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.     

Enrichment versus exercise effects on motor impairments following cortical removals in rats

Groups of rats were exposed to an enriched environment, given access to an activity wheel, or individually housed in wire mesh cages, impoverished. Rats were exposed in groups of four to the enriched environment or placed individually in the activity wheel for 2 h per day for 25 days preoperatively. Within each exposure group, rats sustained bilateral removals of sensorimotor cortex, or were sham-operated controls. Animals were trained preoperatively to locomote across a narrow elevated runway. Postoperatively, locomotor testing was initiated 17 days after surgery throughout which time all animals were maintained under impoverished conditions. Locomotor deficits following cortical damage were a function of preoperative exposure: enriched rats were least impaired; impoverished rats were most impaired. Rats allowed running wheel activity initially showed the same marked deficits as impoverished animals but recovered more rapidly. The opportunity for physical exercise afforded wheel animals preoperatively may have enhanced motor capabilities that aided recovery. However, physical activity alone did not yield the same protective effects from initial impairment as enrichment. Greater elaboration of neural structures associated with perceptual-motor enrichment probably accounted for the initial sparing of the enriched group.     

CHRONIC SOCIAL STRESS, AFFILIATION, AND CELLULAR IMMUNE RESPONSE IN NONHUMAN PRIMATES

Abstract ——We report the first experimental study of the effect of long–term (over 2 years) exposure to a stressor on cellular immune response Forty–three male cynomolgus monkeys were randomly assigned to stable or unstable social conditions for 26 months The proportion of time spent in affiliative behaviors was assessed by observations made twice weekly T–cell immune response (mitogen–stimulated cell proliferation) was assessed weekly for 3 weeks immediately following the 26–month manipulation The possibility that affiliative behavior represents an attempt to cope with social stress was supported by greater affiliation among animals m the unstable condition than in the stable condition Animals in the unstable condition also demonstrated relatively suppressed immune response More affiliative animals showed enhanced immune response, with the beneficial effects of affiliation occurring primarily among unstable animals The data are interpreted as consistent with the stress–buffering hypothesis, that IS, affiliation protects animals from the potentially pathogenic influences of chronic social stress     

Serial stressors: prior exposure to a stressor modulates its later effectiveness on gastric ulceration and corticosterone release

Several studies have focused on the proactive effects of prior exposure to a stressor on ulcerogenic and endocrine responses to exposure to a similar final stressor. In the present study, we explored the effects of prior exposure of M?ll-Wistar rats to water-restraint stress on gastric ulceration and corticosterone responses to a final stressor. The number of prior exposures to water-restraint challenge was varied from one to four, and the durations of the prior exposures varied from 30 min to 2 h. The duration of the final stress challenge was 75 min. The two indices of the stress response to the final stressor challenge yielded different results. For neither index was the duration of prior exposures a significant factor in modulating the response to the final challenge. For gastric ulceration, those animals receiving one prior exposure, but not four, exhibited less gastric ulceration than animals receiving no prior exposure. These animals also developed less ulceration than those receiving four prior exposures. For corticosterone, those animals receiving four prior exposures exhibited a lower adrenocortical response to the final stressor than did animals receiving no prior exposure, or only one prior exposure. The results indicate the complexity of proactive effects of earlier stress experience on responses to a final stressor challenge.     

Enhanced spatial ability in aged dogs following dietary and behavioural enrichment

We examined the benefits of a broad spectrum antioxidant diet and enrichment comprised of physical exercise, environmental stimulants and cognitive testing, on spatial memory performance in beagle dogs. Both aged (N=48) and young (N=16) beagle dogs (Canus familiaris) were tested yearly on a three-component delayed non-match to position spatial task for three consecutive years. The results showed that young enriched animals acquired the task in fewer sessions, made fewer errors, responded slower and made fewer positional responses, compared to aged enriched animals. An analysis restricted to aged animals revealed that antioxidant administration and enrichment resulted in fewer errors, slower responses and decreased positional responses, particularly in Year 3. Finally, cohort differences emerged, which exemplify the significance of early environmental intervention. Aged dogs that were housed with other animals and exposed to an outdoor environment in early development displayed greater benefits from both interventions. These findings indicate that long-term dietary intervention and enrichment can buffer age-associated cognitive decline.     

