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Acute stress impairs spatial memory in male but not female rats: Influence of estrous cycle
Abstract
We investigated how sex and estrous cycle influenced spatial recognition memory in the Y-maze after exposure to acute restraint stress. In Experiment 1, intact male and female rats were restrained for 1 h and then 2 h after the start of restraint, rats were trained on the Y-maze. After a 4 h delay, hippocampal-dependent spatial recognition memory was assessed. Acute stress produced opposite patterns between the sexes with spatial memory being impaired in males and facilitated in females. Serum corticosterone measures indicated that both sexes showed a robust corticosterone response after restraint and a moderate corticosterone response after Y-maze exposure. Serum corticosterone levels in response to restraint and Y-maze were not statistically different between the sexes. Experiment 2 examined the influence of the estrous cycle on spatial memory ability after acute stress. Acute stress facilitated spatial memory in females compared to controls, regardless of the estrous cycle phase (estrus and proestrus). Moreover, females in proestrus showed higher serum corticosterone levels during restraint compared to females in estrus. No differences in corticosterone levels were observed at baseline or following 2 h of recovery from restraint. These data show important differences in how sex and estrous cycle influence cognitive functions following acute stress.
... Further, while stress facilitated habit control in male rats [15], little is known about how stress influences control by goal-directed and habitual processes in female rats. This is especially relevant given women's higher risk for stress-related disorders [16], and the sexually dimorphic influences of stress on other learning processes [17][18][19]. ...
... In contrast, Braun & Hauber [15] found that males rats remained goal-directed after 60 min of restraint stress and habit was observed only after multiple stress exposures in male rats. Further work including direct comparisons of female and male rats under the same conditions is needed to assess a Other work on sex differences suggests that female rats exhibit similar or greater corticosterone responses to restraint stress than males [17,37,38], as well as different effects of restraint stress on spatial [17] and Pavlovian memory (reviewed in [39]). These differences, along with ovarian hormone effects in females, may mediate the differential effects of stress upon these behavior systems in males and females. ...
... In contrast, Braun & Hauber [15] found that males rats remained goal-directed after 60 min of restraint stress and habit was observed only after multiple stress exposures in male rats. Further work including direct comparisons of female and male rats under the same conditions is needed to assess a Other work on sex differences suggests that female rats exhibit similar or greater corticosterone responses to restraint stress than males [17,37,38], as well as different effects of restraint stress on spatial [17] and Pavlovian memory (reviewed in [39]). These differences, along with ovarian hormone effects in females, may mediate the differential effects of stress upon these behavior systems in males and females. ...
nstrumental behavior can reflect the influence of goal-directed and habitual systems. Contemporary research suggests that stress may facilitate control by the habitual system under conditions where the behavior would otherwise reflect control by the goal-directed system. However, it is unclear how stress modulates the influence of these systems on instrumental responding to achieve this effect, particularly in females. Here, we examine whether a mild psychogenic stressor experienced before acquisition training (Experiment 1), or prior to the test of expression (Experiment 2) would influence goal-directed and habitual control of instrumental responding in female rats. In both experiments, rats acquired an instrumental nose-poke response for a sucrose reward. This was followed by a reinforcer devaluation phase in which half the rats in Stressed and Non-Stressed conditions received pairings of the sucrose pellet with illness induced by lithium chloride until they rejected the pellet when offered. The remaining rats received a control treatment consisting of pellets and illness on separate days (Unpaired). Control by goal-directed and habitual systems was evaluated in a subsequent nonreinforced test of nose poking. The results of Experiment 1 indicated that the Non-Stressed Paired group reduced nose-poking compared to the Unpaired controls, identifying the response as goal directed, whereas the Stressed Paired and Unpaired groups made a similar number of nose pokes identifying the response as habitual despite a similar amount of training. Results from Experiment 2 indicated habitual control of nose-poke responding was present when stress was experienced just prior to the test. Collectively, these data suggest that stress may facilitate habitual control by altering the relative influence of goal-directed and habitual processes underpinning instrumental behavior. These results may be clinically relevant for understanding the contributions of stress to dysregulated instrumental behavior in compulsive pathologies.
... Indeed, there are known sex differences in the rates of addition (Chow et al., 2013), maturation (Yagi et al., 2020) and activation of adult-born neurons (Yagi et al., 2016). Furthermore, there are sex differences in hippocampal plasticity (Juraska et al., 1985;Warren et al., 1995;Shors et al., 2001a;Scharfman and MacLusky, 2014;Le et al., 2022) and behavioral responses to acute and chronic stress (Luine, 2002;Conrad et al., 2004;Bangasser and Shors, 2007). ...
... It is typically understood that neurogenesis benefits cognition and so it may seem paradoxical that blocking neurogenesis improved water maze learning in females. However, it has been repeatedly demonstrated that males and females can display opposite patterns of hippocampal-dependent learning, with manipulations facilitating performance in males in some paradigms and facilitating performance in females in others (Luine, 2002;Conrad et al., 2004;Bangasser and Shors, 2007). Our findings also may seem paradoxical if it is assumed that "faster is better" in the water maze. ...
... Another possibility, related to the fact that neurogenesis effects were selectively observed in 16°C water, is that emotional functions of neurogenesis were differentially engaged by stress. In other studies, stress impairs spatial learning in males and is either without effect, or actually improves learning, in females (Luine, 2002;Conrad et al., 2004). These divergent effects may reflect differential effects of stress on cognition (males) and hyperarousal (females; Bangasser et al., 2018). ...
Adult neurogenesis modifies hippocampal circuits and behavior, but removing newborn neurons does not consistently alter spatial processing, a core function of the hippocampus. Additionally, little is known about sex differences in neurogenesis since few studies have compared males and females. Since adult-born neurons regulate the stress response, we hypothesized that spatial functions may be more prominent under aversive conditions and may differ between males and females given sex differences in stress responding. We therefore trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. In the standard water maze, ablating neurogenesis did not alter spatial learning in either sex. However, in cold water, ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape the maze and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment (Fos expression) of the dorsal hippocampus than males, particularly in cold water. However, blocking neurogenesis did not alter Fos expression in either sex. Finally, morphologic analyses revealed greater experience-dependent plasticity in males. Adult-born neurons in males and females had similar morphology at baseline but training increased spine density and reduced presynaptic terminal size, specifically in males. Collectively, these findings indicate that adult-born neurons contribute to spatial learning in stressful conditions and they provide new evidence for sex differences in their behavioral functions.
... Moreover, the number of experiments that have compared how acute stress affects spatial memory retrieval in males versus females is limited. One study found that females showed better spatial recognition memory on the Ymaze following an acute restrained stress than stressed male rats [10]. Based upon these findings, we hypothesized that the stressor given to the rats in the present experiment would impair memory retrieval in male, but not female rats. ...
... In male rats, acute stress has previously been shown to impair retrieval of long-term spatial memory in a water maze task [13]. Conrad [10] found that mild acute stress benefits female, but not male rats during spatial recognition memory task, tested via a Ymaze. Furthermore, Conrad [10] showed that serum corticosterone levels, induced by acute restraint stress exposure, do not differ between male and female rats. ...
... Conrad [10] found that mild acute stress benefits female, but not male rats during spatial recognition memory task, tested via a Ymaze. Furthermore, Conrad [10] showed that serum corticosterone levels, induced by acute restraint stress exposure, do not differ between male and female rats. Our results are consistent with these findings. ...
Many studies provide evidence that differences in spatial learning exist between males and females. However, it is necessary to consider non-mnemonic factors that may influence these findings. The present experiment investigated acquisition, retention, and the effects of stress on response- and place-learning in male and female rats. Rats were trained in an open-field tower maze. Procedures were used to minimize stress in the rats, and their ability to solve place- or response-learning in the maze was determined by analyzing a response variable (i.e., first choice correct response) that was not influenced by general locomotor activity. The results revealed that male and female rats acquire place- and response-learning at the same rate even though females moved significantly faster in the maze. However, females showed better retrieval of place-, but not response-learning compared to male rats. This effect appeared to be enhanced when the rats were tested immediately following an acute restraint stress. Furthermore, both female and male rats that were exposed to acute restraint stress showed less impairment than controls when subsequently tested in a novel situation. These findings have clinical implications that a mild physiological stress response can make one more cognitively resistant to adversities later in life.
... It is known that female mice are easier to modulate in relation to aversive memories compared to males, these sexual differences being directly linked to hormones (Ribeiro et al., 2010). Thus, it is suggested that the action of gonadal hormones goes beyond sexual activity, also being capable of modulating behavioral responses in females (Conrad et al., 2004;Blakland et al., 2006) as well as playing a role in the adoption of different strategies for tasks involving learning and memory processes. ...
... The improvement in the memory and learning task in the CTRL +500 group of the PSD protocol may be explained by the association of the Hb protective effect with the presence of estrogenic hormones in higher concentrations during the proestrus phase of the estrous cycles of the female mice (Conrad et al., 2004). In the SR protocol, however, the results showed no protective influence of female sexual hormones as the majority of the females were in the diestrus phase throughout the passive avoidance test. ...
... Furthermore, there is a crosstalk between the hypothalamic-pituitary-adrenal axis (HPA) and the hypothalamic-pituitary-gonadal (HPG) axis, insofar as activation of the former can be modulated by the latter (Toufexis et al., 2014). Oscillations in the levels of sex hormones across the estrous cycle may also buffer deficits triggered by chronic stress exposure in female rats (Pisu et al., 2016) inasmuch as stressful conditions fail to alter learning and memory processes during proestrus and estrus phases (Conrad et al., 2004). Besides their influence on cognitive processes, glucocorticoids and estrogens also affect anxiety-like behavior (see Maeng and Milad, 2015 for review) and the animal's emotional state influences its performance in memory tasks (Silva and Frussa-Filho, 2000). ...
... In line with our results, Sava and Markus (2005) reported that the estrous cycle did not affect learning in the MWM task. In contrast, restraintstressed females submitted to Y-maze task displayed a phase-dependent acquisition performance (Conrad et al., 2004). However, unstressed females in EST (Frye and Sturgis, 1995) or PRO (Rubinow et al., 2004) take longer to reach the platform in the MWM, suggesting that this outcome is due to the stressful experience of swimming. ...
A growing body of evidence demonstrates that estrogen and corticosterone (CORT) impact on cognition and emotion. On the one hand, ovarian hormones may have beneficial effects on several neurophysiological processes , including memory. On the other hand, chronic exposure to stressful conditions has negative effects on brain structures related to learning and memory. In the present study, we used the plus-maze discriminative avoidance task (PMDAT) to evaluate the influence of endogenous variations of sex hormones and exposure to different types of prolonged stressors on learning, memory, anxiety-like behavior and locomotion. Female Wistar rats were submitted to seven consecutive days of restraint stress (4 h/day), overcrowding (18 h/day) or social isolation (18 h/day) and tested in different phases of the estrous cycle. The main results showed that: (1) neither stress conditions nor estrous cycle modified PMDAT acquisition; (2) restraint stress and social isolation induced memory impairments; (3) this impairment was observed particularly in females in metestrus/diestrus; (4) stressed females in estrus displayed less risk assessment behavior, suggesting reduced anxiety-like behavior; (5) restraint stress and social isolation, but not overcrowding, elevated corticosterone levels. Taken together, our findings suggest that the phase of the estrous cycle is an important modulatory factor of the cognitive processing disrupted by stress in female rats. Negative effects were observed in metestrus/diestrus, indicating that the peak of sex hormones may protect females against stress-induced memory impairment.
... Moreover, the effects of acute stress on spatial memory were found to differ between sexes where acute restraint stress enhanced spatial memory performance in female rats but not in male rats (Conrad et al., 2004). However, exposure to predator stress for 30 min impaired the consolidation and retrieval process in both male and female rats (Park et al., 2008), although stressed males had more profound deficits than stressed females. ...
Deficits in hippocampus-dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety, and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via activation of hypothalamic-pituitary adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation, and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signaling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress-related disorders. We argue that such efforts should consider recent conceptualizations on the dynamic nature of cholinergic signaling in modulating distinct subcomponents of memory, and its interactions with cellular substrates that regulate the adaptive stress response.
... The interaction between stress and the estrous cycle is unclear, with some studies in the literature finding an effect following stress (do Nascimento et al. 2019;Hokenson et al. 2021) and others not (Conrad et al. 2004;ter Horst et al. 2013). A discussion of the influence of estrous cycle on the stressed-induced changes in cognition is beyond the scope of this review (see ter Horst et al. 2012). ...
Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic–pituitary–adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.
... Acute stress can often reveal resilient or susceptible behavioral responses that differ in males and females. For example, spatial memory in the Y-maze is impaired in males and facilitated in females after acute stress (Conrad et al., 2004). Others have shown that, 10 days after acute stress, males show increased anxiety-like behavior and females do not (Gupta and Chattarji, 2021). ...
Stress induces allostatic responses, whose limits depend on genetic background and the nature of the challenges, consistent with the theory of allostatic load. Acute stress is usually associated with adaptive responses, although, depending on the intensity and individual reaction, some may experience maladaptive coping that persist through life and may influence subsequent experiences of stressful events, as is the case of post-traumatic stress disorder. We investigated the behavioral and epigenetic signatures in a double-hit mouse model of acute stress in which heterotypic stress (acute swim stress and acute restraint stress) were applied within a 7-day interval period. The ventral hippocampus was isolated to study the footprints of chromatin accessibility driven by exposure to heterotypic stress. Using ATAC sequencing to determine regions of open chromatin, we revealed that depending on the timing and number of acute stressors, exclusive gene sets related to development, immune function, cell starvation, translation, the cytoskeleton, and DNA modification were reprogrammed in both males and females. Analyzing chromatin accessibility for transcription factor binding sites revealed that stress altered the accessibility for androgen, glucocorticoid, and mineralocorticoid receptor binding sites (AREs/GREs) at the genome-wide level, with double-hit stressed mice displaying a profile unique from either single hit of acute stress. The investigation of AREs/GREs adjacent to gene coding regions showed several stress-related genes, including Fkbp5, Zbtb16, and Ddc, whose chromatin accessibility was affected by prior exposure to stress. These data demonstrate that acute stress is in fact not truly acute but induces allostatic signatures that persist in the epigenome and may not manifest until a second challenge hits.
