An enriched environment and 17-beta estradiol produce similar pro-cognitive effects on ovariectomized rats

Estrogen depletion due to aging, surgery or pathological events can cause a multitude of problems, including neurodegenerative alterations. In rodents without ovaries, 17-beta estradiol (E2) has been shown to produce beneficial effects on cognition, stimulating brain regions (e.g., the neocortex, hippocampus and amygdala) related to cognition and learning. Another treatment that stimulates these brain regions is an enriched environment (EE), which is a complex set of external factors in the immediate surroundings that facilitates greater stimulation of sensorial, cognitive and motor circuits of the brain. The aim of the present study was to test, using an animal model of ovariectomy-induced impairment of memory, the relative effect of E2 (with a time-released pellet; 1 μg/rat/day), EE exposure and a combination of both treatments. Experimental and control groups were submitted to two memory tests 18 weeks post-surgery: the autoshaping learning task (ALT) for measuring associative learning and the novel object recognition test (NORT) for evaluating short- and long-term memory. To assess potential motor impairments caused by treatments, all rats were tested after the ALT in an automatic activity counter. Results from ALT show that the ovariectomy blocked the conditioned responses displayed, an effect rescued by chronic treatment with estrogen or EE exposure. The combination of both treatments did not improve the results obtained separately. In the NORT, the exploration time for recognizing a novel object was similar in the short run with all groups, but greater in the long run with hormone administration or EE exposure. As with the ALT, in the NORT there was no improvement shown by the combination treatment. These data were not masked by changes in spontaneous activity because this parameter was not modified in the rats by either treatment. Possible action mechanisms are proposed, taking into account the role of corticosterone and BDNF on cognition.     

Environmental enrichment in male CD-1 mice promotes aggressive behaviors and elevated corticosterone and brain norepinephrine activity in response to a mild stressor

Housing rodents in an enriched environment (EE) has been typically considered to have positive effects on well-being and cognitive functioning of the animals. However, in some strains of mice, EEs have also been reported to elicit aggression and to promote stress-related outcomes. In the current investigation, we examined whether environmental enrichment would elicit aggression among CD-1 male mice and thus sensitize responses to a subsequent mild stressor. It was first observed that mice housed in an EE for 2 weeks displayed more aggressive behaviors than did mice that had been housed in a standard environment (SE). In the second experiment, it was noted that after 4 weeks of EE or SE housing, mice exhibited comparable plasma corticosterone concentrations as well as levels of brain norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the absence of a challenge. However, upon exposure to mild stressor (placement in a novel cage), relative to their SE counterparts, EE mice were more active and displayed higher plasma corticosterone concentrations and enhanced MHPG accumulation in the prefrontal cortex and hippocampus. It seems that enrichment in male CD-1 mice promotes aggression, and may sensitize biological processes, possibly increasing vulnerability to stressor-related outcomes.     

Alteration of cingulate long-term plasticity and behavioral sensitization to inflammation by environmental enrichment

Exposure to an enriched environment (EE) has been shown to induce cortical plasticity. Considerable amount of research is focused on the effects of EE in the hippocampus; however, effects of EE on other brain regions and the mechanisms involved are not well known. To investigate this, we induced cortical plasticity by placing mice in an EE for one month and measured the effects of EE in the anterior cingulate cortex (ACC). Here, we show that EE enhanced the expression of the plasticity gene, egr-1, in the ACC of EE animals accompanied by enhanced cingulate long-term potentiation (LTP) and decreased cingulate long-term depression (LTD). The increased NMDA receptor NR2B/NR2A subunits current ratio is associated with the plasticity seen in the ACC while total protein levels remain unchanged. Furthermore, behavioral experiments show that these mice exposed to EE demonstrate enhanced responses to acute and long-term inflammation. Our findings suggest that exposure to EE alters physiological properties within the ACC which results in enhanced responses to inflammation.     

情景记忆成功年老化的神经机制

随着年龄的增长, 大部分老年人的情景记忆会出现衰退, 但也会有一部分老年人的情景记忆表现出成功的年老化, 即记忆成绩较好或随增龄的衰退程度较小。脑保持理论、神经去分化理论、认知储备理论以及神经补偿理论分别从不同角度解释了情景记忆成功年老化的神经机制。基于选择性优化与补偿模型对现有理论进行整合, 发现情景记忆成功年老化可能与个体的认知储备水平直接相关：高认知储备的老年人能够对情景记忆相关的脑区和脑网络进行优化且具备更强的神经补偿能力, 因而其脑功能(比如, 神经表征和神经加工通路的特异性)可能会保持地更好。未来研究需要更多地采用纵向设计来考察各理论之间的关系及其影响因素, 从而更好地解释记忆成功年老化的神经机制并为提升老年人的脑与认知健康提供支持。     

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition

In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced 'steroid psychosis' in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the 'age-related memory impairments' observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.     

