Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory

cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.     

Enriched environment treatment restores impaired hippocampal synaptic plasticity and cognitive deficits induced by prenatal chronic stress

Prenatal stress can cause long-term effects on cognitive functions in offspring. Hippocampal synaptic plasticity, believed to be the mechanism underlying certain types of learning and memory, and known to be sensitive to behavioral stress, can be changed by prenatal stress. Whether enriched environment treatment (EE) in early postnatal periods can cause a recovery from these deficits is unknown. Experimental animals were Wistar rats. Prenatal stress was evoked by 10 foot shocks (0.8 mA for 1s, 2-3 min apart) in 30 min per day at gestational day 13-19. After weaning at postnatal day 22, experimental offspring were given the enriched environment treatment through all experiments until tested (older than 52 days age). Electrophysiological and Morris water maze testing was performed at 8 weeks of age. The results showed that prenatal stress impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in the hippocampal CA1 region in the slices. Furthermore, prenatal stress exacerbated the effects of acute stress on hippocampal LTP and LTD, and also impaired spatial learning and memory in the Morris water maze. However, all these deficits induced by prenatal stress were recovered by enriched environment treatment. This work observes a phenomenon that may contribute to the understanding of clinically important interactions among cognitive deficit, prenatal stress and enriched environment treatment. Enriched environment treatment on early postnatal periods may be one potentially important target for therapeutic interventions in preventing the prenatal stress-induced cognitive disorders.     

Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP

Neurogranin (Ng), a PKC substrate, is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng caused severe deficits in spatial learning and LTP in the hippocampal CA1 region of mice. These Ng-/- mice also exhibit deficits in the amplification of their hippocampal signaling pathways critical for learning and memory. A short-term exposure to an enriched environment failed to improve their behavioral performances. Here, we showed that a long-term enrichment protocol for the aging mice was beneficial to the Ng-/- as well as Ng+/+ and Ng+/- mice in preventing age-related cognitive decline. Enrichment also caused an increase in the hippocampal CREB level of all three genotypes and Ng level of Ng+/+ and Ng+/- mice, but not that of alphaCaMKII or ERK. Interestingly, hippocampal slices of these enriched aging Ng-/- mice, unlike those of Ng+/+ and Ng+/- mice, did not show enhancement in the high frequency stimulation (HFS)-induced LTP in the CA1 region. It appears that the learning and memory processes in these enriched aging Ng-/- mice do not correlate with the HFS-induced LTP, which is facilitated by Ng. These results demonstrated that long-term enrichment for the aging Ng-/- mice may improve their cognitive function through an Ng-independent plasticity pathway.     

Neural and behavioral measures of error-related cognitive control predict daily coping with stress

This study tested the hypothesis that individual differences in cognitive control can predict individual differences in emotion regulation. Participants completed color-word and emotional Stroop tasks while an electroencephalogram was recorded, and then they reported daily stressful events, affect, and coping for 14 days. Greater posterror slowing in the emotional Stroop task predicted greater negative affect in response to stressors and less use of task-focused coping as daily stressors increased. Participants whose neural activity best distinguished errors from correct responses tended to show less stress reactivity in daily self-reports. Finally, depression levels predicted daily affect and coping independent of cognitive control variables. The results offer qualified support for an integrated conception of cognitive and emotional self-regulation.     

The effects of alcohol and variable amount of cognitive stress on the estimation of time

Abstract.— The estimated durations of 4 standard intervals, 3, 5, 7, and 9 sec, and of the total experimental period, 11.5 min, were studied (a) in the absence of stress, during the rising and falling blood alcohol level phases, and (b) in situations involving variables stress (maximum, control, and anti-stress). Alcohol was found to lead to underestimation (a verbal estimate smaller than a given standard) in the absence of stress, but did not affect the estimates when stress was involved. A pronounced central effect was found under maximal stress which was not affected by alcohol. Ss under stress tended to overestimate the length of the experiment when compared to Ss under anti-stress. The Ss rated their current mood on 16 variables, but no significant effects could be related to their time estimates.     