... Although normally thought to regulate reproductive behaviors, the steroid estrogen also plays a crucial role in learning and memory (1). Investigating the effects of estrogen on learning and memory has been motivated by observations of changes in the cognitive performance of female rats during different phases of the estrus cycle (2,3), estrogen induced neuronal alterations in brain regions associated with learning and memory (4), and most importantly, epidemiologic observations indicating that estrogen replacement therapy enhances certain cognitive functions and delays the onset of memory disorders in post-menopausal women (1). In recent decades, the effects of estrogen on learning and memory have been the subject of extensive investigation. ...
estrogen has differential effects on learning and memory. The direction of these effects depends on a variety of factors including the type of memory process, task specific demands, dose and time course of treatment. While some processes, including working memory, spatial memory and place learning, are improved in high estrogen conditions, other processes such as amygdala-dependent associative memory, reference memory and response learning are impaired. Furthermore, learning strategy is sensitive to the effects of estrogen. specifically, high estrogen conditions promote the use of a hippocampus-dependent strategy, while low estrogen levels bias learning towards a response strategy. In humans, the evidence for effects of estrogen on cognitive function is controversial and the mechanisms of action are not fully understood. This review will discuss major findings from animal studies, highlighting the modulatory effects of estrogen on learning and memory, possible neurobiological mechanisms underlying these effects and the implications of these findings for future investigations of the cognitive effects of estrogen in humans.
... Several studies report that spatial memory tested in the Morris water maze or object placement tasks was enhanced during proestrus relative to estrus and/or diestrus in mice and rats (Frick & Berger-Sweeney, 2001;Frye, 1995;Paris & Frye, 2008;Pompili et al., 2010). However, the reported proestrus advantage in spatial tasks is inconsistent with other data in rats showing enhanced spatial reference memory during estrus relative to proestrus (Frye, 1995;Sutcliffe et al., 2007;Warren & Juraska, 1997) or no detectable effect of the cycle on memory (Berry et al., 1997;Bucci et al., 2008;Cimadevilla et al., 2000;Conrad et al., 2004;Pompili et al., 2010; This document is copyrighted by the American Psychological Association or one of its allied publishers. ...
The ability to remember sequences of events is fundamental to episodic memory. While rodent studies have examined sex and estrous cycle in episodic-like spatial memory tasks, little is known about these biological variables in memory for sequences of events that depend on representations of temporal context. We investigated the role of sex and estrous cycle in rats during training and testing stages of a cross-species validated sequence memory task (Jayachandran et al., 2019). Rats were trained on a two four-odor sequence memory task delivered on opposite ends of a linear track. Training occurred in six successive stages starting with learning to poke in a nose-port for ≥ 1.2 s; eventually demonstrating sequence memory by holding their nose in the port ≥ 1 s for in-sequence odors and < 1 s for out-of-sequence odors. Performance was analyzed across sex and estrous cycle (proestrus, estrus, metestrus, and diestrus), the latter being determined by cellular composition of a daily vaginal lavage. We found no evidence of sex differences in asymptotic sequence memory performance, similar to humans performing an analogous task (Reeders et al., 2021). Likewise, no differences in sequence memory performance were found across the estrous cycle. Some caveats are that males acquired out-of-sequence trials faster during training with a 3-odor sequence, but this apparent advantage did not carry over to the 4-odor sequence. Additionally, males had shorter poke times overall which seem consistent with a decreased overall response inhibition because they occurred regardless of sequence demands. Together, these results suggest sex and estrous cycle are not major factors in sequence memory capacities. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
... In addition to the well-known functions of sex steroids in reproductive behaviors and secondary sex characteristics, these steroids catalyze a range of changes in physiology through neuronal actions (McEwen and Parsons, 1982) and influence glial development (McCarthy et al., 2002;Marin-Husstege et al., 2004) and function (Kuo et al., 2010). Importantly, sex steroids and GCs also interact with one another and influence the impact of one another to influence both physiology and behavior (Conrad et al., 2004;Hiroi and Neumaier, 2006) illustrating the centrality of considered sex differences in the examination of stress and related neuropsychiatric disorders. This is particularly important in the context of glial biology because, in addition to the impact of sex steroids on glia through estrogen receptors expressed on both astrocytes and oligodendrocytes (Azcoitia et al., 1999;Takao et al., 2004), glia also influence sex steroid function in that they provide a central source of steroid synthesis. ...
Animal models have been utilized to explore the mechanisms by which mood disorders develop. Ethologically based stress paradigms are used to induce behavioral responses consistent with those observed in humans suffering from anxiety and depression. While mood disorders are more often diagnosed in women, animal studies are more likely to be carried out in male rodents. However, understanding the mechanisms behind anxiety- and depressive-like behaviors in both sexes is necessary to increase the predictive and construct validity of the models and identify therapeutic targets. To understand sex differences following stress, we must consider how all cell types within the central nervous system are influenced by the neuroendocrine system. This review article discusses the effects of stress and sex steroids on the macroglia: astrocytes and oligodendrocytes. Glia are involved in shaping the synapse through the regulation of neurotransmitter levels and energy resources, making them essential contributors to neural dynamics following stress. As the role of glia in neuromodulation has become more apparent, studies exploring the mechanisms by which glia are altered by stress and steroids will provide insight into sex differences in animal models. These insights will facilitate the optimization of animal models of psychiatric disorders and development of future therapeutic targets.
... The literature contains data showing that impulsive behavior infl uenced by early stress is manifest more strongly at adolescent age in males than females. This occurs in the case of maternal deprivation [Renard et al., 2007], restraint stress [Conrad et al., 2004], or learned helplessness [Dalla et al., 2008]. In humans, ADHD and impulsive behavior develop more often in boys than girls [Carlson et al., 1997]. ...
Experiments on Wistar rats addressed the manifestations of impulsive behavior in relation to age and sex in three groups of animals. One group received s.c. proinflammatory bacterial lipopolysaccharide (LPS) 50 μg/kg at ages three and five days; the other two groups were controls. One of these received the same volume of physiological saline on the same days and the other, the intact group, received no treatment. Impulsive behavior was assessed by the delay discounting method. Administration of LPS had no significant effect on the manifestation of impulsive behavior in males or females at young age (2.5 months). However, females generally (the overall group) were less impulsive at young age than males. Assessment of impulsivity at mature age (six months) in new groups of animals showed that there were no between-sex differences. Impulsivity at this age was most marked in the LPS group. Control adult animals were less impulsive than young controls. No such age-related differences were seen in rats of the LPS group, particularly males.
... Duloxetine which is a selective serotonin/noradrenaline reuptake inhibitor was used for memory improvement, [5] anxiety, [6] treatment of neuropathic pain, chronic pain, fibromyalgia, [7] anti-depressant, [8] antioxidant activity, [9] diabetic retinopathy, [10] anti-epileptic activity, [11] neuroprotective actions [12,13] and many other. Hence, in the present study, duloxetine was selected to assess the effect on chronic immobilisation stress (CIS)-induced behavioural, neurochemical, biochemical, enzymatic and histopathological alterations in male mice. ...
Objectives
This study aimed to evaluate the effect of duloxetine (10 and 20 mg/kg) against chronic immobilisation stress (CIS)-induced anxiety, depression, cognitive impairment and neurodegeneration in mice.
Methods
CIS, 2 h/10 days (11:00 AM–1:00 PM) was applied after 30 min of pretreatment with saline, duloxetine 10 mg/kg and 20 mg/kg to the respective groups of animals, except the control group. Animals were examined for physiological (body weight, locomotion and grip strength), psychological (memory impairment, anxiety and depression), neurochemical (GABA and glutamate), biochemical (MDA, catalase, glutathione, superoxide dismutase) and histopathological changes.
Key findings
CIS exposure revealed anxiety-like behaviour, depression-like behaviour, motor in-coordination and learning and memory impairment in mice. Besides, CIS induction decreased the antioxidant enzymes (GSH, SOD and catalase), GABA and the viable neuronal cell count, whereas CIS exposure significantly elevated the MDA, AChE activity and glutamate content in the cortex and hippocampus. Pretreatment with duloxetine10 and 20 mg/kg showed dose-dependent ameliorated effect against the CIS-induced alterations in mice.
Conclusion
In conclusion, the results of this study demonstrated the protective effect of duloxetine against neuropsychiatric symptoms, memory impairment caused by CIS-induction through inhibition of oxidative stress, AChE activity and glutamate release.
... В литературе имеются данные о том, что импульсивное поведение под влиянием раннего стресса проявляется у самцов в подростковом возрасте сильнее, чем у самок. Это происходит в случае отлучения от матери (Renard et al., 2007), ограничительного стресса (Conrad et al., 2004) или выученной беспомощности (Dalla et al., 2008). У людей мальчики также чаще подвержены СДВГ и импульсивному поведению, чем девочки (Carlson et al., 1997). ...
19.04.2020 г. После доработки 08.09.2020 г. Принята к публикации 05.10.2020 г. В опытах на крысах линии Вистар исследовали проявления импульсивного поведения в за-висимости от возраста и пола у трех групп животных. Одной группе в возрасте трех и пяти дней вводили подкожно провоспалительный бактериальный липополисахарид, ЛПС, в до-зе 50 мкг/кг; две другие группы были контрольными. Одной из них в те же дни и в том же объеме вводили физиологический раствор, а другой, интактной группе, ничего не вво-дили. Импульсивное поведение оценивали с помощью методики delay discounting. Вве-дение ЛПС не оказывало существенного влияния на проявление импульсивного пове-дения у самцов и самок в молодом возрасте (2.5 мес). Однако самки в целом (с учетом данных по всем группам) в молодом возрасте были более импульсивными, чем самцы. Исследование импульсивности в зрелом возрасте (6 мес) на новых группах животных показало отсутствие у них различий по полу. Наиболее выраженной в этом возрасте импульсивность была у ЛПС-группы. Контрольные взрослые животные были менее импульсивными, чем молодые. У крыс ЛПС-группы, особенно у самцов, таких различий по возрасту не наблюдалось. Ключевые слова: "когнитивная" импульсивность, импульсивное поведение, модель delay discounting, липополисахаридный провоспалительный стресс, половые и возрастные раз-личия
... Furthermore, the results reveal that 8 Hz stimulation of the BLA-mEC pathway enhanced retention for spatial learning while shifting the balance of ARC expression in the DH and DLS for both sexes. However, this shift occurred via increased ARC in the DH in males and decreased ARC in the DLS in females, supporting prior evidence suggesting that sex differentially influences multiple memory systems [57,58]. These results are surprising and yet, in light of the paucity of previous studies using both males and females, it is difficult to determine how unexpected. ...
The basolateral amygdala (BLA) modulates the consolidation of dorsal hippocampus (DH)-dependent spatial and dorsolateral striatum (DLS)-dependent cued-response memories, often in competition with one another. Evidence suggests that a critical mechanism for BLA influences on memory consolidation is via effects on activity-regulated cytoskeletal-associated protein (ARC) in downstream brain regions. However, the circuitry by which the BLA modulates ARC in multiple competing memory systems remains unclear. Prior evidence indicates that optogenetic stimulation of BLA projections to the medial entorhinal cortex (mEC) enhances the consolidation of spatial learning and impairs the consolidation of cued-response learning, suggesting this pathway provides a circuit for favoring one system over another. Therefore, we hypothesized the BLA-mEC pathway mediates effects on downstream ARC-based synaptic plasticity related to these competing memory systems. To address this, male and female Sprague–Dawley rats underwent spatial or cued-response Barnes maze training and, 45 min later, were sacrificed for ARC analysis in synaptoneurosomes from the DH and DLS. Initial experiments found that spatial training alone increased ARC levels in the DH above those observed in control rats and rats that underwent a cued-response version of the task. Postspatial training optogenetic stimulation of the BLA–mEC pathway altered the balance of ARC expression in the DH vs. DLS, specifically shifting the balance in favor of the DH-based spatial memory system, although the precise region of ARC changes differed by sex. These findings suggest that BLA–mEC pathway influences on ARC in downstream regions are a mechanism by which the BLA can favor one memory system over another.
... Shansky et al. (2004) also found that females tested in the estrus phase displayed less impairments in a learning task following administration of a pharmacological stressor as compared to females tested in the proestrus phase. The increase in corticosterone levels produced by presentation of an acute stressor was lower in females tested in the estrus versus proestrus phase (Viau and Meaney, 1991;Conrad et al., 2004). Baseline measurements of anxiety-like behavior have also been shown to be lower in females that were tested in the estrus versus diestrus phase (Frye and Rhodes, 2006;Gouveia et al., 2004;Marcondes et al., 2001;Mora et al., 1996). ...