Effects of neonatal forebrain noradrenaline depletion on recovery from brain damage: performance on a spatial navigation task as a function of age of surgery and postsurgical housing

The experiments examined the contributions of forebrain noradrenaline and environmental enrichment to recovery of place navigation ability in rats after hemidecortication in infancy or adulthood. Noradrenaline depletion did not affect recovery from neonatal hemidecortication, although the early hemidecortications did allow sparing of function relative to adult operates. Noradrenaline depletion also failed to attenuate the positive effects of enriched housing on otherwise normal rats. Noradrenaline depletion did retard recovery of adult hemidecorticate rats housed in standard laboratory cages, but it did not retard recovery of adult hemidecorticate rats housed in enriched environments. The results suggest that noradrenaline is importantly involved in enhancing recovery from brain damage when other sources of compensation (e.g., neonatal injury, enriched environment) are absent.     

Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice

Environmental enrichment paradigms that incorporate cognitive stimulation, exercise, and motor learning benefit memory and synaptic plasticity across the rodent lifespan. However, the contribution each individual element of the enriched environment makes to enhancing memory and synaptic plasticity has yet to be delineated. Therefore, the current study tested the effects of three of these elements on memory and synaptic protein levels. Young female C57BL/6 mice were given 3h of daily exposure to either rodent toys (cognitive stimulation) or running wheels (exercise), or daily acrobatic training for 6 weeks prior to and throughout behavioral testing. Controls were group housed, but did not receive enrichment. Spatial working and reference memory were tested in a water-escape motivated radial arm maze. Levels of the presynaptic protein synaptophysin were then measured in frontoparietal cortex, hippocampus, striatum, and cerebellum. Exercise, but not cognitive stimulation or acrobat training, improved spatial working memory relative to controls, despite the fact that both exercise and cognitive stimulation increased synaptophysin levels in the neocortex and hippocampus. These data suggest that exercise alone is sufficient to improve working memory, and that enrichment-induced increases in synaptophysin levels may not be sufficient to improve working memory in young females. Spatial reference memory was unaffected by enrichment. Acrobat training had no effect on memory or synaptophysin levels, suggesting a minimal contribution of motor learning to the mnemonic and neuronal benefits of enrichment. These results provide the first evidence that different elements of the enriched environment have markedly distinct effects on spatial memory and synaptic alterations.     

Stereotyping starlings are more ‘pessimistic’

Negative affect in humans and animals is known to cause individuals to interpret ambiguous stimuli pessimistically, a phenomenon termed ‘cognitive bias’. Here, we used captive European starlings (Sturnus vulgaris) to test the hypothesis that a reduction in environmental conditions, from enriched to non-enriched cages, would engender negative affect, and hence ‘pessimistic’ biases. We also explored whether individual differences in stereotypic behaviour (repetitive somersaulting) predicted ‘pessimism’. Eight birds were trained on a novel conditional discrimination task with differential rewards, in which background shade (light or dark) determined which of two covered dishes contained a food reward. The reward was small when the background was light, but large when the background was dark. We then presented background shades intermediate between those trained to assess the birds’ bias to choose the dish associated with the smaller food reward (a ‘pessimistic’ judgement) when the discriminative stimulus was ambiguous. Contrary to predictions, changes in the level of cage enrichment had no effect on ‘pessimism’. However, changes in the latency to choose and probability of expressing a choice suggested that birds learnt rapidly that trials with ambiguous stimuli were unreinforced. Individual differences in performance of stereotypies did predict ‘pessimism’. Specifically, birds that somersaulted were more likely to choose the dish associated with the smaller food reward in the presence of the most ambiguous discriminative stimulus. We propose that somersaulting is part of a wider suite of behavioural traits indicative of a stress response to captive conditions that is symptomatic of a negative affective state.     

Behavioral variability in SHR and WKY rats as a function of rearing environment and reinforcement contingency.

