Stress-induced Memory Impairment Research Articles

Terminalia chebula attenuates restraint stress-induced memory impairment and synaptic loss in the dentate gyrus of the hippocampus and the basolateral and central nuclei of the amygdala by inhibiting oxidative damage

Chronic restraint stress induces cognitive abnormalities through changes in synapses and oxidant levels in the amygdala and hippocampus. Given the neuroprotective effects of fruit of Terminalia chebula (Halileh) in different experimental models, the present investigation aimed to address whether Terminalia chebula is able to reduce chronic restraint stress-induced behavioral, synaptic and oxidant markers in the rat model. Thirty-two male Wistar rats were randomly divided into four groups as follows: control (did not receive any treatment and were not exposed to stress), stress (restraint stress for 2 h a day for 14 consecutive days), Terminalia chebula (received 200 mg/kg hydroalcoholic extract of Terminalia chebula), and stress + Terminalia chebula groups (received 200 mg/kg extract of Terminalia chebula twenty minutes before stress) (n = 8 in each group). We used the shuttle box test to assess learning and memory, Golgi-Cox staining to examine dendritic spine density in the dentate gyrus region of the hippocampus and the basolateral and central nuclei of the amygdala, and total antioxidant capacity (TAC) and total oxidant status (TOS) in the brain. The shuttle box test results demonstrated that Terminalia chebula treatment had a profound positive effect on memory parameters, including step-through latency (STL) and time spent in the dark room, when compared to the stress group. Daily oral treatment with Terminalia chebula effectively suppressed the loss of neural spine density in the dentate gyrus region of the hippocampus and the basolateral and central nuclei of the amygdala caused by chronic restraint stress, as demonstrated by Golgi-Cox staining. Additionally, the results indicate that Terminalia chebula significantly reduced the TOS and increased TAC in the brain compared to the stress group. In conclusion, our results suggest that Terminalia chebula improved memory impairment and synaptic loss in the dentate gyrus of the hippocampus and the basolateral and central nuclei of the amygdala induced by restraint stress via inhibiting oxidative damage.

Exercise before pregnancy exerts protective effect on prenatal stress-induced impairment of memory, neurogenesis, and mitochondrial function in offspring.

Stress during pregnancy has a negative effect on the fetus. However, maternal exercise has a positive effect on the cognitive function of the fetus and alleviates the negative effects of stress. This study aimed to demonstrate whether exercise before pregnancy has a protective effect on prenatal stress-induced impairment of memory, neurogenesis and mitochondrial function in mice offspring. In this experiment, immunohistochemistry, Western blot, measurement of mitochondria oxygen respiration, and behavior tests were performed. Spatial memory and short-term memory of the offspring from the prenatal stress with exercise were increased compared to the offspring from the prenatal stress. The numbers of doublecortin-positive and 5-bromo-2'-deoxyuridine-positive cells in the hippocampal dentate gyrus of the offspring from the prenatal stress with exercise were higher compared to the offspring from the prenatal stress. The expressions of brain-derived neurotrophic factor, postsynaptic density 95 kDa, and synaptophysin in the hippocampus of the offspring from the prenatal stress with exercise were enhanced compared to the offspring from the prenatal stress. Oxygen consumption of the offspring from the prenatal stress with exercise were higher compared to the offspring from the prenatal stress. Exercise before pregnancy alleviated prenatal stress-induced impairment of memory, neurogenesis, and mitochondrial function. Therefore, exercise before pregnancy may have a protective effect against prenatal stress of the offspring.

Effects of the suppression of 5-HT1A receptors in the left, right, or bilateral basolateral amygdala on memory consolidation in chronic stress in male rats.

The serotonin-1A receptors (5-HT1A) in the two cerebral hemispheres are differentially involved in memory. The distribution of 5-HT1A receptors in the left and right amygdala is different. Furthermore, evidence shows that the 5-HT1A receptors in the left and right amygdala work differently in memory function. The basolateral amygdala (BLA) also regulates hippocampal long-term potentiation (LTP) during stress. However, which BLA structure in each hemisphere underlies such lateralized function is unclear. The present research investigated the possible involvement of 5-HT1A lateralization in the BLA on stress-induced memory impairment. 5-HT1A receptor antagonist (Way-100-635) was injected into the left, right, or bilateral BLA twenty minutes before chronic restraint stress (CRS) for 14 consecutive days. Results indicated that suppression of 5HT1A-receptors in the BLA plays an essential role in reducing the acquisition of passive avoidance in the shuttle box test and spatial memory in the Barnes maze test in the stress animals. This decrease was significant in the CRS animals with left and bilateral suppressed 5HT1A-receptors in the BLA. Field potential recording results showed that the left, right, and bilateral injection of Way-100-635 into the BLA significantly reduced the slope and amplitude of fEPSP in the CA1 area of the hippocampus in stressed rats. No significant difference was observed in neuronal arborization in the CA1 area of the hippocampus. In conclusion, the 5-HT1A receptor in the left and right sides of BLA nuclei play a different role in memory consolidation in the hippocampus under stress.