The present study assessed sex differences and the role of ovarian hormones in nicotine withdrawal. Study 1 compared physical signs, anxiety-like behavior, and corticosterone levels in male, intact female, and ovariectomized (OVX) female rats during nicotine withdrawal. Estradiol (E2) and progesterone levels were also assessed in intact females that were tested during different phases of the 4-day estrous cycle. Study 2 assessed the role of ovarian hormones in withdrawal by comparing the same measures in OVX rats that received vehicle, E2, or E2+progesterone prior to testing. Briefly, rats received a sham surgery or an ovariectomy procedure. Fifteen days later, rats were prepared with a pump that delivered nicotine for 14 days. On the test day, rats received saline or the nicotinic receptor antagonist, mecamylamine to precipitate withdrawal. Physical signs and anxiety-like behavior were assessed on the elevated plus maze (EPM) and light-dark transfer (LDT) tests. During withdrawal, intact females displayed greater anxiety-like behavior and increases in corticosterone levels as compared to male and OVX rats. Females tested in the estrus phase (when E2 is relatively low) displayed less anxiety-like behavior and had lower corticosterone levels versus all other phases. Anxiety-like behavior and corticosterone were positively correlated with E2 and negatively correlated with progesterone. Intact females displaying high E2/low progesterone showed greater anxiety-like behavior and corticosterone levels as compared to females displaying low E2/high progesterone. Lastly, OVX-E2 rats displayed greater anxiety-like behavior than OVX-E2+progesterone rats. These data suggest that E2 promotes and progesterone reduces anxiety-like behavior produced by nicotine withdrawal.
... hypothesis on at least two aspects. First, the animals underwent movement restraint for 30 s while in acute stress studies that reveal memory effects, rats are generally submitted to much longer immobilization, i.e. 30 min, 1 h and even more (Blank et al., 2002;Conrad et al., 2004;Telegdy and Adamik, 2015;Uwaya et al., 2016;Aguayo et al., 2018). Second, memory consolidation is generally enhanced following stress (Roozendaal et al., 2006;Schwabe et al., 2012). ...
PACAP-38 (P38) is a pleiotropic peptide that exerts multiple peripheral and central actions, including neurotrophic, neuroprotective and anti-inflammatory actions. Previous studies have suggested an improvement of memory in rats that have received a single systemic injection of P38. In a therapeutic perspective, we used an analog, acetyl-[Ala¹⁵, Ala²⁰]PACAP-38-propylamide (ALG), to improve both stability and affinity for PAC1 receptors vs. endogen PACAP. We investigated the effect of P38 and ALG on memory consolidation using a spatial novelty detection (SND) task in which rats had to memorize a configuration of objects to identify that, during a test session, a familiar object has been moved to a new location. Rats received an intravenous injection of P38 or ALG after the last training session. In experiment 1, P38 (30 µg/kg) improved spatial memory consolidation allowing detection of novelty vs. saline injection. In experiment 2, we confirmed this effect and showed that P38 restored the performance similar to what was found using non-injected rats. This suggests that, contrary to ALG, P38 exerted a promesiant rather than an anxiety-related effect whereas ALG did not show similar action. We also examined whether P38 effect involved an interaction with NR2B-containing NMDA receptors (NMDARs) by administrating ifenprodil (IFE; a selective NR2B-containing NMDAR antagonist) alone or in combination with P38 or ALG. The results suggested that P38 action on memory involved NR2B-containing NMDARs. Lastly, brain-derived neutrophic factor (BDNF) modulation appeared to be not related to the behavioral performance in the SND task. Overall, the results indicate that P38 exerted a beneficial effect on memory consolidation in a non-associative task, whereas ALG did not have this action.
... However, we cannot rule out the possibility that pathfinding behaviour in large venues could be potentially different. Decision making in large environments relies heavily on the spatial memory recall and there is evidence in the literature (mostly based on experiments with rodents) that acute stress caused by heightened stress can impair spatial memory (Conrad et al., 2003(Conrad et al., , 2004Sandi et al., 2005). This could be a worthy topic for further research. ...
How does evacuation behaviour of crowds vary based on the level of perceived urgency? This question was investigated using two simulated experiments of crowd evacuations, collectively exploring three important aspects of evacuees’ decision-making: reaction time, exit choice and exit-choice adaptation. The analysis of reaction time observations identified a range of factors that determine the delay between the evacuation onset and decisive movement of occupants towards exits. Occupant reactions were on average slower when they were under the low-urgency treatment, when exit capacities were more restrictive and when the individual was located relatively far from the exit locations. Exit-choice observations showed that people’s behaviour fitted a multi-attribute trade-off that reflected the joint role of peer influence, choosing nearest exits and choosing visible exits. The shape of this trade-off remained, to large degrees, similar regardless of the urgency level. Observations of exit-choice adaptation showed that evacuees were two times more likely to change their exit choices when the simulated urgency level was higher. Further analysis revealed the joint effect of the queue-size imbalance at exits, exit visibility and peer influence on decision adaptation. The modelling outputs strikingly showed that evacuees exhibited notable follow-the-neighbour tendencies in their decision changing, whereas, they displayed the opposite tendency when making exit choices. The macro-scale analyses showed that the higher-urgency treatment triggered a more instant and faster rush to exits. This resulted in the formation of denser crowds at bottlenecks, but never prolonged the evacuation time. Evacuation times remained invariably shorter in high-urgency scenarios.
... The tasks used in these and other studies may not differentially engage specific brain regions or explicitly match features of training that interact with estrogen effects such as task difficulty (Bimonte and Denenberg, 1999;Galea et al., 2001;Sandstrom and Williams, 2001;Wang et al., 2009) and stress (Conrad et al., 2004;Perrot-Sinal et al., 1996;Wood and Shors, 1998), making it difficult to extract task by memory system dissociations. Direct tests of the multiple memory systems model can be made by comparing across tasks that require different strategies but are otherwise the same, such as single solution tasks that require the use of hippocampus-or striatum-sensitive strategies and dual solution tasks that allow for either strategy. ...
Estrogens produce robust yet mixed effects on cognition, at times enhancing learning and memory, at times impairing learning and memory, and still at other times having no measurable effects on learning and memory. When viewed through a multiple memory systems lens, these variable actions of estrogenic compounds are explained in part by the strategies required and the neural systems tapped during learning and memory. Estrogens tend to promote hippocampus-sensitive functions yet impair striatum-sensitive functions through the activation of multiple estrogen receptor subtypes. Thus, there are cognitive costs and benefits resulting from exposures to estrogens that illuminate an important notion: Depleting circulating ovarian hormones is not singularly detrimental to learning but instead can lead to learning improvements depending upon the type of task at hand. Approaching the effects of estrogens on problem-solving from this perspective may provide important insight to the range of cognitive health risks that may accompany menopause and hormone therapies.
... Shansky et al. (2004) also found that estrus females displayed less impairments in a learning task following administration of a pharmacological stressor as compared to proestrus females. Other studies have also reported that the increase in corticosterone levels produced by presentation of an acute stressor was lower in estrus versus proestrus female rats (Viau & Meaney 1991;Conrad et al., 2004). Baseline measurements of anxiety-like behavior have also been shown to be lower in estrus versus diestrus females (Frye & Rhodes et al., 2006;Gouveia et al., 2004;Marcondes et al., 2001;Mora et al., 1996). ...
The present study assessed sex differences and the role of ovarian hormones in the behavioral effects of nicotine withdrawal. Study 1 compared physical signs, anxiety-like behavior, and corticosterone levels in male, intact female, and ovariectomized (OVX) female rats during nicotine withdrawal. Estradiol (E2) and progesterone levels were also assessed in intact females that were tested during different phases of the 4-day estrous cycle. Study 2 assessed the role of ovarian hormones in withdrawal by comparing the same measures in OVX rats that received vehicle, E2, or E2+progesterone prior to testing. Briefly, rats received a sham surgery or an ovariectomy procedure. Fifteen days later, rats were prepared with a pump that delivered nicotine for 14 days. On the test day, rats received saline or the nicotinic receptor antagonist, mecamylamine to precipitate withdrawal. Physical signs and anxiety-like behavior were assessed on the elevated plus maze (EPM) and light-dark transfer (LDT) tests. During withdrawal, intact females displayed greater anxiety-like behavior and corticosterone levels as compared to male and OVX rats. Females tested in estrus (when E2 is relatively low) displayed less anxiety-like behavior and corticosterone versus all other phases. Anxiety-like behavior and corticosterone were positively correlated with E2 and negatively correlated with progesterone. Intact females displaying high E2/low progesterone displayed greater anxiety-like behavior and corticosterone as compared to females displaying low E2/high progesterone. Lastly, OVX-E2 rats displayed greater anxiety-like behavior than OVX-E2+progesterone rat. These data suggest that E2 promotes and progesterone reduces anxiety-like behavior produced by withdrawal.
... Thus, hippocampusdependent tasks are negatively affected during reproductive phases with high estrogen at pro-oestrous: females in pro-oestrous perform worse in spatial tasks, such as the MWM, compared to oestrous females (Warren and Juraska, 1997;Frye, 1995). These findings may be related to the higher level of stress reactivity that occurs during pro-oestrous (Viau and Meaney, 1991;Conrad et al., 2004). In contrast, pro-oestrous has been shown to be associated with increased object memory (Cordeira et al., 2018) showing that the effects of estrus cycle are complex and perhaps task dependent. ...
Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don't model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.
... Studies with humans have demonstrated a strong association with decreased hippocampal volume in patients with PTSD and depression (Davidson et al., 2002;Gilbertson et al., 2002). These findings are consistent with a study that reported a greater cognitive impairment in stressed males (Conrad et al., 2004). ...
Stress has been considered as a risk factor for the development and aggravation of several diseases. The hypothalamic-pituitary-adrenal axis (HPA) is one of the main actors for the stress response and homeostasis maintenance. Positron emission tomography (PET) has been used to evaluate neuronal activity and to study brain regions that may be related to the HPA axis response. Since neuroimaging is an important tool in detecting neuroendocrine-related changes, we used fluorodeoxyglucose-18 (18F-FDG) and positron emission microtomography (microPET) to evaluate sexual differences in the glucose brain metabolism after 10, 30 and 40 min of acute stress in Balb/c mice. We also investigated the effects of restraint stress in blood, liver and adrenal gland 18F-FDG biodistribution using a gamma counter. A decreased glucose uptake in the whole brain in both females and males was found. Additionally, there were time and sex-dependent alterations in the 18F-FDG uptake after restraint stress in specific brain regions, indicating that males could be more vulnerable to the short-term effects of acute stress. According to the gamma counter biodistribution, only females showed a significant decreased glucose uptake in the blood, liver and right adrenal after restraint stress. In addition, in comparisons between the sexes, males showed a decreased glucose uptake in the whole brain and in several brain regions compared to females. In conclusion, exposure to acute restraint stress resulted in significant decreased glucose metabolism in the brain, with particular effects in different regions and organs in a sex-specific manner.
... In rats and mice stress or high concentrations of circulating corticosterone inhibited LTP induction in vitro and in vivo (for review (Lynch, 2004) and (Hui et al., 2005, Kim et al., 2005b, Kavushansky et al., 2006). Behavioral experiments revealed that acute stress led to spatial recognition memory impairment in male rats but facilitation in female rats (Conrad et al., 2004). In another study in rats, impairment of recognition memory was found after exposure to stress 30-60 min before the acquisition phase of the object recognition task (Baker and . ...
... RS is a broadly used model of stress-induced depressive-like behavior (Buynitsky and Mostofsky, 2009). Prolonged RS results in morphological changes in the brain such as retraction of processes in hippocampal neurons and astrocytes McEwen et al., 1997), neuroinflammation (Bauer et al., 2001;de Andrade et al., 2012;Tymen et al., 2013), and cognitive deficits (Thorsell et al., 2000;Abidin et al., 2004;Conrad et al., 2004;Cherian et al., 2009;Mika et al., 2012) and depressivelike behavior in rodents (Buynitsky and Mostofsky, 2009;Chiba et al., 2012). It has been shown that cotinine administered before and after RS, reduces the depressive-like behavior, synaptic deficits, astrocyte alterations, and cognitive impairment in mice (Grizzell et al., 2014;Grizzell and Echeverria, 2015;Perez-Urrutia et al., 2017). ...
Restraint stress (RS) is a condition affecting millions of people worldwide. The investigation of new therapies to alleviate the consequences of prolonged RS is much needed. Cotinine, a nicotine-derivative, has shown to prevent the decrease in cerebral synaptic density, working memory deficits, anxiety, and depressive-like behavior after prolonged restraint stress (RS) in mice. Furthermore, post-treatment with cotinine reduced the adverse effects of chronic RS on astrocyte survival and architecture. On the other hand, the nutritional supplement krill oil (KO), has shown to be beneficial in decreasing depressive-like behavior and oxidative stress. In this study, in the search for effective preventative treatments to be used in people subjected to reduced mobility, the effect of co-treatment with cotinine plus KO in mice subjected to prolonged RS was investigated. The results show that cotinine plus KO prevented the loss of astrocytes, the appearance of depressive-like behavior and cognitive impairment induced by RS. The use of the combination of cotinine plus KO was more effective than cotinine alone in preventing the depressive-like behavior in the restrained mice. The potential use of this combination to alleviate the psychological effects of reduced mobility is discussed.
... Male rodents have been reported to perform better than females in spatial memory tasks like the Morris water maze (e.g., Beiko et al. 2004). Yet, after acute and chronic stress, performance of male rats in spatial memory tasks was impaired (Diamond et al. 1999;Conrad et al. 2003Conrad et al. , 2004, whereas female animals improved their spatial memory abilities following stress (Bowman et al. 2001). Sex-differences have also been reported in fear-related memory (Dalla and Shors 2009). ...
