observed for most of the brain receptors studied. In adult animals fed the fat diet from weaning onwards, the levels of leptin receptors in the hypothalamus and glucocorticoid receptors in the hippocampus were decreased compared to chow-fed controls. Switching from fat to normal chow at puberty onset restored the diet-induced alterations on circulating leptin, but not on its hypothalamic receptors. These data suggest that when a fat-enriched diet, resembling those consumed by many teenagers, provided in rats during pubertal growth, it can longitudinally influence the actions of leptin and corticosterone in the brain. The observed alterations at a preobese state may constitute early signs of the disturbed energy balance toward overweight and obesity. © 2009 Springer Science+Business Media, LLC

Stress Affects the Activated Form of the Corticosteroid‐Receptor Complex in the Rat Brain

Glucocorticoid actions in the brain, particularly in the hippocampus and the hypothalamus, are critically involved in the response of the organism to stress. The key molecules in this process are the corticosteroid receptors, which upon activation, migrate and act in the nucleus. We have investigated the effect of stress on the activated form of the cytosolic glucocorticoid receptor from the above brain areas, using anion exchange chromatography. Exposure of rats to chronic stress resulted in the disappearance of the chromatographic peak, which corresponds to the activated form (DE II) of the hormone‐receptor complex. For this phenomenon to occur, 1) the animal must be exposed to chronic, and not to acute stress, and 2) the adrenals of the animal must be intact. The disappearance of the activated form of the hormone‐receptor complex (DE II) following chronic stress is most probably due to proteolysis of the receptor molecule, since it is specifically inhibited by the protease inhibitor leupeptin. This phenomenon may represent an adaptive mechanism which helps the organism cope with a repeated stressor. Copyright © 1992, Wiley Blackwell. All rights reserve