Acute stress alters recognition memory and AMPA/NMDA receptor subunits in a sex-dependent manner

Several studies have consistently reported a detrimental effect of chronic stress on recognition memory. However, the effects of acute stress on this cognitive ability have been poorly investigated. Moreover, despite well-documented sex differences in recognition memory observed in clinical studies, most of the preclinical studies in this field of research have been carried out by using solely male rodents. Here we tested the hypothesis that acute stress could affect the consolidation of different types of recognition memory in a sex-dependent manner. For this purpose, male and female C57BL6/J mice were exposed to 2-h of restrain stress immediately after the training session of both the novel object recognition (NOR) test and novel object location (NOL) tasks. Acute restraint stress did not affect memory performance of male and female mice, after a 4-h delay between the training session and the test phase of both tasks. By contrast, acute restraint stress altered memory performance in a sex-dependent manner, after a 24-h delay. While stressed mice of both sexes were impaired in the NOL test, only male stressed mice were impaired in the NOR test. Because ionotropic glutamate receptors-mediated neurotransmission is essential for shaping recognition memory, we further tested the hypothesis that post training acute stress could induce sex-dependent transcriptional changes of ionotropic glutamate receptor subunits in the dorsal hippocampus. We uncovered that acute stress induced sex-, time- and type of memory-dependent transcriptional changes of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. These findings suggest that the effect of acute stress on recognition memory can be strongly biased by multiple factors including sex. These findings also indicate that the same stress-induced memory impairment observed in both sexes can be triggered by different sex-dependent molecular mechanisms. At the therapeutic level, this should not be overlooked in the context of personalized and targeted treatments.

Intact Recognition Memory and Altered Hippocampal Glucocorticoid Receptor Signaling in Fkbp5-deficient Mice Following Acute Uncontrollable Stress.

The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

Reversal of chronic restraint stress-induced memory impairment by Japanese sake yeast supplement in mice: Role of adenosine A1 and A2A receptors

Controversial studies indicate the adenosine compound (a neuromodulator with neuroprotective activity) intervention on cognitive performance. On the other hand, Japanese sake yeast has been enriched with oral adenosine analogs as a novel natural agent. As the first report, we aimed to evaluate the effects of Japanese sake yeast supplement in a mouse model of chronic restraint stress-induced cognitive dysfunction. Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose level of 100, 200 and 300 mg/kg once daily for a week. The spatial and conditioned fear memory functions were evaluated with the Morris Water Maze (MWM) and the Passive Avoidance Learning (PAL) test, respectively. In all dosing regimens, improvements in spatial cognition were observed significantly in the MWM. 200 and 300 mg/kg of sake yeast significantly improved short- and long-term fear memory functions in the PAL test. Memory-enhancing effect of sake yeast was potentiated by the injection of ZM241385 (15 mg/kg), a selective adenosine A2A receptor (A2AR) antagonist, but completely disappeared by the injection of 8-cyclopentyltheophylline (CPT-8, 10 mg/kg), a selective adenosine A1 receptor (A1R) antagonist. The findings of the present study demonstrate the efficacy of sake yeast in acting as a cognitive performance-enhancing agent. Eventually, sake yeast and its ingredient S-adenosyl methionine (SAM) may be useful in improving memory in patients suffering from many dementia forms including Alzheimer's disease (AD).