The spontaneously hypertensive rat (SHR) may model aspects of human attention deficit hyperactivity disorder (ADHD). For example, just as responses by children with ADHD tend to be variable, so too SHRs often respond more variably than do Wistar-Kyoto (WKY) control rats. The present study asked whether behavioral variability in the SHR strain is influenced by rearing environment, a question related to hypotheses concerning the etiology of human ADHD. Some rats from each strain were reared in an enriched environment (housed socially), and others were reared in an impoverished environment (housed in isolation). Four groups--enriched SHR, impoverished SHR, enriched WKY, and impoverished WKY--were studied under two reinforcement contingencies, one in which reinforcement was independent of response variability and the other in which reinforcement depended upon high variability. The main finding was that rearing environment did not influence response variability (enriched and impoverished subjects responded similarly throughout). However, rearing environment affected body weight (enriched subjects weighted more than impoverished subjects) and response rate (impoverished subjects generally responded faster than enriched subjects). In addition, SHRs tended to respond variably throughout the experiment, whereas WKYs were more sensitive to the variability contingencies. Thus, behavioral variability was affected by genetic strain and by reinforcement contingency but not by the environment in which the subjects were reared.     

Influence of Regularity of Exposure to Chronic Stress on the Pattern of Habituation of Pituitary-Adrenal Hormones, Prolactin and Glucose

The effect of regularity of exposure to two different chronic stressors (noise or immobilization (IMO)) on the pattern of habituation of pituitary-adrenal (PA) hormones, prolactin and glucose was evaluated in adult male rats. Animals were chronically subjected to either regular or irregular time schedule of noise (30 min/day) or IMO (2 h/day) for two weeks. The day after the last stress session the rats were killed without stress or after having been subjected to 30 min of the homotypic stressor. Whereas regular noise did not affect food intake, body weight gain or adrenal weight, irregular noise decreased body weight gain and induced a moderate adrenal hypertrophy. In addition, previous daily exposure to regular but not to irregular noise reduced both prolactin and corticosterone responses to acute noise. In contrast, glucose response to acute noise was reduced after both regular and irregular exposure to chronic noise. Either regular or irregular exposure to chronic IMO decreased food intake and body weight and increased adrenal weight to the same extent. Likewise, no influence of regularity of exposure to chronic IMO on corticosterone and prolactin responses to acute IMO was observed. However, habituation of the ACTH response to acute IMO was observed in rats subjected to chronic regular IMO, but not in rats subjected to chronic irregular IMO. Finally, acute IMO-induced hyperglycemia diminished to the same extent after regular and irregular IMO. From these results we can conclude that: first, the process of habituation of the PA axis to chronic stress is greatly dependent upon factors such as regularity of exposure to the stressor and stressor intensity, and second, the influence of regularity on the pattern of habituation to a repeated stressor is dependent on the physiological variable we are dealing with.     

Influence of rearing conditions on voluntary ethanol intake and response to stress in rats

The effects of exposure to four environmental rearing conditions on subsequent voluntary ethanol intake and response to immobilization stress were examined. Male weanling rats were reared in an enriched environment, with a female partner, with a male partner, or individually, for 90 days. At 111 days of age, voluntary consumption of ethanol in increasing concentrations (3 to 9%, v/v) was assessed. Following the ethanol-exposure period, rats were randomly divided into stressed and nonstressed groups and exposed to 3 h of immobilization. Results indicated that the enriched animals consumed greater amounts of ethanol as compared to all other groups, suggesting that the enriched environment and not handling, housing conditions, or the presence of another male or female is responsible for the observed increase in ethanol drinking behavior. Ulcer data indicated that among environmentally enriched rats, ethanol attenuated stress ulcer development relative to their non-ethanol-exposed but stressed controls. In nonstressed enriched rats, ethanol alone exacerbated stomach damage. We suggest that environmental rearing conditions markedly influence the complex interaction between ethanol intake and the response to stress.     