Effects of daily environmental enrichment on memory deficits and brain injury following neonatal hypoxia-ischemia in the rat

Environmental enrichment (EE) results in improved learning and spatial memory, as well as attenuates morphological changes resulting from cerebral ischemia in adult animals. This study examined the effects of daily EE on memory deficits in the water maze and cerebral damage, assessed in the hippocampus and cerebral cortex, caused by neonatal hypoxia-ischemia. Male Wistar rats in the 7th postnatal day were submitted to the Levine-Rice model of neonatal hypoxia-ischemia (HI), comprising permanent occlusion of the right common carotid artery and a period of hypoxia (90 min, 8%O(2)-92%N(2)). Starting two weeks after the HI event, animals were stimulated by the enriched environment (1h/day for 9 weeks); subsequent to the stimulation, performance of animals in the water maze was assessed. HI resulted in spatial reference and working memory impairments that were completely reversed by EE. Following the behavioral study, animals were killed and the hippocampal volume and cortical area were estimated. There was a significant reduction of both hippocampal volume and cortical area, ipsilateral to arterial occlusion, in HI animals; environmental stimulation had no effect on these morphological measurements. Presented data indicate that stimulation by the daily environmental enrichment recovers spatial memory deficits caused by neonatal hypoxia-ischemia without affecting tissue atrophy in either hippocampus or cortex.     

Preventing Vascular Effects on Brain Injury and Cognition Late in Life: Knowns and Unknowns

For some researchers, the relationship between prevalent cardiovascular risk factors and late-life cognitive decline is not worthy of further study. It is already known that effective treatment of vascular risk factors lowers risk of such major outcomes as stroke and heart attack, the argument goes; thus, any new information about the relationship between vascular risk factors and another major outcome - late-life cognitive decline-- is unlikely to have an impact on clinical practice. The purpose of this review is to probe the logic of this argument by focusing on what is known, and what is not known, about the relationship between vascular risk factors and late-life cognitive decline. The unknowns are substantial: in particular, there is relatively little evidence that current vascular risk factor treatment protocols are adequate to prevent late-life cognitive decline or the clinically silent brain injury that precedes it. In addition, there is relatively little understanding of which factors lead to differential vulnerability or resilience to the effects of vascular risk factors on silent brain injury. Differential effects of different classes of treatments are similarly unclear. Finally, there is limited understanding of the impact of clinically-silent neurodegenerative disease processes on cerebrovascular processes. Further study of the relationships among vascular risk factors, brain injury, and late-life cognitive decline could have a major impact on development of new vascular therapies and on clinical management of vascular risk factors, and there are promising avenues for future research in this direction.     

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.     

Repetition priming across the adult lifespan--the long and short of it

Previous reports suggest that repetition priming (i.e., enhanced processing of a stimulus after experience with that stimulus) is long lasting and impervious to the effects of age, in contrast to the pattern found with explicit memory. However, the nature of repetition priming in aged individuals remains unclear, as conflicting findings have also been reported. We used a longitudinal design to examine how repetition priming is affected by multiple stimulus repetitions (three presentations) and different delay intervals (no delay, 1 day, 1 week, and 1 month) in young adults, as well as in two groups of aging adults (young-elderly and old-elderly). Our findings extend previous reports that priming is long lasting, even when 1 month intervenes between the initial experience with an item and the subsequent priming test of that item (Cave, 1997), and is relatively impervious to the effects of age (Mitchell, et al., 1990). In addition, a more detailed characterization of priming and the effects of aging was revealed. Although priming is long lasting, remaining significant even at the month delay for all groups, it did decline over time and the rate of that decline differed with age. Both young-elderly and old-elderly groups showed a marked drop-off at 1 day, whereas young adults did not show a decline until 1 week. All groups benefited from multiple repetitions; however, this benefit disappeared at the month delay (in contrast to recognition memory, where the benefit remained significant). These findings support the assertion that repetition priming and explicit memory reflect the operation of distinct systems, and that these systems may undergo different rates of change in aging.     

Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): a Review

Chronic traumatic encephalopathy (CTE) is a neuropathologically defined disease reportedly linked to a history of repetitive brain trauma. As such, retired collision sport athletes are likely at heightened risk for developing CTE. Researchers have described distinct pathological features of CTE as well a wide range of clinical symptom presentations, recently termed traumatic encephalopathy syndrome (TES). These clinical symptoms are highly variable, non-specific to individuals described as having CTE pathology in case reports, and are often associated with many other factors. This review describes the cognitive, emotional, and behavioral changes associated with 1) developmental and demographic factors, 2) neurodevelopmental disorders, 3) normal aging, 4) adjusting to retirement, 5) drug and alcohol abuse, 6) surgeries and anesthesia, and 7) sleep difficulties, as well as the relationship between these factors and risk for developing dementia-related neurodegenerative disease. We discuss why some professional athletes may be particularly susceptible to many of these effects and the importance of choosing appropriate controls groups when designing research protocols. We conclude that these factors should be considered as modifiers predominantly of the clinical outcomes associated with repetitive brain trauma within a broader biopsychosocial framework when interpreting and attributing symptom development, though also note potential effects on neuropathological outcomes. Importantly, this could have significant treatment implications for improving quality of life.     

Implicit memory is not immune to interference

Does interference, a primary source of forgetting in explicit memory, also affect implicit memory? Several early and highly influential studies have suggested that implicit memory is immune to interference. In contrast, a number of subsequent investigations have reported evidence for interference. As well, amnesic patients, whose performance relies primarily on implicit memory, often show interference effects. A review of methods, materials, and findings suggests that interference occurs on implicit tests when targets and nontargets are similar and so compete as potential responses to the memory cue. Further, there is some evidence that the degree of interference on implicit tasks is affected by the number of competing items and their strength relative to the target. Interference effects in implicit memory seem to parallel those in explicit memory, and the authors consider the implications of this conclusion for theoretical concepts of memory and the brain.     

Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins

Experience-dependent plasticity is thought to involve selective change in pre-existing brain circuits, involving synaptic plasticity. One model for looking at experience-dependent plasticity is environmental enrichment (EE), where animals are exposed to a complex novel environment. Previous studies using electron microscopy showed that EE resulted in synaptic plasticity in the visual cortex and hippocampus. However, the areas in the brain that have been examined following EE have been limited. The present study quantified potential synaptic plasticity throughout the brains of C57BL/6 mice using an enzyme-linked immunosorbent assay (ELISA) for two synaptic proteins, synaptophysin and PSD-95. EE resulted in increased synaptophysin and PSD-95 levels through major brain regions, including anterior and posterior areas of the forebrain, hippocampus, thalamus, and hypothalamus. However, no changes in synaptophysin were detected in the cerebellum. These results demonstrate that EE results in an increase in levels of both pre- and post-synaptic proteins in multiple regions of the brain, and it is possible that such changes represent the underlying synaptic plasticity occurring in EE.     

Stress, glucocorticoids, and memory: a meta-analytic review

Although a strong psychoneuroendocrine linkage exists between stress, glucocorticoids and memory, the relationship is not always straightforward. Eighty-eight effect sizes and 1642 participants from 28 studies were meta-analyzed for the effects of stress on memory performance and glucocorticoid activation. Analyses showed that stress was associated with glucocorticoid activation and declarative memory decline. In animal studies, predator stress affected memory performance more than physical stress. In human studies, males showed higher cortisol levels than females in response to stress. Further, the correlation between cortisol levels and memory deficits was stronger in studies using laboratory stressors than those examining long term effects of chronic exposure to rising basal levels of glucocorticoids and chronic life stressors. It was concluded that, although the relationship between stress, glucocorticoids, and memory loss was empirically supported, there were other factors, such as stress condition and gender, as well as individual differences within groups, that influenced the association between these variables, and warrant further examination.     

Effect of enriched (complex) environment on nerve conduction velocity: New data and review of implications for the speed of information processing

Extensive research with genetically heterogeneous rats and other mammals haa shown many effects of environmental enrichment (EE; comparing complex, stimulating environment with simple environment) on brain and behavior. Increased nerve conduction velocity (NCV) in brain nerve pathways is one of these effects. Research with a genetically heterogeneous mouse strain (HS) also strongly suggests that increased stimulation or usage increases peripheral NCV (PNCV) and this study on 54 HS mice confirms this. Human data also indicate that increased activity increases PNCV. Therefore, both brain NCV and PNCV appear to increase after EE. Since extensive human data indicate that the speed of information processing (SIP) is positively correlated with intelligence level, and brain NCV should be a component of SIP, these results suggest a role, at the physiological level, for EE (or deprivation) in affecting measured intelligence.     