Mediating effects of heart rate variability on the association between chronic stress, cardiorespiratory fitness and working memory maintenance

Young adulthood is a demanding developmental stage during which an individual is required to learn to adequately respond to physical and psychosocial stressors (Malter Cohen et al., 2013). High degrees of chronic stress have been shown to have detrimental effects on physical and mental health outcomes in young adults, accompanied by decreases in academic achievement and subjective well-being (Bayram & Bilgel, 2008; Malter Cohen et al., 2013). While effects of acute stress on neurocognitive functioning have been examined, documentation on effects of prolonged stress exposure on working memory is scarce. While chronic stress may impair working memory, empirical evidence supports the assumption that exercise targeting cardiorespiratory fitness has the potential to buffer harmful effects of stress on working memory performance (Loprinzi & Frith, 2019). According to the Neurovisceral Integration Theory, shared neurophysiological areas are involved in cardiac autonomic control as well as the modulation of attentional and emotional regulatory processing (Forte et al., 2019). Therefore, heart rate-variability (HRV) may be a physiological correlate mediating the association between chronic stress, cardiorespiratory fitness and working memory maintenance.
 The present study investigated the mediating role of resting heart rate-variability on the association between chronic stress, cardiorespiratory fitness and working memory maintenance in young healthy adults.
 Working memory maintenance was assessed in N = 115 healthy adults (48% female) aged 18 to 35 years (M = 24.1, SD = 3.8) using a modified version of the Sternberg task with low (3 items) and high cognitive load (6 items). Additionally, the Åstrand test was conducted on a bicycle ergometer to estimate maximal oxygen consumption (VO2max). Resting HRV was recorded using electrocardiography. The LF/HF ratio was extracted for mediation analyses.
 Path analysis revealed a significant association between cardiorespiratory fitness and accuracy on high cognitive load trials, but not on trials with low cognitive load. Levels of perceived chronic stress showed a trend for a positive association with working memory maintenance, independently of cognitive load. The pattern of results remained unchanged after introduction of HRV as a mediator.
 Results indicate that despite young adulthood being characterized by peak cognitive performance, cardiorespiratory fitness influences working memory maintenance. The lack of mediating effects of HRV, indicates that this association cannot be explained by vagal influences on memory processing driven by the autonomic nervous system. As working memory is crucial for performance in many real-life domains, such as workplace and learning environments in general maintenance and promotion of cardiorespiratory fitness is encouraged.
 References
 Bayram, N., & Bilgel, N. (2008). The prevalence and socio-demographic correlations of depression, anxiety and stress among a group of university students. Social Psychiatry and Psychiatric Epidemiology, 43(8), 667-672. https://doi.org/10.1007/s00127-008-0345-x
 Forte, G., Favieri, F., & Casagrande, M. (2019). Heart rate variability and cognitive function: A systematic review [Mini Review]. Frontiers in Neuroscience, 13, Article 710. https://doi.org/10.3389/fnins.2019.00710
 Loprinzi, P. D., & Frith, E. (2019). Protective and therapeutic effects of exercise on stress-induced memory impairment. Journal of Physiological Sciences, 69(1), 1-12. https://doi.org/10.1007/s12576-018-0638-0
 Malter Cohen, M., Tottenham, N., & Casey, B. J. (2013). Translational developmental studies of stress on brain and behavior: Implications for adolescent mental health and illness? Neuroscience, 249, 53-62. https://doi.org/https://doi.org/10.1016/j.neuroscience.2013.01.023

Cellular and molecular mechanisms of stress-induced memory impairment

Exposure to stressful conditions plays a critical role in brain processes, including neural plasticity, synaptic transmission, and cognitive functions. Since memory-related brain regions, the hippocampus (Hip), the amygdala, and the prefrontal cortex, express high glucocorticoid receptors (GRs), these areas are the potential targets of stress hormones. Stress affects memory encoding, consolidation, and retrieval, which may depend on many factors such as the type, duration, the intensity of the stressor or the brain region. Here, this review mainly focused on the mechanisms involved in stress-induced memory impairment. Acute/chronic stress induces structural and functional changes in neurons and glial cells. Dendritic arborization, reduction of dendritic spine density, and alteration in glutamatergic-mediated synaptic transmission via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are mechanisms that stress affect long-term memory formation. Exposure to acute or chronic stress could interplay with multiple neurotransmitter signaling, modulating the neuronal circuits involved in memory impairment or state-dependent learning. Stress hormones also modulate the expression of microRNAs in the specific brain regions responsible for stress-induced behaviors. Because of expressing GRs in astrocytes and microglial cells, stress could affect the morphology, structure, and functions of these glial cells in memory-related brain regions. Astrocytes play a crucial role in stress-induced aversive or fear memory formation. Over-activation of the microglial cells enhances the release of inflammatory cytokines, which results in neuronal injury. Stress has a prominent role in cognitive decline to induces memory problems, particularly in older adults. Due to the issue’s importance, here the provided overview attempted to address the question of how stress alters neuronal epigenetic regulators, synaptic transmissions, and glial activity in the brain.