Multiple lines of evidence suggest that glucocorticoid hormones enhance memory consolidation of fearful events. However, most of these studies involve male individuals. Since anxiety, fear, and fear-associated disorders present differently in male and female subjects we investigated in mice whether male and female mice perform differently in a mild, auditory fear conditioning task and tested the modulatory role of glucocorticoid hormones. Using an auditory fear conditioning paradigm with different footshock intensities (0.1, 0.2, and 0.4 mA) and frequencies (1× or 3×), we find that intraperitoneal injections with corticosterone (2 mg/kg) immediately after training, altered freezing behavior when repeated footshocks were applied, and that the direction of the effects were opposite in male and female mice. Effects were independent of footshock intensity. In male mice, corticosterone consistently increased freezing behavior in response to the tone, whereas in female mice, corticosterone reduced freezing behavior 24 h after training. These effects were not related to the phase of the oestrous cycle. In addition, corticosterone enhanced extinction learning for all tones, in both male and female mice. These results emphasize that glucocorticoid hormones influence memory consolidation and retrieval, and underscore sex-specific effects of glucocorticoid hormones in modulating conditioned fear responses.
... For example, exposure to an acute or repeated stressful event is associated with enhanced learning in a classical conditioning task in male rats, but impaired performance in females (132); though this is only the case in adult females with mature oestrous cycles (133). By contrast, the opposite effect has been found in spatial learning and memory tasks, where acute stress exposure impairs males' performance in a Y maze, but enhances female rats' performances regardless of their oestrous cycle (134). Similar effects have been shown in another memory test, the Morris water maze test (135,136). ...
For farmed species, good health and welfare is a win-win situation: both the animals and producers can benefit. In recent years, animal welfare scientists have embraced cognitive sciences to rise to the challenge of determining an animal's internal state in order to better understand its welfare needs and by extension, the needs of larger groups of animals. A wide range of cognitive tests have been developed that can be applied in farmed species to assess a range of cognitive traits. However, this has also presented challenges. Whilst it may be expected to see cognitive variation at the species level, differences in cognitive ability between and within individuals of the same species have frequently been noted but left largely unexplained. Not accounting for individual variation may result in misleading conclusions when the results are applied both at an individual level and at higher levels of scale. This has implications both for our fundamental understanding of an individual's welfare needs, but also more broadly for experimental design and the justification for sample sizes in studies using animals. We urgently need to address this issue. In this review, we will consider the latest developments on the causes of individual variation in cognitive outcomes, such as the choice of cognitive test, sex, breed, age, early life environment, rearing conditions, personality, diet, and the animal's microbiome. We discuss the impact of each of these factors specifically in relation to recent work in farmed species, and explore the future directions for cognitive research in this field, particularly in relation to experimental design and analytical techniques that allow individual variation to be accounted for appropriately.
... The application of different experimental protocols in studies on the effects of acute stress on cognitive function may give controversial results. This result is not only related to the use of positive or negative reinforcement learning models but also with the exposure to different types of stressor (Conrad et al., 2004). Various factors are used as stressors, while forced swimming, foot-shock, a rotating drum, and similar methods are considered as models of physical stress; immo-bilization (restriction of movement), exposure to a predator, and other stressors are used as the models of emotional stress (Abraham and Kovacs, 2000;Cazakoff et al., 2010). ...
The effect of acute restrained stress on cognitive functions and anxiety-like behavior in white rats has been studied; furthermore, the influence of the fragment ACTH(4–10) analog Semax on the stress effects was evaluated. It was shown that stress exposure leads to impaired retention of previously acquired food-motivated maze task as well as reduced anxiety-like behavior in the elevated plus maze in rats. Preliminary intraperitonial administration of Semax (0.1 mg/kg) attenuates cognitive impairment caused by acute restrained stress, but it does not affect stress-induced changes in anxiety.
... show interactions as well in studies of sex differences in spatial memory (Bowman et al., 2003;167 Bowman et al., 2001;Conrad et al., 2004;Luine et al., 1994;Shors et al., 1998;Williams et al., 168 1990;Wood et al., 2001). In the following sections, we first review evidence of sex differences 169 in spatial memory under non-stressful conditions. ...
Across three different domains, there are similar sex differences in how men and women process information. There tends to be a male advantage in attending to and remembering the gist (essential central information of a scene or situation), but a female advantage in attending to and remembering the details (non-essential peripheral information of a scene or situation). This is seen in emotional memory, where emotion enhances gist memory more for males than for females, but enhances detail memory more for females than for males. It also occurs in spatial memory, where men tend to notice and remember the gist of where they or objects are in space, allowing them to more flexibly manipulate themselves or objects within that space, whereas women tend to recall the details of the space around them, allowing them to accurately remember the locations of objects. Finally, such sex differences have also been noted in perception of stimuli such that men attend to global aspects of stimuli (such as a large letter A) more than women, whereas women attend more to the local aspects (such as the many smaller letter Ts making up the A). We review the parallel sex differences seen across these domains in this paper and how they relate to the different brain systems involved in each of these task domains. In addition, we discuss how sex differences in evolutionary pressures and in the locus coeruleus and norepinephrine system may account for why parallel sex differences occur across these different task domains.
... To add complexity, the female estrus cycle alters the levels of the female sex hormones, which is known to change behavior. [127][128][129][130][131] Additionally, steroid hormone receptors, which can be found in different densities throughout the brain, are known to act as transcription factors and influence epigenetic machinery (coactivators and corepressors). 123,126 Interestingly, there is even a sex-specific difference in the expression of these coactivators. ...
Pregnancy represents a critical period in fetal development, such that the prenatal environment can, in part, establish a lifelong trajectory of health or disease for the offspring. Poor nutrition (macro- or micronutrient deficiencies) can adversely affect brain development and significantly increase offspring risk for metabolic and neurological disease development. The concentration of dietary methyl-donor nutrients is known to alter DNA methylation in the brain, and alterations in DNA methylation can have long-lasting effects on gene expression and neuronal function. The decreased availability of methyl-donor nutrients to the developing fetus in models of poor maternal nutrition is one mechanism hypothesized to link maternal malnutrition and disease risk in offspring. Animal studies indicate that supplementation of both maternal and postnatal (early- and later-life) diets with methyl-donor nutrients can attenuate disease risk in offspring; however, clinical research is more equivocal. The objective of this review is to summarize how specific methyl-donor nutrient deficiencies and excesses during pre- and postnatal life alter neurodevelopment and cognition. Emphasis is placed on reviewing the current literature, highlighting challenges within nutrient supplementation research, and considering potential strategies to ensure robust findings in future studies.
... Interestingly, while helplessness behavior appears to predominantly be manifested in males when exposed to uncontrollable stress, effects of shock exposure on associative learning, and spine architecture are observed in females (Dalla, Edgecomb, Whetstone, & Shors, 2008;Shors, Chua, & Falduto, 2001;Wood & Shors, 1998). In addition, acute restraint stress is reported to impair spatial memory in males and result in an opposing enhancement in females (Conrad et al., 2004). Given the important role brain regions such as the mPFC, hippocampus, LS, habenula, and amygdala play in both the perception and processing of stress, and the modulatory control they exert on the PVN and HPA axis (L opez, Akil, & Watson, 1999;Ulrich-Lai & Herman, 2009), it is important to understand whether these brain regions are differentially activated by acute or short-term stress in the male and female brain. ...
Stress enhances the risk for psychiatric disorders such as anxiety and depression. Stress responses vary across sex and may underlie the heightened vulnerability to psychopathology in females. Here, we examined the influence of acute immobilization stress (AIS) and a two-day short-term forced swim stress (FS) on neural activation in multiple cortical and subcortical brain regions, implicated as targets of stress and in the regulation of neuroendocrine stress responses, in male and female rats using Fos as a neural activity marker. AIS evoked a sex-dependent pattern of neural activation within the cingulate and infralimbic subdivisions of the medial prefrontal cortex (mPFC), lateral septum (LS), habenula, and hippocampal subfields. The degree of neural activation in the mPFC, LS, and habenula was higher in males. Female rats exhibited reduced Fos positive cell numbers in the dentate gyrus hippocampal subfield, an effect not observed in males. We addressed whether the sexually dimorphic neural activation pattern noted following AIS was also observed with the short-term stress of FS. In the paraventricular nucleus of the hypothalamus and the amygdala, FS similar to AIS resulted in robust increases in neural activation in both sexes. The pattern of neural activation evoked by FS was distinct across sexes, with a heightened neural activation noted in the prelimbic mPFC subdivision and hippocampal subfields in females and differed from the pattern noted with AIS. This indicates that the sex differences in neural activation patterns observed within stress-responsive brain regions are dependent on the nature of stressor experience.
... However, a finer analysis of decades of work is that estrogens produce robust yet mixed effects on learning and memoryat times enhancing, at times impairing, and at other times having no measurable effects on cognition. The direction of effect seems to vary with task, treatment, and subject factors including sex, age, and reproductive status [17,28,46,47], the type of estrogen, its dose, and regimen [16,48], and task attributes such as type of memory probed, stressful elements, or phase of learning [14,16,30,42,49,50]. Given these varied effects, it is possible that estrogens up-or down-regulate cognition by modulating function of select neural systems that mediate learning and memory during the training experience. ...
Understanding the organizing and activating effects of gonadal steroids on adult physiology can guide insight into sex differences in and hormonal influences on health and disease, ranging from diabetes and other metabolic disorders, emotion and stress regulation, substance abuse, pain perception, immune function and inflammation, cognitive function and dysfunction accompanying neurological disorders. Because the brain is highly sensitive to many forms of estrogens, it is not surprising that many adult behaviors, including cognitive function, are modulated by estrogens. Estrogens are known for their facilitating effects on learning and memory, but it becoming increasingly clear that they also can impair learning and memory of some classes of tasks and may do so through direct actions on specific neural systems. This review takes a multiple memory systems approach to understanding how estrogens can at the same time enhance hippocampus-sensitive place learning and impair striatum-sensitive response learning by exploring the role estrogen receptor signaling may play in the opposing cognitive effects of estrogens. Accumulating evidence suggests that neither receptor subtype nor the timing of treatment, i.e. rapid vs slow, explain the bidirectional effects of estrogens on different types of learning. New findings pointing to neural metabolism and the provision of energy substrates by astrocytes as a candidate mechanism for cognitive enhancement and impairment are discussed.
... These sex hormones can also exhibit effects during adulthood, when females are exposed to high levels of estradiol and progesterone while males are exposed to high testosterone levels. To add complexity, the female estrus cycle alters the levels of the female sex hormones which is known to change behavior (Conrad et al., 2004;Frye, 1995;Kolb et al., 2012;Korol et al., 2004;Stackman et al., 1997). In all of the current studies, we measured effects after 6 weeks of age, when the sex hormones are present and active within the mice and can create sex-specific behaviors. ...
Gaining excessive weight during pregnancy occurs in over 50% of pregnancies in the United States. This excessive weight gain can lead to development of Large for Gestational Age (LGA) babies, or babies born in the top 10% for weight class at birth. LGA babies have increased risk for neurological disorders, including autism, schizophrenia and ADHD. Our lab models excessive gestational weight gain and LGA in a mouse model by feeding dams a 60% high fat (HF) diet throughout gestation and lactation. At weaning all offspring are fed control diet for the remainder of life. HF offspring have increased preference for palatable foods, increased learning and motivation deficits, disrupted gene expression in reward system neurocircuitry and both global- and promoter-specific DNA hypomethylation within the prefrontal cortex (PFC). Dietary methyl donor nutrient supplementation (MS) during pregnancy has been shown to ameliorate some of these phenotypes in HF offspring as well as alter DNA methylation patterns. Because the PFC continues developing postnatally, we were interested in understanding whether MS given during early postnatal life (3–6 weeks) would also ameliorate behavioral and molecular phenotypes. Also, because HF offspring exhibit DNA hypomethylation throughout the brain, we were interested in whether DNA methyltransferase (DNMT) function could mediate these changes. Utilizing operant behavior training, gene and protein expression analysis and mass spectrometry we were able to answer these questions. We determined that early life MS can counteract deficits in motivation and learning in female offspring. Also that MS alters the concentrations of folate and methionine intermediates and gene expression directly after supplementation in the PFC tissue of male and female offspring. Finally, we determined that perinatal HF diet alters overall DNMT activity within the PFC without altering DNMT1 or DNMT3a expression in adult male and female offspring. This work adds to our understanding that long-term behavior and disease risk can be influenced by both maternal and early life diet. Therefore, it is important to continue study the mechanistic links between excessive gestational weight gain, perinatal HF diet exposure and MS to make better dietary recommendations that may combat disease risk.
... We observed that male offspring of CORT-treated fathers show increased exploratory behavior compared with controls by increased total distance travelled and reduced latency to leave the home arm in the Y-maze. Behavioral performance in the Y-maze is based on a rodent's innate exploratory drive and is therefore sensitive to the effects of stress (Conrad et al., 2004). Furthermore, we have previously observed that male offspring of CORT-treated fathers show augmented anxiety-like behavior (Short et al., 2016). ...
Recent studies have demonstrated that behavioral traits are subject to transgenerational modification by paternal environmental factors. We previously reported on the transgenerational influences of increased paternal stress hormone levels on offspring anxiety and depression-related behaviors. Here, we investigated whether offspring sociability and cognition are also influenced by paternal stress. Adult C57BL/6J male mice were treated with corticosterone (CORT; 25 mg/L) for four weeks prior to paired-matings to generate F1 offspring. Paternal CORT treatment was associated with decreased body weights of female offspring and a marked reduction of the male offspring. There were no differences in social behavior of adult F1 offspring in the three-chamber social interaction test. Despite male offspring of CORT-treated fathers displaying hyperactivity in the Y-maze, there was no observable difference in short-term spatial working memory. Spatial learning and memory testing in the Morris water maze revealed that female, but not male, F1 offspring of CORT-treated fathers had impaired memory retention. We used our recently developed methodology to analyze the spatial search strategy of the mice during the learning trials and determined that the impairment could not be attributed to underlying differences in search strategy. These results provide evidence for the impact of paternal corticosterone administration on offspring cognition and complement the cumulative knowledge of transgenerational epigenetic inheritance of acquired traits in rodents and humans.