High second‐language proficiency protects against the effects of reverberation on listening comprehension

The purpose of this experiment was to investigate whether classroom reverberation influences second‐language (L2) listening comprehension. Moreover, we investigated whether individual differences in baseline L2 proficiency and in working memory capacity (WMC) modulate the effect of reverberation time on L2 listening comprehension. The results showed that L2 listening comprehension decreased as reverberation time increased. Participants with higher baseline L2 proficiency were less susceptible to this effect. WMC was also related to the effect of reverberation (although just barely significant), but the effect of WMC was eliminated when baseline L2 proficiency was statistically controlled. Taken together, the results suggest that top‐down cognitive capabilities support listening in adverse conditions. Potential implications for the Swedish national tests in English are discussed.     

Evidence for a sensitive period in the effects of early life stress on hippocampal volume

Exposure to stress has been causally linked to changes in hippocampal volume (HV). Given that the hippocampus undergoes rapid changes in the first years of life, stressful experiences during this period may be particularly important in understanding individual differences in the development of the hippocampus. One hundred seventy‐eight early adolescents (ages 9–13 years; 43% male) were interviewed regarding exposure to and age of onset of experiences of stress; the severity of each stressful event was rated by an objective panel. All participants underwent structural magnetic resonance imaging, from which HVs were automatically segmented. Without considering the age of onset for stressful experiences, there was a small but statistically significant negative association of stress severity with bilateral HV. When considering the age of onset, there was a moderate and significant negative association between stress severity during early childhood (through 5 years of age) and HV; there was no association between stress severity during later childhood (age 6 years and older) and HV. We provide evidence of a sensitive period through 5 years of age for the effects of life stress on HV in adolescence. It will be important in future research to elucidate how reduced HV stemming from early life stress may contribute to stress‐related health outcomes.     

Acute and chronic stress effects on performance in a forced-swim task

The effects of uncontrollable stressors on performance in a subsequent forced-swim paradigm were assessed in mice. Uncontrollable shock initially induced behavioral invigoration; however, within 24 h of stressor application, swimming behavior was depressed relative to nonstressed mice. The controllability of the stressor did not influence the initial invigoration, being present among escapably shocked mice as well as among mice that received (yoked) inescapable shock. In contrast, the depression of responding evident 24 h after stressor application was related to the availability of behavioral coping methods. Finally, following repeated exposure to footshock there was no indication of adaptation to the behavioral changes ordinarily induced by acute shock stress. The data were related to the effects of uncontrollable stressors on escape performance, and with respect to the use of this preparation as an animal model of human depression.     

Treatment of chronic stress in employees: subjective, cognitive and neural correlates

This study reports the effect of an affect-focused intervention program, the Affect School, on stress, psychological symptoms, cognitive functioning and neural activity. Fifty employees in social service and education, with high levels of chronic stress, were randomly divided into a treatment (N=27) and control (N=23) group. Complete sets of data were available in 20 participants in the treatment group and 17 in the control group. The Perceived Stress Questionnaire assessed stress and the Symptom Check List-90 psychological symptoms before and after treatment. Episodic-memory functioning under focused and divided attention conditions was also assessed. Prior and after the Affect School, seven participants in the treatment group were studied with functional magnetic resonance imaging (fMRI) during episodic memory processing. After the Affect School there was a reduction in stress and psychological symptoms for the treatment group but not in the control group. The controls showed a reduction in episodic memory functioning whereas the performance of the treatment group remained intact. The fMRI scanning indicated a qualitative change in the neural network subserving episodic memory. These preliminary results suggest that the Affect School is effective on individuals with high stress.     