Protective Effects of Melatonin on Prenatal Restraint Stress-Induced Memory Impairment in Offspring Rats

Protective Effects of Melatonin on Prenatal Restraint Stress-Induced Memory Impairment in Offspring Rats

Object recognition memory and anti-anxiety potentials of stem-bark extract of Nauclea latifolia (African peach), taurine and vitamin E on Albino rats exposed to water immobilisation stress

Memory loss is a typical symptom of generalized anxiety disorder, a condition that affects millions of individuals. Memory loss with anxiety can be quite distressing, but if you can find strategies to address the anxiety, your memory may improve as well. In this study, the effects of Nauclea latifolia extract, taurine and vitamin E supplementation on object identification and stress-induced anxiety in Albino rats exposed to water immobilisation stress were investigated. 24 rats weighing between 100 and 120 grams were employed. The control group (A), received 1ml/kg pure water. Vitamin E was given to Group B at a dosage of 0.2 ml/kg. Group C received 200mg/kg taurine, while Group D received 200mg/kg Nauclea latifolia extract. For three weeks, the administration was completed. The rats were famished for 24 hours before the stress process began. The rats were sedated with chloroform vapour, and then restrained using a hardwood board (25 by 18 cm) with the four limbs fixed sideways, then dipped for two hours in water up to the xiphoid level. During the training phase, the taurine group examined the novel object the most (64.9 percent), followed by the Vitamin E group (63.90 percent), when compared to the Nauclea latifolia (52.75 percent) and the control groups (54.76 percent). The consolidation phase similarly, revealed that, taurine and Vitamin E groups explored the novel object the most (71.52 percent) and (70.05 percent) accordingly. In the anxiety model, Nauclea latifolia, taurine and vitamin E groups showed significant increase in time spent on closed arms. This study has shown that, when rats are treated to water immersion restraint stress, administration of Nauclea latifolia extract, taurine, and vitamin E, may decrease stress-induced anxiety-like behaviours. The significance of this study is that, administration of taurine, vitamin E and Nauclea latifolia extract may prevent stress-induced memory impairment.

Neuroprotective Effect of Acupuncture against Single Prolonged Stress-Induced Memory Impairments and Inflammation in Rat Brain via Modulation of Brain-Derived Neurotrophic Factor Expression.

Posttraumatic stress disorder (PTSD) is a serious mental disorder that can appear after exposure to extreme stress. Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseases, as well as cognitive and memory impairments. The aim of this study was to examine whether acupuncture stimulation at a specific acupoint (Shenmen or heart meridian, HT7) could improve memory defects caused by single prolonged stress (SPS) in rats. After exposure to SPS, acupuncture on the HT7 acupoint in male rats was performed, once daily for 21 days. We confirmed that this treatment improved fear memory, cognitive function, and spatial memory by modulating the neuroinflammation and expression of brain-derived neurotrophic factor (BDNF) mRNA in the brain. It also significantly inhibited the activation of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β and the enzyme cyclooxygenase-2 in the brain; it increased the expression of BDNF mRNA in the hippocampus. Our findings provide valuable information concerning the clinical usefulness of acupuncture in the treatment of PTSD.

A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

Neuroprotective effect of Korean Red Ginseng against single prolonged stress-induced memory impairments and inflammation in the rat brain associated with BDNF expression

BackgroundPost-traumatic stress disorder (PTSD) is a psychiatric disease that develops following exposure to a traumatic event and is a stress-associated mental disorder characterized by an imbalance of neuroinflammation. Korean Red Ginseng (KRG) is the herbal supplement that is known to be involved in a variety of pharmacological activities. We aimed to investigate the effects of KRG on neuroinflammation as a potential mechanism involved in single prolonged stress (SPS) that negatively influences memory formation and consolidation and leads to cognitive and spatial impairment by regulating BDNF signaling, synaptic proteins, and the activation of NF-kB. MethodsWe analyzed the cognitive and spatial memory, and inflammatory cytokine levels during the SPS procedure. SPS model rats were injected intraperitoneally with 20, 50, or 100 mg/kg/day KRG for 14 days. ResultsKRG administration significantly attenuated the cognitive and spatial memory deficits, as well as the inflammatory reaction in the hippocampus associated with activation of NF-κB in the hippocampus induced by SPS. Moreover, the effects of KRG were equivalent to those exerted by paroxetine. In addition, KRG improved the expression of BDNF mRNA and the synaptic protein PSD-95 in the hippocampus. Taken together, these findings demonstrate that KRG exerts memory-improving actions by regulating anti-inflammatory activities and the NF-κB and neurotrophic pathway. ConclusionOur findings suggest that KRG is a potential functional ingredient for protecting against memory deficits in mental diseases, such as PTSD.