... Also, we believe that larger or more complex venues can present significantly higher levels of wayfinding uncertainty than small rooms. Moreover, we would like to point out a noticeable body of studies suggesting the possible impairing impact of stress on spatial memory, mostly inferred from behavioural studies with rodents (Conrad, Galea, Kuroda, & McEwen, 1996;Conrad, Grote, Hobbs, Ferayorni, 2003;Conrad et al., 2004;Harrison, Hosseini, & McDonald, 2009;Sandi et al., 2005). As acute stress and fear can be a major factor in certain emergency situations, we think of this effect as an indirect source of uncertainty that has the potential to change the balance between the role of the environmental factors (e.g. ...
When humans escape from a threat in a crowded space, how do they choose the best wayfinding strategy for their survival? This is a decision context in which individuals are heavily exposed to the actions of others; it is thus plausible to assume that they are influenced by the social interactions. It has been suggested by some influential theoretical studies that in emergency escape situations, ‘people show a tendency towards mass behaviour, that is, to do what other people do’ (Helbing, D., Farkas, I., Vicsek, T., 2000. Simulating dynamical features of escape panic. Nature, 407, 487–490, page 487). However, the validity of this assumption has not come under scrutiny, nor has the role of context-specific factors that may strengthen or weaken the possibility of displaying the so-called herd-type (or imitative) behaviour been adequately understood in this context. Here, we report on novel wayfinding decision experiments that simulated the escape of human crowds from multi-exit spaces. Participants' perceptions of different contributing factors were quantitatively inferred from their observed choices (N = 3015) using econometric modelling methods. Results showed that the direction at which the social interactions (i.e. observing the movements of other evacuees towards different exit alternatives) impacted on individuals' navigational choices depended significantly on the decision maker's knowledge about the attributes of the alternatives chosen by the crowd flows. Contrary to the conventional belief, people's dominant wayfinding strategy was not to copy the escape directions that other people (i.e. the majority) chose. In fact, in a heavily crowded space with little or no choice uncertainty, observing many people choosing a certain exit direction reduced the desirability of that escape route. The assumption of herd-like behaviour does not necessarily apply to all contexts of evacuations and it should be considered in conjunction with the moderating role of context-specific factors, particularly the level of information available to individual evacuees.
... The PPI enhancement after daily injections could be interpreted in the sense that this injection procedure might have facilitated attention and vigilance after the animals had been exposed to an adverse condition [14] [55] [57]. In fact, other authors have reported that epeated injections [58], or even blood sampling [52] [59] , are sufficient to increase corticosterone (CORT) levels (an indicator of stress response) and to increase the startle reflex (in the first presentation trials) [58] and PPI in rodents [52]. However, although it has been reported that changes in the environment are sufficient to enhance PPI in both humans and rodents [18] [55] [57] [60] —in humans PPI may even be increased if the prepulse stimulus has an affective component [60]—the route through which the drugs are supplied is not normally taken into account and its aversion value is not considered [ , the importance of taking the time to respond to the startle stimulus as an adaptive ability has recently been reported [61] . ...
Unlabelled:
Stress is an important environmental factor affecting mental health that cannot be ignored. Moreover, due to the great physiological differences between males and females, the effects of stress may vary by sex. Previous studies have shown that terrified-sound stress, meaning exposed mice to the recorded vocalizations in response to the electric shock by their kind to induce psychological stress, can cause cognitive impairment in male. In the study, we investigated the effects of the terrified-sound stress on adult female mice.
Methods:
32 adults female C57BL/6 mice were randomly divided into control (n=16) and stress group (n=16). Sucrose preference test (SPT)was carried out to evaluate the depressive-like behavior. Using Open field test (OFT) to evaluate locomotor and exploratory alterations in mice. Spatial learning and memory ability were measured in Morris Water maze test (MWM), Golgi staining and western blotting showed dendritic remodeling after stress. In addition, serum hormone quantifications were performed by ELISA.
Results:
we found the sucrose preference of stress group was significantly decreased (p<0.05) compared with control group; the escape latency of the stress group was significantly prolonged (p<0.05), the total swimming distance and the number of target crossings(p<0.05) were significantly increased (p<0.05) in MWM; Endocrine hormone, Testosterone (T) (p<0.05), GnRH (p<0.05), FSH and LH levels was decreased; Golgi staining and western blotting showed a significant decrease in dendritic arborization ,spine density and synaptic plasticity related proteins SYN, PSD95 and BDNF in the stress group.
Conclusion:
Terrified-sound stress induced depressive-like behaviors, locomotor and exploratory alterations. And impairs cognitive by altering dendritic remodeling and the expression of synaptic plasticity-related proteins. However, females are resilient to terrified-sound stress from a hormonal point of view.
The locus coeruleus (LC)-norepinephrine system is a stress responsive system that regulates arousal and cognitive functions through extensive projections, including to the prefrontal cortex. LC-cortical circuits are activated by stressors, and this activation is thought to contribute to stress-induced impairments in executive function. Because corticotropin-releasing factor (CRF) is a mediator of stress-induced LC activation, we examined the effects of CRF administered into the LC of male and female rats on network activity of two functionally distinct regions of the PFC, the medial PFC (mPFC) and the orbitofrontal cortex (OFC). Network activity, measured as local field potentials, was recorded in awake animals before and after intra-LC infusion of aCSF or CRF (2 or 20 ng). CRF had qualitatively distinct effects on network activity in males and females with respect to dose, region and timecourse. CRF (20 ng) produced a prominent theta oscillation (7–9 Hz) selectively in female rats shortly after LC infusion and 20 min later. In contrast, in male rats, CRF (2 and 20 ng) decreased the amplitude of power in the 4–6 Hz range in the mPFC 10 min after injection. Lastly, CRF (20 ng) increased mPFC-OFC coherence in females and decreased mPFC-OFC coherence in males. In sum, these results show sex differences in CRF modulation of the LC-norepinephrine system that regulates prefrontal cortical networks, which may underlie sex differences in cognitive and behavioral responses to stress.
Acute stress exerts pleiotropic actions on learning behaviors. The induced negative effects are sometimes adopted to measure the efficacy of particular drugs. Until now, there are no detailed experimental data on the time-gradient effects of acute stress. Here, we developed the time gradient acute restraint stress (ARS) model to precisely assess the roles of different restrain times on inducing acute stress. Time gradient ARS facilitates escape behaviors and learning outcomes, peaking at 2 h-ARS and then declining to baseline at 3.5 h-ARS as confirmed by time gradient post-stress data. Furthermore, time gradient ARS activates glucocorticoid receptor (GR) phosphorylation site at Serine211 (P S221) as an inverted V-shaped pattern peaking at 2 h-ARS, whereas that of the GR phosphorylation site at Serine226 (P S226) from 2 h-ARS to 3.5 h-ARS. The 2 h-ARS but not 3.5 h-ARS enhances synaptic plasticity and genes transcription associated with learning and memory in the hippocampus of male mice. The Cdk5 inhibitor, roscovitine, blocks this facilitation effect by intervening in GR phosphorylation at Serine211 in the 2 h-ARS mice. Altogether, these findings show that the time gradient ARS selectively activates GR phospho-isoforms and differentially influences the behaviors along with maintaining a relationship between 2 h-ARS and Cdk5/GR P S211-mediated transcriptional activity.
It took almost a century to get over the dogma of impossibility of adult neurogenesis. A growing number of researches in the past few decades have brought phenomena of adult neurogenesis into light. Ideas of therapeutic possibilities of neural stem cells in managing brain stroke, traumatic brain and spinal cord injury, as well as growing number of neurodegenerative diseases, represent the basis of huge research projects. After the development of CNS is finished, neurogenesis continues in two regions of the adult brain: sub ventricular zone of lateral ventricles and sub granular zone of dentate gyri of hippocampus. The process of neurogenesis brings two main questions concerning the regulatory mechanism: which factors enhance or suppress it and what is the significance of the process in humans. Brain development is under crucial influence of steroid hormones (effects are mediated through gene interaction or by neuromodulation of ion channel), so their influence on behaviour cannot be neglected. Studies have shown that hormones modulate learning and memory, but the specific roles of each of them should be monitored under a wide context of time, pre-exposition test manipulation, training as well as type of testing. Stress is another important factor in the regulation of adult neurogenesis, but current results highlight the importance of the opposite direction as well and young neurons interaction activity with HPA axis. Neurosteroids (allopregnanolone, dihydroepiandrosterone) are synthesized in the brain, and their concentrations are found higher than in blood of mammals. A number of steroidogenic enzymes (rate limiting enzymes in synthesis from cholesterol) are targeted in the brain, spinal cord and peripheral nervous system. The significance of neurosteroids' existence in brain tissue is explored through experiments of epileptogenesis. Numerous researches are trying to determine whether and how hormone alterations in neuroplasticity and neurogenesis are related to changes in cognition. Progesterone has been shown to improve neurologic outcome in multiple experimental models but it failed to show effect through two phase III clinical trials in patients with traumatic brain injury.
Adult hippocampal neurogenesis has been implicated in the spatial processing functions of the hippocampus but ablating neurogenesis does not consistently lead to behavioral deficits in spatial tasks. Parallel studies have shown that adult-born neurons also regulate behavioral responses to stressful and aversive stimuli. We therefore hypothesized that spatial functions of adult-born neurons may be more prominent under conditions of stress, and may differ between males and females given established sex differences in stress responding. To test this we trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. At standard temperatures (25°C) ablating neurogenesis did not alter learning and memory in either sex, consistent with prior work. However, in cold water (16°C), ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment of the dorsal hippocampus than males, particularly at 16°C. However, blocking neurogenesis did not alter activity-dependent immediate-early gene expression in either sex. Finally, morphological analyses of retrovirally-labelled neurons revealed greater experience-dependent plasticity in new neurons in males. Neurons had comparable morphology in untrained rats but 16°C training increased spine density, and 25°C training caused shrinkage of mossy fiber presynaptic terminals, specifically in males. Collectively, these findings indicate that neurogenesis functions in memory are prominent under conditions of stress, they provide the first evidence for sex differences in the behavioral function of newborn neurons, and they suggest possibly distinct roles for neurogenesis in cognition and mental health in males and females.
Nitric oxide (NO) has been implicated as an important neurotransmitter in stress responses and sleep regulatory processes. However, the role of NO in the relationship between stress and sleep remains unclear. The medial septum (MS) and vertical diagonal band (VDB), regions of the basal forebrain involved in sleep regulation, contain nitric oxide synthase (NOS) producing neurons. Additionally, NOS neurons in the dorsal raphe nucleus (DRN) encode information about stress duration. The role of nitrergic neurons in these regions in subserving sex-specific responses to stress and sleep loss has yet to be elucidated. In this study, NADPH-d, an index of NOS activity, was used to examine the effects of acute restraint stress and sleep loss on NOS activity in the MS, VDB, and DRN. We show that NOS activity in response to restraint stress, total sleep deprivation (TSD), and partial sleep restriction (PSR) differs based on sex and region. Initial analysis showed no effect of restraint stress or TSD on NOS activity in the basal forebrain. However, investigation of each sex separately revealed that restraint stress and TSD significantly decrease NOS activity in the MS of females, but not males. Interestingly, the difference in NOS activity between restraint stress and TSD in females was not significant. Furthermore, PSR was not sufficient to affect NOS activity in males or females. These data suggest that restraint stress and sleep loss regulate NOS activation in a sex-dependent manner, and that the NOS stress response in females may be mediated by sleep loss.
Acute stress can have variable and sometimes sex-dependent effects on different executive functions, including cognitive flexibility, some of which may be mediated by increased corticotropin releasing factor (CRF). Previous studies on the effects of stress and CRF on cognitive flexibility have used procedures entailing deterministic rewards, yet how they may alter behavior when outcomes are probabilistic is unclear. The present study examined how acute stress and increased CRF activity alters probabilistic reversal learning (PRL) in male and female rats. Rats learned to discriminate between a ‘correct’ lever rewarded on 80 % of trials, and an “incorrect” lever delivering reward on 20 % of trials, with reward contingencies reversed after 8 consecutive correct choices. Separate groups received either intracerebroventricular infusions of CRF (3 μg) or restraint stress prior to a PRL session. Experiments examined how these manipulations affected learning when given prior to a one-day acquisition test or during performance in well-trained rats. Exogenous CRF, and to a lesser extent acute stress, impaired motivation across sexes, slowing deliberation times and increasing the number of trials omitted, particularly following a switch in reward contingencies. Neither manipulation significantly altered errors or reversal performance. However, increased CRF activity reduced negative feedback sensitivity. Across manipulations, females showed increased omissions and choice latencies, and were less sensitive to feedback than males. These results reveal the complexity with which stress, CRF, sex, and experience interact to alter aspects of motivation and probabilistic reinforcement learning and provide insight into how CRF activity may contribute to symptoms of stress-related disorders.
Spatial navigation is a universal behavior that varies depending on goals, experience and available sensory stimuli. Spatial navigational tasks are routinely used to study learning, memory and goal-directed behavior, in both animals and humans. One popular paradigm for testing spatial memory is the Morris water maze, where subjects learn the location of a hidden platform that offers escape from a pool of water. Researchers typically express learning as a function of the latency to escape, though this reveals little about the underlying navigational strategies. Recently, a number of studies have begun to classify water maze search strategies in order to clarify the precise spatial and mnemonic functions of different brain regions, and to identify which aspects of spatial memory are disrupted in disease models. However, despite their usefulness, strategy analyses have not been widely adopted due to the lack of software to automate analyses. To address this need we developed Pathfinder, an open source application for analyzing spatial navigation behaviors. In a representative dataset, we show that Pathfinder effectively characterizes the development of highly-specific spatial search strategies as male and female mice learn a standard spatial water maze. Pathfinder can read data files from commercially- and freely-available software packages, is optimized for classifying search strategies in water maze paradigms, but can also be used to analyze 2D navigation by other species, and in other tasks, as long as timestamped xy coordinates are available. Pathfinder is simple to use, can automatically determine pool and platform geometry, generates heat maps, analyzes navigation with respect to multiple goal locations, and can be updated to accommodate future developments in spatial behavioral analyses. Given these features, Pathfinder may be a useful tool for studying how navigational strategies are regulated by the environment, depend on specific neural circuits, and are altered by pathology.
Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders.
Hyperphosphorylation of tau is one of the main hallmarks for Alzheimer's disease (AD) and many other tauopathies. Norepinephrine (NE), a stress-related hormone 17-β-estradiol (E2) and thought to influence tau phosphorylation (p-tau) and AD pathology. The controversy around the impact of NE and E2 requires further clarification. Moreover, the combination effect of physiological and psychological stress and estrogen alteration during menopause, which affect p-tau, has not been addressed. Exposure to E2 is believed to reduce NE release, however, the link between these two hormones and AD at cellular level was also remained unknown. Here, we examined whether NE and E2 treatment of differentiated SH-SY5Y cells affected tau phosphorylation. The involvement of adenosine monophosphate kinase protein kinase (AMPK) and target of Rapamycin (mTOR) as the possible mechanisms, underlying this effect was also investigated. Subsequent to SH-SY5Y differentiation to mature neurons, we treated the cells with NE, E2 and NE plus E2 in presence and absence of Compound C and Rapamycin. Cell viability was not affected by our treatment while our Western blot and immunofluorescent findings showed that exposure to NE and E2 separately, and in combination enhanced p-tau (Ser396) and (Ser262)/tau but not (Ser202/Thr205)/tau. Blocking AMPK by Compound C reduced p-tau (Ser396) and (Ser262), while GSK-3β and PP2A activities were remained unchanged. We also found that blocking mTOR by Rapamycin did not change increased p-tau (Ser396) and (Ser262) due to NE + E2 treatment. Collectively, our results suggested that tau hyperphosphorylation due to exposure to NE/E2 was mediated by AMPK, the main energy regulator of cells during stress with no significant involvement of mTOR, GSK-3β and PP2A.
Previous research on the activational effects of testosterone on spatial memory has produced mixed results, possibly because such effects are dose-dependent. We tested a wide range of testosterone doses using two spatial memory tasks: a working-reference memory version of the radial-arm maze (RAM) and an object location memory task (OLMT). Adult male Sprague-Dawley rats were castrated or sham-castrated and given daily injections of drug vehicle (Oil Sham and Oil GDX) or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.000 mg T) beginning seven days before the first day of behavioral tests and continuing throughout testing. For the RAM, four arms of the maze were consistently baited on each day of testing. Testosterone had a significant effect on working memory on the RAM, with the Oil Sham, 0.125 mg T, and 0.500 mg T groups performing better than the Oil GDX group. In contrast, there was no significant effect of testosterone on spatial reference memory on the RAM. For the OLMT, we tested long-term memory using a 2 h inter-trial interval between first exposure to two identical objects and re-exposure after one object had been moved. Only the 0.125 and 0.500 mg T groups showed a significant increase in exploration of the moved object during the testing trials, indicating better memory than all other groups. Testosterone replacement restored spatial memory among castrated male rats on both behavioral tasks, but there was a complex dose-response relationship; therefore, the therapeutic value of testosterone is likely sensitive to dose.
Atopic dermatitis (AD), also known as atopic eczema, is chronic pruritic skin disease. AD can increase psychological stress as well, increasing glucocorticoid release and exacerbating the associated symptoms. Chronic glucocorticoid elevation disturbs neuroendocrine signaling, and can induce neuroinflammation, neurotoxicity, and cognitive impairment; however, it is unclear if AD-related psychological stress elevates glucocorticoids enough to cause neuronal damage. Therefore, we assessed the effects of AD-induced stress in a mouse AD model. AD-related psychological stress increased astroglial and microglial activation, neuroinflammatory cytokine expression, and markers of neuronal loss. Notably, melatonin administration inhibited the development of skin lesions, scratching behavior, and serum IgE levels in the model mice, and additionally caused a significant reduction in corticotropin-releasing hormone responsiveness, and a significant reduction in neuronal damage. Finally, we produced similar results in a corticosterone-induced AD-like skin model. This is the first study to demonstrate that AD-related psychological stress increases neuroendocrine dysfunction, exacerbates neuroinflammation, and potentially accelerates other neurodegenerative disease states. This article is protected by copyright. All rights reserved.
Several factors modulate learning and memory in animals and humans, including age, biological sex, and even the type of information being learned. However, one of the most important modulators of learning and memory processes is steroid hormones, particularly sex and stress steroids. Over the last decade, the manipulations used to understand the mechanisms underlying steroid hormone influences on learning and memory have greatly advanced the field. This research has shown that across species, steroid hormones exert their influence on processes well beyond reproduction and stress; estradiol, progesterone, and cortisol substantially affect how information is encoded, consolidated, and subsequently, recalled.
This study showed that facilitation of recall of a weak version of the 1-trial passive avoidance learning task could be achieved by behavioral “stressing” of day-old chicks after training. Recall, usually retained for less than 9 hr, was extended by socially isolating the chicks for 1 hr immediately after training. There was a brief 3-fold increase in plasma corticosterone levels 10 min after isolation. Facilitated recall was not evident when chicks were isolated 2 hr after training, and it was blocked by intracerebral administration of 2-ng RU 38486, a specific glucocorticoid receptor antagonist, per chick. Male chicks responded more to isolation than did female chicks, presumably a consequence of the additional stress of the injection procedure.
Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.
Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.
Stress has been shown to impair subsequent learning. To determine whether stress would impair classical conditioning, rats were exposed to inescapable, low-intensity tail shock and subsequently classically conditioned under freely moving conditions with a brief periorbital shock unconditioned stimulus and a white noise conditioned stimulus. Unexpectedly stressed rats exhibited significantly more conditioned eyeblink responses and the magnitude of their individual responses was also enhanced. These results stand in contrast to the learning deficits typically observed and suggest that stress can enhance the acquisition of discrete conditioned responses.
In this paper we describe a new memory test in rats, based on the differential exploration of familiar and new objects. In a first trial (T1), rats are exposed to one or to two identical objects (samples) and in a second trial, to two dissimilar objects, a familiar (the sample) and a new one. For short intertrial intervals (approximately 1 min), most rats discriminate between the two objects in T2: they spend more time in exploring the new object than the familiar one. This test has several interesting characteristics: (1) it is similar to visual recognition tests widely used in subhuman primates, this allows interspecies comparisons; (2) it is entirely based on the spontaneous behavior of rats and can be considered as a 'pure' working-memory test completely free of reference memory component; (3) it does not involve primary reinforcement such as food or electric shocks, this makes it comparable to memory tests currently used in man.
Central administration of a Corticotropin-Releasing Factor (CRF) antagonist is well documented to attenuate a variety of behavioral responses to several distinct stressors; however, it is not yet clear whether the activation of CRF neurons is dependent on the type or intensity of the experimental stressor, or rather on the particular behavioral response to stress under study. To test the generality of the stress-protective effect of the CRF antagonist, alpha-helical CRF9-41, (1, 5 or 25 micrograms intracerebroventricularly), the present experiments employed a sensitive index of anxiogenic-like behavior by measuring suppression in exploration on the elevated plus-maze following exposure to social, swim, or restraint stressors. A 1 but not 5 or 25 micrograms dose of the CRF antagonist administered just prior to social, swim, or restraint stress reversed the stress-induced inhibition of exploratory behavior. Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups. Although the stressors produced a graded secretion of adrenocorticotropin (ACTH) with the ranking restraint > swim > social, the relative amplitude of behavioral reactivity to social, swim, and restraint stress was comparable. The relative efficacy of the CRF antagonist to reverse the stressor effects was also comparable. These results suggest that antagonism of activated brain CRF systems attenuates the behavioral response to stress regardless of the type or intensity of the stressor as measured by ACTH secretion.
Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.
Post-training administration of corticosterone (0.1-1 mg/kg) dose-dependently improves retention of an inhibitory avoidance response in C57BL/6 mice, whilst impairing it in the DBA/2 strain. The effects on retention performance induced by the hormone in C57BL/6 and DBA/2 mice appear to be due to an effect on memory consolidation. In fact, they were observed when the drug was given at short, but not long, periods of time after training, i.e., when the memory trace is susceptible to modulation. In the absence of pharmacological manipulations, the two strains showed a significant increase of plasma corticosterone levels 15 min after passive avoidance training that disappeared within 30 min, and similar step-through latencies on the test day. However, although no strain differences were observed for sensitivity to shock thresholds, the increase in plasma corticosterone levels elicited by passive avoidance training was more pronounced in mice of the DBA/2 strain (+160%) than in C57BL/6 mice (+52%). Moreover, DBA/2 mice were characterised by a higher number of either Type I or Type II corticosteroid receptors in the hippocampus in comparison with C57BL/6 mice. Finally, the strain-dependent effects of an intermediate dose of corticosterone were enhanced by pretreatment with either the selective D1 or D2 dopamine (DA) receptor agonists SKF 38393 and LY 171555 and reversed by pretreatment with either selective D1 or D2 DA receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses. The present results indicate that studies in inbred strains of mice can dissect opposite effects of corticosterone on memory consolidation possibly due to its action at different steps or components of the multiphasic pathway of memory consolidation. Moreover, they suggest that some of these steps involve an interaction between the hormone and brain DA system.
Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.
Sex differences in rats' performance on a stationary hidden-platform task (spatial task) in the Morris water maze and the effects of initial nonstationary hidden platform training (NSP training) were examined. The NSP training was designed to familiarize rats with the general requirements of the water-maze task without providing spatial information. NSP training led to faster acquisition and improved retention of the subsequent spatial task in both males and females. There was a sex difference favoring males on acquisition and retention of the spatial task only in rats that had not received previous NSP training. Moreover, there was an apparent reversed sex difference favoring females on some measures of spatial performance in NSP-trained rats. These results suggest that performance on the water-maze task, including the expression of sex differences, can be altered by previous familiarization with nonspatial aspects of the task.
In the adult rat, hippocampal dendritic synaptic connectivity in region CA1 fluctuates across the estrous cycle. This study examined the potential functional impact of such fluctuations on spatial working memory in regularly cycling Long-Evans rats. Rats were trained in a delayed non-match-to-sample radial-arm maze task and performance was monitored across the estrous cycle. There were no significant alterations in the acquisition or performance of the working memory task across the estrous cycle, with 1- or 4-h delays imposed between training and testing sessions. However, rats performed the task significantly more slowly on proestrus than on any other estrous cycle day under both delay conditions. These results indicate that while working memory remains stable, sensorimotor or motivational aspects of the performance of this radial-arm maze task may vary across the estrous cycle.
Learning based on hippocampal-dependent spatial navigation in female rats was assessed at identified points in the estrous cycle corresponding to low (estrus) and high (proestrus) circulating estrogen. With background training in water-maze procedures, rats learned the location of an escape platform in the maze in a single session of 8 training trials. A strong spatial bias for the escape platform was also evident in a probe trial used to assess retention of learning 30 min after the training session. This entire protocol was completed in less than an hour. The performance of the estrus and proestrus rats was indistinguishable on all behavioral measures, irrespective of the stage of estrous cycle during the task. These results indicate that rapid learning and retention for spatial information over a relatively short interval may be preserved despite morphological alterations in hippocampal dendritic spine density in the normally cycling female rat.
Recent evidence has demonstrated that there are fluctuations in both the anatomy and physiology of the hippocampus across the estrous cycle of the female rat. In the present study we examined the behavioral implications of these changes by testing females on either a hippocampal or nonhippocampal version of the Morris water maze during the various phases of the estrous cycle. Males were also tested on these tasks. Although there was little variance on the nonhippocampal cue task, females in proestrus performed significantly better than those in estrus. Optimal female performance on the spatial version of the task occurred during the phase of estrus, whereas the least efficient performance occurred during proestrus. These results do not support the traditional view that hippocampal long-term potentiation is positively correlated with spatial learning.
Adrenal steroid hormones modulate learning and memory processes by interacting with specific glucocorticoid receptors at different
brain areas. In this article, certain components of the physiological response to stress elicited by learning situations are proposed to form an
integral aspect of the neurobiological mechanism underlying memory formation. By reviewing the work carried out in different learning models in chicks (passive avoidance learning) and rats (spatial orientation in the Morris water maze and contextual fear conditioning), a role for brain corticosterone action through the glucocorticoid receptor type on the mechanisms of memory consolidation is hypothesized. Evidence is also presented to relate post-training corticosterone levels to the strength of memory storage. Finally, the possible molecular mechanisms that might mediate the influences of glucocorticoids in synaptic plasticity subserving long-term memory formation are considered, mainly by focusing on studies implicating a steroid action through (i) glutamatergic transmission and (ii) cell adhesion molecules.
Learning based on hippocampal-dependent spatial navigation in female rats was assessed at identified points in the estrous cycle corresponding to low (estrus) and high (proestrus) circulating estrogen. With background training in water-maze procedures, rats learned the location of an escape platform in the maze in a single session of 8 training trials. A strong spatial bias for the escape platform was also evident in a probe trial used to assess retention of learning 30 min after the training session. This entire protocol was completed in less than an hour. The performance of the estrus and proestrus rats was indistinguishable on all behavioral measures, irrespective of the stage of estrous cycle during the task. These results indicate that rapid learning and retention for spatial information over a relatively short interval may be preserved despite morphological alterations in hippocampal dendritic spine density in the normally cycling female rat.