Sex differences in chronic stress effects on memory in rats

Recent studies in rodent models and in humans have shown that the status of both the gonadal and adrenal axes (hypothalamic-pituitary-gonadal, HPG and hypothalamic-pituitary-adrenal, HPA, respectively) can influence learning and memory function. In this article, the effects of activating the HPA axis (stress) on performance of memory tasks in rats are reviewed. More importantly, results are presented which show that chronic stress has a different impact on performance of these tasks depending upon the sex of the rat. These observations are novel and potentially important since few studies, animal or human, have utilized females as subjects in studies of the stress response. Sex differences in the effects of chronic stress on memory were investigated in rats using an object recognition task and two spatial memory tasks, radial arm maze and object location. Given the same chronic stress--21 days of restraint for 6 h each day--males were impaired in all of the memory tests while females showed enhanced performance of the spatial memory tasks and no changes in object recognition performance. Levels of neurotransmitters and metabolites were measured in brain areas important for cognition in the subjects in order to determine neural systems that may respond to stress and mediate the cognitive responses. These results show that responses of monoamine and amino acid containing neural systems may contribute to or underlie sex differences in stress effects on cognition. Stress decreased dopaminergic activity in the frontal cortex and amygdala of males but not females; whereas, in CA3 of the hippocampus, stress increased levels of 5-HT and norepinephrine in females, but not males, and increased GABA in males, but not females. Finally, a possible role for estradiol in mediating sexually differentiated responses to stress was examined. Behavioral and neurochemical evaluations in ovariectomized, stressed females, with or without estrogen replacement, suggest that sex differences in response to stress are influenced by both the organizing and activating effects of estradiol. A few, recent studies in humans, that show sexually dimorphic relationships between chronic stress and cognition, are also highlighted. These results in humans are consistent with the pattern of results in rats. Clearly, further studies are necessary to substantiate sex differences in stress effects on memory function in humans and to understand mechanisms whereby estrogen may influence the stress response in rats. Nonetheless, recent studies show sexually differentiated cognitive responses to chronic stress and underline the importance of considering the sex/gender of subjects when studying the stress response.     

Estimating the false positive rate for alternative measures of integrity

Estimates of the false positive rate were computed for three methods of assessing integrity: 1) a paper and pencil integrity test; 2) a weighted application blank and; 3) the traditional selection interview. Based on available validation research, the integrity test yielded the most acceptable false positive rate. This type of analysis highlights the need to compare alternative assessment procedures when evaluating the utility of a selection instrument.     

Effects of traumatic stress and perceived stress on everyday cognitive functioning

Stressful or traumatic events have been shown to impair cognitive functioning on laboratory-based tasks due to stress-related intrusive thoughts and avoidance. However, research on the effects of stress on everyday cognitive functioning has been lacking. A sample of 909 undergraduates completed measures of perceived stress, PTSD symptoms, and everyday cognitive failures. The results revealed that both perceived stress and PTSD symptoms uniquely predicted cognitive failures, even after controlling for a number of potentially confounding variables. Additionally, there was a significant interaction. Participants with low scores on both measures of stress reported the fewest occurrences of everyday cognitive failures. In contrast, participants with elevated scores on either measure of stress reported higher levels of cognitive failures. These results suggest that there are unique negative effects of perceived stress and PTSD symptoms on everyday cognitive functioning and sharpen our understanding of the relationship between stress and cognition.     

Effects of traumatic stress and perceived stress on everyday cognitive functioning

Stressful or traumatic events have been shown to impair cognitive functioning on laboratory-based tasks due to stress-related intrusive thoughts and avoidance. However, research on the effects of stress on everyday cognitive functioning has been lacking. A sample of 909 undergraduates completed measures of perceived stress, PTSD symptoms, and everyday cognitive failures. The results revealed that both perceived stress and PTSD symptoms uniquely predicted cognitive failures, even after controlling for a number of potentially confounding variables. Additionally, there was a significant interaction. Participants with low scores on both measures of stress reported the fewest occurrences of everyday cognitive failures. In contrast, participants with elevated scores on either measure of stress reported higher levels of cognitive failures. These results suggest that there are unique negative effects of perceived stress and PTSD symptoms on everyday cognitive functioning and sharpen our understanding of the relationship between stress and cognition.     

The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry

To assess a possible role for serotonin in the mediation of the behavioral changes induced by enriched housing conditions (EC), adult female Long-Evans rats sustaining a serotonin depletion (150 microg of 5,7-dihydroxytryptamine, icv) and sham-operated rats were housed postoperatively for 30 days in enriched (12 rats/large cage containing various objects) or standard housing conditions (2 rats/standard laboratory cage). Thereafter, anxiety responses (elevated plus-maze), locomotor activity (in the home-cage), sensori-motor capabilities (beam-walking task), and spatial memory (eight-arm radial maze) were assessed. Monoamine levels were subsequently measured in the frontoparietal cortex and the hippocampus. Overall, EC reduced anxiety-related responses, enhanced sensori-motor performance and improved the memory span in the initial stage of the spatial memory task. Despite a substantial reduction of serotonergic markers in the hippocampus (82%) and the cortex (74%), these positive effects of EC were not altered by the lesion. EC reduced the serotonin levels in the ventral hippocampus (particularly in unlesioned rats: -23%), increased serotonin turnover in the entire hippocampus (particularly in lesioned rats: +36%) and augmented the norepinephrine levels in the dorsal hippocampus (+68% in unlesioned and +49% in lesioned rats); no such alterations were found in the frontoparietal cortex. Our data suggest that an intact serotonergic system is not a prerequisite for the induction of positive behavioral effects by EC. The neurochemical changes found in the hippocampus of EC rats, however, show that the monoaminergic innervation of the hippocampus is a target of EC.     