Memory aging and brain maintenance

Episodic memory and working memory decline with advancing age. Nevertheless, large-scale population-based studies document well-preserved memory functioning in some older individuals. The influential ‘reserve’ notion holds that individual differences in brain characteristics or in the manner people process tasks allow some individuals to cope better than others with brain pathology and hence show preserved memory performance. Here, we discuss a complementary concept, that of brain maintenance (or relative lack of brain pathology), and argue that it constitutes the primary determinant of successful memory aging. We discuss evidence for brain maintenance at different levels: cellular, neurochemical, gray- and white-matter integrity, and systems-level activation patterns. Various genetic and lifestyle factors support brain maintenance in aging and interventions may be designed to promote maintenance of brain structure and function in late life.     

The impact of stress on neutral and emotional aspects of episodic memory

The present experiment demonstrates that exposure to a significant psychological stressor (administered before watching a slide show) preserves or even enhances memory for emotional aspects of an event, and simultaneously disrupts memory for non-emotional aspects of the same event. Stress exposure also disrupted memory for information that was visually and thematically central to the event depicted in the slide show. Memory for peripheral information, on the other hand, was unaffected by stress. These results are consistent with theories invoking differential effects of stress on brain systems responsible for encoding and retrieving emotional memories (the amygdala) and non-emotional memories (e.g., the hippocampal formation), and inconsistent with the view that memories formed under high levels of stress are qualitatively the same as those formed under ordinary emotional circumstances. These data, which are also consistent with results obtained in a number of studies using animals and humans, have implications for the traumatic memory debate and theories regarding human memory.     

Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice

Although environmental enrichment improves spatial memory and alters synaptic plasticity in aged rodents, it is unclear whether all types of enrichment treatments yield similar benefits. The present study examined the effects in aged male mice of three types of enrichment on spatial memory in Morris water maze and radial arm maze tasks, and on levels of the presynaptic protein synaptophysin in several brain regions. Non-enriched young and aged males were compared with males exposed to one of the following treatments for 10 weeks: 5 min of daily handling, 3 h of daily basic enrichment, or 24 h of continuous complex enrichment. Young controls outperformed aged controls in both tasks. Neither daily handling nor daily enrichment affected spatial memory or synaptophysin levels. In contrast, continuous enrichment significantly reduced age-related spatial memory decline in both tasks, such that this group was statistically indistinguishable from young controls in most measures of performance. Continuously enriched mice were also significantly better than other aged mice in several spatial memory measures. Despite these improvements, synaptophysin levels in the continuous enrichment group were significantly lower than those of young and aged controls in the frontoparietal cortex, hippocampus, and striatum, suggesting a negative relationship between synaptophysin levels and spatial memory in aged males. These data demonstrate that different types of enrichment in aged male mice have disparate effects on spatial memory, and that the relationship between enrichment-induced changes in synaptophysin levels and spatial memory in aged males differs from that we have previously reported in aged female mice.     

Odour‐based context reinstatement effects with indirect measures of memory: The curious case of rosemary

Previous studies examining environmental context‐dependent memory (ECDM) effects using indirect measures of memory have produced inconsistent findings. We report three experiments that examined ECDM in an indirect memory paradigm (word‐fragment completion) using ambient odours as environmental contexts. Expt 1 manipulated the odour present at learning and testing (rosemary or lemon) to produce reinstated‐context or switched‐context conditions. Reinstating rosemary led to a striking ECDM effect, indicating that indirect memory testing can be sensitive to ECDM manipulations. Odour ratings also indicated that rosemary induced a more unpleasant mood in participants than lemon. Expt 2 assessed the influence on indirect retrieval of odour‐based mood induction as well as odour distinctiveness, and indicated that rosemary's capacity to promote ECDM effects appears to arise from an additive combination of its unpleasantness‐inducing properties and its distinctiveness. Expt 3 partially supported these proposals. Overall, our findings indicate that some odours are capable of producing ECDM effects using indirect testing procedures. Moreover, it appears that it is the inherent proprieties of odours on dimensions such as unpleasantness and distinctiveness that mediate the emergence of ECDM effects, thereby explaining the particular potency of rosemary's mnemonic influence when it is reinstated.     

Memory and brain volume in adults prenatally exposed to alcohol

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.