Uncontrollable stressors produce changes both in hippocampal physiology and in cognitive performance. It has been suggested that some of the cognitive effects of uncontrollable shock may be mediated by disturbances in hippocampal processes. We evaluated the prediction that inescapable shock should produce a learning deficit in a task known to be particularly sensitive to disruption in hippocampal function-the Morris water-maze spatial-learning task. Exposure to a single session of inescapable shock of the type typically employed in learned helplessness experiments produced no apparent effect on performance regardless of whether shock was given 30 min or 6 h prior to water-maze training or whether animals were tested at retention intervals of 0, 1, 4, or 24 h following training. Similarly, no effect of inescapable shock was observed when shock treatment and water-maze training were distributed over three daily sessions. These results are inconsistent with the hypothesis that the effects of inescapable shock on cognitive performance result from disturbances in hippocampal function.
Although the roles of estrogen, progesterone, and testosterone in the activation and maintenance of re-productive function are well established, emerging ev-idence indicates that these same steroids influence per-formance on measures of learning and memory in various species, including humans. These effects are complex and vary with task, gender, and age, as well as the regimens of steroid exposure. Gonadal steroids can affect performance on appetitive and aversive tasks; spatial and nonspatial tasks; conditioning; and acqui-sition, consolidation, and retention. However, the ef-fects of steroids on learning and memory often are moderate in magnitude and can improve, impair, or not affect performance on various measures of learn-ing and memory. Consequently, the biological and be-havioral significance of steroid modulation of cogni-tive performance remains to be determined. A more important action of gonadal steroids may prove to be their ability to assist neurons in confronting risks en-countered thoughout life. These neuroprotective ac-tions could have profound consequences for the pre-vention and treatment of diseases of aging, including Alzheimer's disease and other well-known pathologies. A better understanding of the mechanisms of steroid action and cognitive function should lead to the devel-opment of new steroid treatments to improve neuronal function that has been compromised by trauma, age, or disease.
Repeated restraint stress induces an atrophy of apical dendrites of CA3c pyramidal neurons in the hippocampus, but the relationship between stress and adrenocortical activation has not been thoroughly investigated. In order to better understand the relationship between neural and non-neural indices of the severity of stress, we investigated the temporal relationship between CA3c dendritic atrophy and indices of adrenal steroid stress responsiveness. For this purpose, we used two different stress regimens: repeated restraint stress (6 h/day) and a chronic multiple stress paradigm (shaking, restraint and swimming, each day), differing in the degree of adrenal activation produced over 14 and 21 days. Atrophy of dendrites of CA3c neurons was found after 21 days of stress, but not after 14 days, and was of a similar magnitude for both stressors. However, non-neural measures differed between the two stress paradigms: (i) chronic restraint stress caused a significant habituation by day 21 in the corticosterone response to acute restraint, whereas chronic multiple stress exposure was not accompanied by habituation of the corticosterone response to restraint; (ii) chronic restraint stress caused neither adrenal hypertrophy nor thymus atrophy, but did reduce the rate of body weight gain throughout the 21 days, whereas chronic multiple stress caused a transient adrenal hypertrophy (on day 14), delayed suppression of thymus weight (on day 21) and transient reduction of body weight gain (on days 7 and 14, but not on day 21). Thus the non-neural indices of response to stress—although complex in their time course—suggest that the multiple stress regimen is a somewhat more potent chronic stressor for corticosterone and adrenal responses. Yet both stress regimens produced the same degree of apical dendritic atrophy in CA3c pyramidal neurons.
hormone organization and activation of behavior / mechanisms of testicular hormone action: aromatization and reduction / sexually dimorphic behaviors: varying dependence on organizational and activational effects of hormones / activity [wheel running, open-field activity, home cage activity] / social behaviors [intraspecific aggression; mice; rats; play fighting; influence of gonadal hormones; mechanism of hormone organization; adrenocortical hormones; influence of testing method; play fighting, aggression, and social development]
feeding and body weight regulation [activational effects: estrogen, central versus peripheral action of estrogen, activational effects: androgens, possible organizational effects, evolutionary aspects] / sensory factors [taste preference, taste aversion] / learning [active avoidance, activational effects, organizational effects, passive avoidance, maze learning] / brain laterality [postural asymmetry, rotational behavior, sex and laterality] (PsycINFO Database Record (c) 2012 APA, all rights reserved)
20 male and 24 naturally cycling female rats were tested in a fear conditioning paradigm that encompassed both hippocampus-dependent and -independent components. The females were both conditioned and tested for retention at the same stage of the estrous cycle, during either estrus or proestrus. Male rats followed a regime similar to that for the female rats. Approximately 2 wks after conditioning, the animals were examined for retention of the spatial context and of an explicitly paired conditioning tone. All animals showed a similar degree of conditioning to the tone. However, female proestrous rats showed less spatial-contextual conditioning than did male or estrous female rats. Results suggest that the changes found during the proestrous part of the cycle are related to hippocampal information processing and not to general changes in learning ability, to shock sensitivity, or to state-dependent learning. Results are discussed and related to previous findings (e.g., J. B. Becker et al, 1987) regarding estrous cycle changes in behavior, anatomy, and physiology. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Eight rats were restrained and exposed to 90 1-sec, 1-mA tailshocks (stress condition), and another 8 rats served as unstressed controls. 24 hrs later, Ss were reexposed to 5 shocks, and 30 min later, they were tested on the radial maze with the use of obvious spatial cues. Compared with controls, stressed Ss displayed a significantly different distribution of errors across the 12 trials, an effect attributable, in part, to their initial decrease in exploration and increase in perseveration. Calculations from an equation that controls for changing probability of choices and errors during a trial suggest that stressed Ss were capable of learning the maze, but their baseline behavior hindered the process. Results are consistent with the hypothesis that stress induces a phenomenon similar to long-term potentiation. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Most contemporary theories of memory are based on the assumption that memory can be divided into multiple psychological systems that are subserved by different neural substrates and that contribute to performance in a relatively independent manner. Although the study of individual memory systems has proved to be enormously useful, recent data increasingly point towards complex interactions between memory systems during performance of any given memory task. Three basic classes of interactions between different memory systems (competition, synergism and independence) are presented that appear to be congruent with the findings of many behavioral studies. Consideration of interactions among multiple memory systems will enhance our current understanding of memory by encouraging the view that memory systems are dynamic interactive units, rather than independent modules that act in isolation.
This study investigated whether appetitive operant food reinforcement or free-feeding behavior in rats, food-restricted to 85% of body weight, was disrupted by exposures to 3 h of restraint stress or by 3 h of restraint plus water immersion stress (RWI). Rats were trained under a 3-cycle 10-min time-out-10-min time-in fixed-ratio 15 (FR15) schedule of food reinforcement. Free-feeding was measured in a 3-cycle 10-min food jar-out-10-min food jar-in test conducted in the operant chambers. Three hours of restraint stress did not significantly affect response rate or food reinforcement in the operant FR15 task or in the free-feeding condition. In contrast, 3 h of RWI completely abolished operant food reinforcement and suppressed response rate, whereas free-feeding was significantly reduced but not abolished in food-restricted, hungry rats. We conclude that acute restraint stress in food-restricted, hungry rats does not affect their appetite or motor ability to lever-press for food nor did it affect their ability to feed in a free-feeding situation. In contrast, RWI stress may have induced a motor impairment, or some other aspect of motivation independent of hunger, that disrupted their performance in the operant FR15 task.
We investigated the effects of two adrenal steroid agonists on adrenalectomized (ADX) rats' performance on the Y-maze. The Y-maze was chosen because memory can be assessed quickly and because it is sensitive to various parameters of exploratory behavior and spatial memory performance. Four days after surgery, ADX rats were injected with aldosterone (ALDO, a selective Type I receptor agonist), RU362 (a selective Type II receptor agonist) or sesame vehicle at three different time points (120 min prior to Trial 1, immediately after Trial 1 or 120 min after Trial 1). SHAM-operated rats injected with vehicle were also tested. The results indicate that vehicle-treated ADX rats were impaired on spatial recognition memory compared to SHAM rats. Treatment with ALDO restored spatial recognition memory performance of ADX rats to a level comparable to SHAM-treated rats by acting on acquisition and consolidation, whereas treatment with RU362 did not change the poor spatial recognition memory performance of ADX rats. Discrimination memory was improved only when either agonist was injected prior to the first trial, strongly suggesting a non-selective effect of corticosteroids on discrimination memory such as increasing arousal. A detailed analysis of exploratory behavior showed that both the ALDO- and RU362-treated rats explored the Y-maze more than the ADX and SHAM groups at all periods of the experiment. These results show that the non-specific increase in exploratory behavior induced by replacing corticosteroids targeted at Type I and Type II receptors was used differentially with the ALDO-treated rats learning and consolidating spatial information better than the RU362-treated rats. These data are discussed along with other evidence to suggest that Type II receptors may require the simultaneous occupancy of Type I receptors to affect learning and memory processes.
Restraint stress, 6 h/day for 21 days, caused an impairment, during acquisition, of the performance of a spatial memory task, the eight-arm radial maze. The impairment was reversible, temporally limited and blocked by phenytoin, a blocker of excitatory amino acid action, or tianeptine, an antidepressant, which lowers extracellular serotonin. These effects on behavior parallel the reversible stress-induced atrophy of dendrites of hippocampal CA3 neurons that are also blocked by the drugs.
The hippocampus is vulnerable to the damaging actions of insults such as transient ischemia and repetitive stimulation, as well as repeated exposure to exogenous glucocorticoids. This study investigated effects of a repeated psychological stressor, restraint, on the CA3 pyramidal neurons which are vulnerable to damage by repetitive stimulation. Repeated daily restraint stress for 21 days caused apical dendrites of CA3 pyramidal neurons to atrophy, while basal CA3 dendrites did not change. Rats undergoing this treatment were healthy and showed some adaptation of the glucocorticoid stress response over 21 days; however, stress reduced body weight gain by 14% and increased adrenal weight relative to body weight by 20%. Results are discussed in relation to the possible role of adrenal steroids and excitatory amino acids.
Exposure to restraint and brief intermittent tailshocks facilitates associative learning of the classical conditioned eyeblink response in male rats. Based on evidence of sex differences in learning and responses to stressful events, we investigated sexually dimorphic effects of a stressor of restraint and intermittent tailshock on classical eyeblink conditioning 24 h after stressor cessation. Our results indicate that exposure to the acute stressor had diametrically opposed effects on the rate of acquisition of the conditioned response in male vs. female rats. Exposure to the stressor facilitated acquisition of the conditioned response in males, whereas exposure to the same stressful event dramatically impaired acquisition in females. We further demonstrate that the stress-induced impairment in female conditioning is dependent on the presence of ovarian hormones. Conditioning of stressed sham-ovariectomized females was significantly impaired relative to the unstressed controls, whereas conditioning in stressed ovariectomized females was not impaired. We present additional evidence that estrogen mediates the stress-induced impairment in female acquisition. Females administered sesame oil vehicle and then stressed were significantly impaired relative to their unstressed controls, whereas females administered the estrogen antagonist tamoxifen prior to stress were not impaired. In summary, these results indicate that exposure to the same aversive event can induce opposite behavioral responses in males vs. females. These effects underscore sex differences in associative learning and emotional responding, and implicate estrogen in the underlying neuronal mechanism.
Exposure to a stressful event facilitates classical eyeblink conditioning in male rats and impairs conditioning in females. The contribution of stages of estrous to the stress-induced impairment of eyeblink conditioning was evaluated. Females in proestrus, estrus and diestrus were either exposed to an acute stressor of intermittent tailshocks or swim stress and compared to unstressed females in the three stages. Females in proestrus, when estrogen levels are high, acquired the conditioned response at a facilitated rate relative to females in other stages. However, exposure to a stressor of either intermittent tailshocks or inescapable swim stress severely impaired acquisition in females during proestrus. These results suggest that the enhancing effect of estrogen on procedural memory formation is disrupted by previous exposure to a stressful event.
To test the ability of the pituitary gland to secrete ACTH in response to repeated stress, 90-day-old male and female rats were subjected first to a 3-min psychological stress and then a second identical stress 5, 10, or 15 min after the onset of the first stress. After decapitation 5, 10, 15, 20, 25, or 35 min after the onset of the second stress, plasma ACTH concentration was determined by bioassay, and plasma corticosterone was measured by a fluorometric method. Although the rate of increase in plasma corticosterone levels after the first stress was about 1.4 μg/100 ml.min in males and 2.1 μg/100 ml.min in females, 5-15 min after the onset of the first stress, no rapid inhibition of the second stress response appeared. Gradual hypersecretion of ACTH occurred in males after exposure to the second stress, and the resultant peak increment in plasma ACTH concentration was 2-3 times greater than the one observed in once-stressed rats. In females, a rapid and significant increase in plasma ACTH concentration occurred, but the ratio was only 0.6:0.9 compared to the control group. These results suggest that the fast feedback inhibition mechanism by endogenous corticosterone is overcome by a more powerful facilitatory effect of the first stress on subsequent ACTH release and that these two antagonistic systems which regulate ACTH release in response to subsequent stress may be sex-related in their onset and magnitude.
A two-trial recognition task, based on place or object exploration in a Y-maze, was developed to study memory in adult and aged rats. This paradigm avoids the use of electric shocks or deprivation that may have non-specific influences on the responses, and the task does not require learning of a rule. A number of behavioral parameters in several animals could be recorded automatically. These behavioral parameters were found to be differently influenced both by the type of recognition (place vs. object) and by the inter-trial interval (recognition retention time). Impaired recognition was also detected in 18-months-old rats. This recognition task which combines simplicity, sensitivity and high specificity may thus be a useful adjunct to our current battery of memory tasks.