Protective Effect of Hydroxysafflor Yellow A against Chronic Mild Stress-induced Memory Impairments by Suppressing Tau Phosphorylation in Mice.

Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease (AD). However, there are currently no effective drugs that can target chronic stress to prevent AD. In this study, we explored the neuroprotective effect of hydroxysafflor yellow A (HSYA) against chronic mild stress (CMS)-induced memory impairments in mice and the underlying mechanism. The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice. HSYA increased the expression of brain-derived neurotrophic factor (BDNF) and activated downstream tropomyosin-related kinase B (TrkB) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin (mTOR) signaling. HSYA decreased the expression of regulator of calcineurin 1-1L (RCAN1-1L) that could promote the activity of glycogen synthase kinase-3β (GSK-3β). HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3β and cyclin-dependent kinase-5 (Cdk5). Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation, tau phosphorylation and memory impairments. HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.

SGK1 knockdown in the medial prefrontal cortex reduces resistance to stress-induced memory impairment

Down-regulation of serum and glucocorticoid-regulated kinase1 (SGK1) expression has been reported in the postmortem prefrontal cortex (PFC) of subjects with post-traumatic stress disorder. Furthermore, experimental treatments that reduce SGK1 function in the medial prefrontal cortex (mPFC) cause depressive-like behaviors and synaptic dysfunction. Therefore, we examined the effect of SGK1 down-regulation in the mPFC on resistance to stress-induced cognitive impairment. Rats with viral-mediated knockdown of SGK1 in the mPFC were subjected to either a brief 20-min restraint plus 20 intermittent tail shocks or a prolonged 60-min restraint plus 60 intermittent tail shocks, after which their performance in an object recognition task was assessed. Recognition memory remained intact in control rats following the brief stress, but was impaired in rats with SGK1 knockdown in the mPFC. Prolonged stress impaired recognition memory in both control rats and rats with SGK1 knockdown. Our findings indicate that altered mPFC SGK1 signaling is a potential mechanism for resistance to stress-induced cognitive impairment.

Selective H3 Antagonist (ABT-239) Differentially Modifies Cognitive Function Under the Impact of Restraint Stress.

Background: A considerable number of competitive antagonists/inverse agonists of histamine H3 receptor (H3R) have progressed to clinical assessment, with pitolisant approved for the treatment of narcolepsy. H3R, highly expressed in the CNS, is regarded as a relevant target in CNS disorders. At the same time, new compounds including ABT-239 H3R antagonist (ABT; benzonitrile, 4-[2-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl]-5-benzofuranyl]-) are continually being tested. The study aimed to test ABT-239 as a prophylactic agent in stress-induced memory impairments.Methods: Stressed and non-stressed rats were pre-treated with ABT-239 and subsequently subjected to several behavioral tests aimed at assessing the animals’ working and spatial reference memory [Morris water maze (MWM), Barnes maze (BM)], assessing the locomotor function and anxiety-like behavior [Open field (OF), elevated “plus” maze—EPM].Results: Chronically stressed rats displayed a significant decline in spatial (working and reference) memory. In the MWM test, we observed an improvement in spatial reference memory in stressed animals and a positive after ABT-239 pre-treatment. In the BM test, the effect of ABT-239 administration on spatial memory changed in successive attempts, from negative initially to favorable in subsequent attempts, and negative in the last trial of the test in the control group of rats. However, a beneficial effect is noted in the group of stressed animals, which remained throughout the entire testing period.Conclusions: Presented findings demonstrate that ABT-239 shows the potential to abolish or prevent restraint stress-induced spatial memory impairments and cognitive deficits. However, in conditions of appetitive modulation, it could increase damage to memory (unstressed animals).