The effects of chronic sleep reduction on the performance of cognitive tasks sensitive to sleep deprivation

In four sleep loss experiments we aimed, first, to compare performance during long-term sleep reduction with performance during short-term total sleep deprivation, and second, to measure the effects of both methods of sleep loss on ability to ignore distracting irrelevant stimuli, using a finding embedded figures test (FEFT). Logical reasoning, auditory vigilance and finding embedded figures tasks were shown to be significantly sensitive to one night's sleep deprivation. However, in one sleep reduction study subjects reduced to a mean of 5.2 hours sleep per night for 4 weeks showed no performance deficits on logical reasoning. In a second sleep reduction study subjects reduced to a mean of 4.3 hours sleep per night for 4 nights, and subjects reduced to a mean of 5.3 hours sleep per night for 18 nights, showed no performance deficits on logical reasoning or auditory vigilance, despite their reports of severe increases in subjective sleepiness and reduced concentration. Both these sleep reduction groups, though, did show decrements on the FEFT, which we interpret in terms of dearousal increasing distractibility, which the sleep-reduced subjects could not overcome with effort, as they did with the other tests.     

The effects of prenatal maternal stress on children's cognitive development: Project Ice Storm

There exists considerable research on the effects of prenatal maternal stress on offspring. Animal studies, using random assignment to experimental and control groups, demonstrate the noxious effects of prenatal maternal stress on physical, behavioural and cognitive development. The generalizability of these results to humans is problematic given that cognitive attributions moderate reactions to stressors. In humans, researchers have relied upon maternal anxiety or exposure to life events as proxies for the stressors used with animals. Yet, the associations between maternal anxiety or potentially non-independent life events and problems in infants are confounded by genetic transmission of temperament from mother to child. We summarize the literature on prenatal maternal stress and infant cognitive development, leading to the conclusion that the human literature lacks the ability to separate the effects of the objective exposure to a stressor and the mother's subjective reaction. We then describe our prospective Project Ice Storm in which we are following 150 children who were exposed in utero to a natural disaster. We demonstrate significant effects of the objective severity of exposure on cognitive and language development at age two years with important moderating effects of the timing during pregnancy. The implications of our findings are discussed.     

Effect of stress on hippocampal nociceptin expression in the rat

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor are not only ubiquitously expressed in mammalian brain and spinal cord but are also abundant in limbic structures, particularly in the hippocampus. The widespread distribution of N/OFQ reflects the broad spectrum of its biological actions such as nociception, food intake, spontaneous locomotor activity, and learning and memory processes. Since the hippocampus is involved in the control of adrenocortical activity, its role in stress-related phenomena is well characterized. In male Wistar rats, we first examined the effects of acute restraint stress (120?min) on the brain immunohistochemical localization of N/OFQ. The analysis carried out on sections obtained at the onset of stress revealed enhanced expression of N/OFQ in CA1, CA3, and the dentate gyrus as well as increased plasma corticosterone concentrations. Next, we examined whether endogenous glucocorticoid hormone plays a role in the modulation of hippocampal N/OFQ expression in response to stress. To this end, rats were injected with corticosterone (1?mg/kg) or subjected to restraint stress 1 week after adrenalectomy. Two hours after corticosterone administration, plasma glucocorticoid concentrations were comparable to those observed after restraint stress, while N/OFQ expression had significantly increased in all the hippocampal subfields examined. By contrast, in adrenalectomized rats, stress did not modify protein expression. These results confirm that stress can affect N/OFQ expression and that glucocorticoids may constitute hormonal mediators of this complex interplay.