Binding parameters of soluble Type I and Type II receptors were assessed in hippocampus of adult, adrenalectomized, male and female rats. No sex differences in the number of either Type I or Type II receptors could be demonstrated between gonadally intact animals. When females treated with 17 beta-estradiol benzoate (10 micrograms/day) were compared with males, a statistically significant reduction in Type II receptors was observed in the females; progesterone produced no further decrease in receptor numbers. The amount of tissue-associated corticosteroid-binding globulin in gonadally intact animals (perfused with dextran-saline) was twice as great in females as males. Sex-dependent differences in these gonadally intact rats were found in the affinity, measured as the dissociation constant (Kd), of both the Type I and Type II receptors. For both receptors, affinity in cytosols from females was reduced. The difference for the Type II receptor was slight, but the Kd value of the Type I receptor was several-fold higher in females. The difference in affinity was evident with both natural and synthetic steroid ligands. There appears to be little, if any, difference in affinity between the hippocampal Type I and the Type II receptors in females. This suggests that the occupancy of Type I receptors in females is substantially less than that of males at low circulating concentrations of corticosteroids.
In four independent studies, sex differences in cortisol responses to psychological stress were investigated in healthy adolescents and adults (total n = 153). Public speaking and mental arithmetic in front of an audience (Studies 1-3) reliably induced increases in free cortisol levels in both sexes with 2- to 4-fold increases above baseline levels. Mean cortisol responses were 1.5- to 2-fold higher in men compared with women. In Study 3, cortisol profiles were additionally investigated after human corticotropin-releasing hormone (h-CRH) and bicycle ergometry until exhaustion. Here, both sexes showed very similar adrenocortical responses. Furthermore, men showed elevated cortisol levels in anticipation of the psychological stress situation without actually having to perform the tasks (Study 4). Under this condition cortisol concentration was unchanged or decreased in women. From these data we conclude that the observed sex difference does not reflect an overall lower responsiveness of the female adrenal cortex. Although these studies do not provide conclusive data, we suggest sex differences in cognitive and/or emotional responses to distressing psychosocial situations which in turn may influence cortisol secretion.
To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (O'), 10 micrograms of E2 (E') 24 h before stress testing, or with E2 and 500 micrograms P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E2 and P occurring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity.
In a previous study, male rats showed behavioural deficits after a single restraint stress but not after 5 daily restraint periods (i.e. adaptation had developed): female rats although less affected by single restraint failed to adapt over the same time course. This sex difference was associated with the male but not the female rats showing enhanced behavioural responses to the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) after 5 restraint periods. In the present study, the role of the greater increases of plasma corticosterone in stressed females in these sex differences was studied. The corticosterone synthesis inhibitor metyrapone (75 mg/kg i.p.) was given to attenuate the rise of corticosterone to a level typical of stressed males. This resulted in the behavioural deficits of the female rats being shifted in the direction of the male pattern. Thus, their deficits in open field activity and food intake after single and repeated stresses were potentiated and opposed respectively. The latter effect was associated with increased responses to 5-MeODMT. Metyrapone alone was without significant effect. Brain regional 5-HT metabolism was unaffected. The results are consistent with corticosterone facilitating adaptation to single restraint but impairing adaptation to repeated restraint. As failure to adapt to repeated stress is an animal model of depression, results as a whole suggest that increased corticoid levels and decreased 5-HT functional activity may have a role in the development of the illness and its greater incidence in women.
Glucocorticoids bind with high affinity to intracellular receptors located in high density within discrete regions of the rodent and primate brain. The binding of [3H]corticosterone was compared in the brains of male vs female rats. The number and affinity of cytosol receptors in the hippocampus and hypothalamus were examined in vitro. The cytosolic binding capacity of the hippocampus is greater in the female than in the male. This difference in binding capacity is not dependent on the presence of gonadal steroids: the effect of gonadectomy was not significant for either sex. The difference is not due to transcortin since the binding capacity of [3H]dexamethasone is also greater in the female hippocampus. Receptor affinity in the female hippocampus is half that of the male value. In the hypothalamus, the dimorphism is in the opposite direction: the number of [3H]corticosterone cytosolic binding sites was found to be greater in the male. The male hypothalamus also showed a greater affinity for [3H]corticosterone than did the female. Ovariectomy increased the number of binding sites in the female hypothalamus. In vivo nuclear uptake of a tracer dose of [3H]corticosterone was determined in animals having intact gonads. The percent of tissue [3H]corticosterone present in cell nuclei from 4 brain regions, including the hippocampus and hypothalamus, was calculated per unit DNA. The concentrations of [3H]corticosterone in nuclei relative to tissue homogenates were higher in females than males for the 4 brain regions, but not for the pituitary or liver. The data are interpreted as suggesting that glucocorticoid secretion under basal conditions and during stress may differentially effect specific brain structures in male vs female rats.
Norepinephrine (NE), epinephrine (E), and corticosterone (C) levels were determined in the same male and female rats before and during a 30-min period of restraint. Individual values were compared within and among NE, E and C. Individual rats responded differently to immobilization and females usually showed higher stress values. NE and E levels rose smoothly and simultaneously in all animals and peaked early. The early (5 min) NE and E levels, but not the baseline values (0 min), predicted the total extent of the NE and E stress responses in both sexes. The C response was relatively independent of either E or NE. The male C response, but not the female C response, was strongly predicted by the C 5-min level, and significantly predicted by the C 15-min level. Additionally, the male C response, unlike the E, NE or female C response, was biphasic, dropping significantly below baseline at 5 min before rising to peak levels at the end of immobilization (30 min).
Resting levels of plasma and adrenal corticosteroids, pituitary content of adrenocorticotropin, and circulating leukocytes were determined at intervals during controlled 24-hr light-dark cycles in intact, castrated, sham-castrated adult and prepubertal male and female rats. To study the influence of environmental lighting rhythms, corticosteroid levels were similarly followed in intact and blinded male and female rats and in ovariectomized females following a 9-hr shift in lighting regimen. All groups of animals showed evidence of cyclic pituitary-adrenal function, but the presence of mature ovaries was associated with marked facilitation of the diurnal excursions in corticosteroid levels. Furthermore, the results indicated that the mechanisms responsible for pituitary-adrenal rhythmicity are influenced by cyclic ovarian function, are sensitive to pentobarbital, and are synchronized by environmental lighting rhythms perceived through the eyes. Several of the features of pituitary-adrenal function under resting conditions resemble those associated with cyclic release of gonadotropin leading to ovulation. Similar or overlapping neural mechanisms may be responsible for these endocrine rhythms.
Three potent stressors (forced running, immobilization, and footshock) were found to increase levels of cyclic AMP in the pituitaries of both female and male rats. The pituitary cyclic AMP response in females was generally similar to that observed in males. The tested stressors elevated both plasma corticosterone and prolactin and decreased plasma growth hormone. Plasma corticosterone rose more rapidly in females than in males following stress. Control growth hormone levels were higher in male rats. There was no clear cause and effect relationship between elevations of pituitary cyclic AMP and changes in plasma levels of prolactin, corticosterone, and growth hormone.
Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.
The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.
Since many hormonal indices of stress responsiveness are sexually dimorphic in rats, we examined sex differences and the effects of gonadectomy on the stress-related changes in GABAA/benzodiazepine receptors in rats. Intact or ovariectomized female rats displayed a markedly greater corticosterone response and a more pronounced increase in benzodiazepine receptors than males (intact or orchidectomized) after acute handling or swim stress. Swim stress increased benzodiazepine receptor density without modifying affinity in cortex, hippocampus, and hypothalamus. Corticosterone treatment induced benzodiazepine receptor levels comparable to those seen after swim stress in all hormone groups. Handling stress also enhanced cortical low-affinity GABAA receptor levels in males and ovariectomized females. Both GABA and benzodiazepine receptor levels were positively correlated with circulating corticosterone levels in female, but not male groups. GABA/benzodiazepine coupling was unaffected by stress or hormonal status. These sexual dimorphisms in hormonal responses to stress may help elucidate the causes and consequences of stress-induced changes in the GABAA/benzodiazepine receptor complex.
To ascertain whether gonadal hormones have activational influences on spatial ability, the relationship between estrous cycle, sex differences and water maze performance was examined in two studies. In the first study, the performance of females at different cycle phases was compared within females and to that of males. All animals were naive to the task. Similar to other studies, females had longer latencies and distances to reach the water maze platform than males. This sex difference was statistically significant only in comparisons of estrous females and males, not in comparisons of diestrous females and males. To determine whether estrus-associated decrements in acquisition of the water maze task extended to postacquisition performance, a second study assesessed performance of ovariectomized rats--trained to criterion in the task--whose cycle phases were mimicked by exogenous hormones. In the initial trial, "estrous" animals had longer latencies to reach the platform than "diestrous" and ovariectomized animals. In subsequent trials, no hormone-dependent differences in performance were observed. Taken together, the results indicate a modest association between phase of estrous cycle, acquisition, and postacquisition performance when the task is novel. These findings suggest estrus-associated decrements in acquisition may account for previous discrepancies among studies of sex differences in spatial ability.
The effects on anxiety and risk assessment of exposure to a cat were tested in hooded rats. Anxiety and risk assessment were measured in an elevated plus maze and hole board in a room different from the cat-exposure room. Behavior was tested either 1, 2, 7, 14, or 21 days after cat exposure in different groups of rats. A single exposure to a cat increased anxiety over controls in the plus maze from 1 to 21 days after exposure to a cat. The effects on anxiety were independent of activity or exploratory tendency. Severity of anxiety produced was predicted by the approach, but not the attack, behavior of the cat. Analogous correlations between traumatic stimuli and anxiety are seen in humans suffering from posttraumatic stress disorder (PTSD). Risk assessment in the plus maze was reduced over the same period in rats exposed to cats. Risk assessment was weakly correlated with anxiety. The findings are discussed with respect to the potential of this phenomenon as a model of generalized anxiety disorder found in PTSD.
Several previous studies have raised the possibility of sex differences in the distribution of corticosteroid receptors in the brain. The direction and magnitude of these differences have, however, remained controversial. In the present study, we have re-examined the concentrations of mineralocorticoid (MR) and glucocorticoid (GR) receptors in the brains of male and female rats at varying times (1 to 6 days) after combined gonadectomy (GDX) and adrenalectomy (ADX). Cytosol binding assays confirmed the presence of higher MR levels in short-term (3-day) GDX-ADX males. This difference disappeared by 6 days after surgery, as receptor levels in females rose to be equivalent to those in males. Using an improved in vitro autoradiographic method, the distribution of MR and GR was studied in males and females 3 days after GDX-ADX. The distribution of MR and GR in the brains of these rats was similar in the two sexes. MR binding in the male, however, was significantly greater than that in the female throughout the principal cell fields of the hippocampus. Measurements of circulating corticosterone levels at the time of GDX-ADX suggest that this sex difference may reflect a more rapid recovery of the MR system in males than in females following the stress-induced rise in corticosterone secretion occurring at the time of surgery.
The propensity to recall unpleasant events may be related to depression and posttraumatic stress disorder. This study examined the extent to which the recall of a previously unpleasant event (i.e., passive avoidance training) may be influenced by another aversive event. The other aversive event was tail shock. Since the Wistar Kyoto (WKY) rat strain has been proposed as an animal model of depressive behavior, this study was conducted with WKY and Wistar rats. Parameters manipulated included shock controllability, shock sequence (i.e., tail shock before avoidance training versus tail shock after training), and rat strain. Performance of the passive avoidance (PA) response was greater in WKY rats. Exposure to inescapable tail shock was related to greater PA performance compared to exposure to escapable or no-shock treatments. Tail shock prior to PA training led to a greater recall of the PA response. The magnitude of the PA response was influenced by the rat strain, shock controllability, and shock sequence. The applicability of these data to the memory bias phenomenon in depression is discussed.
The present study investigated the effects of 21 days of chronic restraint stress on neural and endocrine parameters in male and female rats. Consistent with previous results, repeated restraint stress induced apical dendritic atrophy (a decrease in the number of apical branch points and dendritic length) of the CA3c pyramidal neurons in male rats. In contrast, female rats did not show significant dendritic atrophy in the apical field in response to repeated restraint stress. Female rats did show a decrease in the number of branch points in the basal dendritic tree compared to male rats in response to repeated restraint stress. Baseline and stress levels of plasma corticosterone were higher in female rats compared to male rats. Females exhibited slightly longer increases in corticosterone levels throughout the 21 days of restraint stress than males, indicating that the male corticosterone response to stress exhibited greater habituation. Plasma corticosteroid-binding globulin levels of female rats were also higher than those of male rats throughout the experiment. There was no change in plasma corticosteroid-binding globulin levels in male rats during the restraint stress, while there was a decrease in plasma corticosteroid-binding globulin levels in female rats during the restraint stress. Plasma estradiol levels in female rats also decreased in response to the chronic stress. In view of the qualitatively different dendritic atrophy found in males and females in appears unlikely that sex differences in the corticosteroid-binding globulin and corticosterone response can account for these morphological differences.
This study showed that facilitation of recall of a weak version of the 1-trial passive avoidance learning task could be achieved by behavioral "stressing" of day-old chicks after training. Recall, usually retained for less than 9 hr, was extended by socially isolating the chicks for 1 hr immediately after training. There was a brief 3-fold increase in plasma corticosterone levels 10 min after isolation. Facilitated recall was not evident when chicks were isolated 2 hr after training, and it was blocked by intracerebral administration of 2-ng RU 38486, a specific glucocorticoid receptor antagonist, per chick. Male chicks responded more to isolation than did female chicks, presumably a consequence of the additional stress of the injection procedure.