Effects of running before pregnancy on long-term memory and hippocampal alterations induced by prenatal stress

Studies have shown that an adverse environment in utero influences fetal growth and development, leading to several neuroendocrine and behavioral changes in adult life. Nevertheless, the mechanisms involved in the long-term benefits of pregestational exercise are still poorly understood. Thus, this study aimed to evaluate the effects of physical exercise before the gestational period on memory behavior and gene expression in the hippocampus of adult mice submitted to prenatal stress. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). When adults, male and female offspring were submitted to the object recognition test followed by the hippocampal evaluation of BDNF exons I and IV mRNA expression, as well as hypothalamic-pituitary-adrenal axis related genes. Pregestational exercise did not prevent the decreased recognition index, as well as GR and CRHR1 gene expression observed in PNS males. Conversely, prenatal stress did not influence female memory behavior. Moreover, exercise attenuated the effects of prenatal stress on female BDNF IV gene expression. The results indicate that pregestational exercise was able to prevent the effects of maternal stress on hippocampal BDNF IV gene expression in females, although no effects were seen on the stress-induced memory impairment in males.

Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits.

Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect.SIGNIFICANCE STATEMENT: Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder.

Sex differences in cortisol and memory following acute social stress in amnestic mild cognitive impairment

ABSTRACT Objective Older adults with amnestic mild cognitive impairment (aMCI) develop Alzheimer’s type dementia approximately 10 times faster annually than the normal population. Adrenal hormones are associated with aging and cognition. We investigated the relationship between acute stress, cortisol, and memory function in aMCI with an exploratory analysis of sex. Method Salivary cortisol was sampled diurnally and during two test sessions, one session with the Trier Social Stress Test (TSST), to explore differences in the relationship between cortisol and memory function in age-normal cognition (NA) and aMCI. Participants with aMCI (n = 6 women, 9 men; mean age = 75) or similarly aged NA (n = 9 women, 7 men, mean age = 75) were given tests of episodic, associative, and spatial working memory with a psychosocial stressor (TSST) in the second session. Results The aMCI group performed worse on the memory tests than NA as expected, and males with aMCI had elevated cortisol levels on test days. Immediate episodic memory was enhanced by social stress in NA but not in the aMCI group, indicating that stress-induced alterations in memory are different in individuals with aMCI. High cortisol was associated with impaired performance on episodic memory in aMCI males only. Cortisol in Session 1 moderated the relationship with spatial working memory, whereby higher cortisol was associated with worse performance in NA, but better spatial working memory in aMCI. In addition, effects of aMCI on perceived anxiety in response to stress exposure were moderated by stress-induced cortisol in a sex-specific manner. Conclusions We show effects of aMCI on Test Session cortisol levels and effects on perceived anxiety, and stress-induced impairments in memory in males with aMCI in our exploratory sample. Future studies should explore sex as a biological variable as our findings suggest that effects at the confluence of aMCI and stress can be obfuscated without sex as a consideration.

Morphine improved stress-induced amnesia and anxiety through interacting with the ventral hippocampal endocannabinoid system in rats

The present study aimed to investigate the possible role of the ventral hippocampal (VH) cannabinoid CB1 receptors in the improving effect of morphine on stress-induced memory formation impairment and anxiety. A step-through type passive avoidance task and a hole-board test were used to measure memory formation and anxiety-like exploratory behavior, respectively. The results showed that the exposure to 10-min stress immediately after the successful training phase impaired memory formation and also produced anxiogenic-like exploratory behaviour in adult male Wistar rats. Moreover, morphine administration before stress exposure improved the adverse effects of stress on memory formation and exploratory behaviour. After training, intra-VH microinjection of cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (0.01−0.05 μg/rat) enhanced the response of an ineffective dose of morphine (0.5 mg/kg for memory; 5 mg/kg for anxiety, i.p.) on memory impairment and anxiogenic-like exploratory behaviour induced by acute stress. Intra-VH microinjection of the higher dose of WIN 55,212-2 alone impaired memory formation. Post-training microinjection of a cannabinoid CB1 receptor antagonist/inverse agonist, AM-251 (100−150 ng/rat) into the VH attenuated the response of an effective dose of morphine (5 mg/kg for memory; 6 mg/kg for anxiety, i.p.) in stress-exposed rats. Taken together, the present results showed that morphine administration could improve stress-induced memory impairment and anxiety in the rats exposed to the inescapable acute stress. Interestingly, the improving effect of morphine on the adverse effect of stress on memory formation and anxiety-like exploratory behaviour may be mediated through the VH endocannabinoid CB1/CB2 receptors mechanism.