Chronic restraint stress impairs T-cell immunity and promotes tumor progression in mice

Long-term exposure to stressful situations can affect the immune system. The T-cell response is an important component of anti-tumoral immunity. Hence, impairment of the immune function induced by a chronic stressor has been postulated to alter the immunosurveillance of tumors, thus leading to a worse neoplastic prognosis. Here, we show that chronic restraint stress affects T-cell mediated immunity in mice. This was evidenced by a decrease of mitogen-induced T-cell proliferation, a reduction in CD4(+)T lymphocyte number and a decrease of tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) production in stressed mice. Additionally, mice subjected to chronic restraint stress displayed an enhancement of tumor growth in a syngeneic lymphoma model, i.e. an increase of tumor proliferation and a reduction of animal survival. Finally, stressed mice had a reduced specific cytotoxic response against these tumor cells. These results suggest that chronic exposure to stress promotes cancer establishment and subsequent progression, probably by depressing T-cell mediated immunity. The T-cell immunity impairment as well as the tumor progression enhancement emphasize the importance of the therapeutic management of stress to improve the prognosis of cancer patients.     

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.     

Effects of neocortical ectopias and environmental enrichment on Hebb-Williams maze learning in BXSB mice

Approximately 40-60% of BXSB mice have neocortical ectopias, a developmental anomaly characterized by migration of neurons into the neuron-sparse layer I of cortex. Previous studies have shown that ectopic BXSB mice have superior reference, but inferior working, memory on spatial tasks. Female BXSB mice were housed either in an enriched environment or in standard cages at weaning. Subsequently, these animals were tested on four of the Hebb-Williams mazes in a water-based version of this maze. Theoretically, two of the maze configurations placed greater emphasis on reference memory to find the goal, whereas the other two favored working memory. Ectopics reared in standard housing conditions were better than nonectopics on mazes that favored the use of reference memory, but poorer on mazes that favored working memory. In contrast, subjects raised in the enriched environment showed no ectopia differences. A comparison of enriched and standard housing conditions found that the enriched animals had better reference memory but poorer working memory. The latter effect may be because the enriched environment, although more stimulating, did not change in time or space; and other researchers have shown that daily replacement of stimuli in complex environments is correlated with better working memory.     

Neuronal nitric oxide synthase gene inactivation reduces the expression of vasopressin in the hypothalamic paraventricular nucleus and of catecholamine biosynthetic enzymes in the adrenal gland of the mouse

The impact of a lifelong absence of the neuronal nitric oxide synthase (nNOS) in the neuroendocrine stress response was investigated in nNOS knockout (KO) and wild type (WT) mice under basal conditions and in response to forced swimming. In the hypothalamic paraventricular nucleus oxytocin and corticotropin-releasing-hormone mRNA levels did not differ between these genotypes under resting conditions, whereas vasopressin mRNA levels were significantly lower in nNOS KO than in WT animals. Also, in the adrenal glands basal levels of tyrosine hydroxylase protein, the rate-limiting enzyme for catecholamine biosynthesis, and of phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine, were significantly reduced in nNOS KO mice. Plasma adrenocorticotropin, corticosterone, norepinephrine and epinephrine levels were similar in the KO and WT genotypes under resting conditions. In response to forced swimming, a similar increase in plasma adrenocorticotropin and corticosterone was observed in KO and WT animals. Stressor exposure triggered also an increased epinephrine release in WT animals, but did not significantly alter plasma epinephrine levels in KO mice. These data suggest that the chronic absence of nNOS reduces the capacity of epinephrine synthesising enzymes in the adrenal gland to respond to acute stressor exposure with an adequate epinephrine release.     

Dynamic role of social support in the link between chronic stress and psychological distress.

How a chronic environmental stressor can interfere with the buffering effects of social support by eroding social support was analyzed in this prospective, longitudinal study. A classic buffering effect of support was found after 2 months of exposure to the stressor, household crowding. Crowded residents with low perceived support had greater increases in psychological distress than did crowded residents with high perceived support. However, after 8 months exposure the buffering effect disappeared. Moreover, greater crowding had become directly associated with lower support, which in turn was associated with greater increases in psychological distress. All analyses controlled for prior distress. Under some types of chronic stress, the buffering effects of social support may be short-lived because the stressor eventually erodes social support.     

Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice

The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.     

Enhancement of auditory fear conditioning after housing in a complex environment is attenuated by prior treatment with amphetamine

Prior exposure to drugs of abuse has been shown to occlude the structural plasticity associated with living in a complex environment. Amphetamine treatment may also occlude some cognitive advantages normally associated with living in a complex environment. To test this hypothesis we examined the influence of prior exposure to amphetamine on fear conditioning in rats housed in either a standard or complex environment. Housing in a complex environment facilitated fear learning to an auditory conditioned stimulus (CS), but not to the training context, relative to animals housed singly or in a social group. Prior treatment with amphetamine eliminated this effect. These results indicate that living in a complex environment facilitates conditional freezing to an auditory CS, and that this effect is abolished by pretreatment with amphetamine.     

Some effects of the opioid antagonist, naloxone, upon the rat's reactions to a heat stressor

Eight experiments examined the apparently paradoxical analgesia that accrues when rats are repeatedly injected with an opiate antagonist, naloxone, and exposed to a heat stressor. Experiments 1 and 2 showed that such pairings came to enhance in a dose-dependent manner the latencies with which rats paw-licked in response to the stressor. Experiment 3 demonstrated that the latencies to paw-lick in saline-treated rats decreased with increases in the intensity of the heat, indicating that naloxone had not provoked long latencies to paw-lick by increasing the functional intensity of the stressor. Experiment 4 documented a role for conditioning processes in recruiting the naloxone-induced analgesia. Experiment 5 showed that the analgesic effect was due to the pairings of the drug and the heat stressor, as a history of exposure to naloxone in a distinctive environment did not render the animals analgesic when challenged with the drug and the stressor. Experiments 6 and 7 provided evidence that the conditioned analgesia that accrued from drug-stressor pairings was non-opioid in nature, as the analgesia was observed in morphine-tolerant rats and was not reversed by an administration of naloxone in advance of exposure to the conditioning context. Experiment 8 demonstrated that the administration of morphine in the context previously associated with naloxone-stressor pairings provoked a superanalgesia. Although analgesic on the paw-lick assay, naloxone-treated subjects did not appear to be insensitive to the heat or impaired motorically, as they persistently reared with short latencies. The results were discussed in terms of the collateral inhibition model of the endogenous pain control system, and some speculations were offered concerning the relation between paw-licking and rearing.     

Spatial learning in pigs: effects of environmental enrichment and individual characteristics on behaviour and performance

This study investigated the effects of both environmental enrichment and individual behavioural characteristics on spatial cognitive capabilities of pigs, using a novel latent spatial learning paradigm based on Tolman’s detour experiments (1948). Pigs were housed either in ‘barren’ pens or in pens enriched with straw bedding from birth. Pigs were restrained in a Backtest at 10 and 17 days postpartum. Based on their escape behaviour in this test, which has been shown to reflect their behavioural style, six ‘high-resisting’(HR) and six ‘low-resisting’ (LR) pigs were selected from each housing environment (n = 24 in total). At 12 weeks of age, pairs of pen mates (LR and HR) were exposed to a maze three times (exploration trials). Pigs were then placed individually in the maze, and social reinstatement proved to be a strong incentive to find the exit leading to the home pen. We subsequently blocked the direct route to the exit, forcing animals to find a detour (memory test 1, MT1). This test was repeated once to investigate the relative improvement, i.e. detour learning (memory test 2, MT2). Housing condition and Backtest response strongly affected exploration patterns. In spite of this, no effects on performance during the subsequent memory tests were found. Performance was substantially improved in MT2, indicating that once a goal is apparent, pigs are able to solve a complex spatial memory task easily. In conclusion, social reinstatement provided a good incentive to complete a spatial task, and the substantial improvement in performance between MT1 and MT2 stresses the need for task complexity when testing spatial memory in pigs. Housing conditions or individual behavioural style did not affect spatial memory during MT1 or MT2. However, housing environment and behavioural style strongly affected explorative behaviour of pigs in an unfamiliar maze during both exploration trials and memory tests. This implicates that apparent effects of environmental enrichment on spatial learning and memory in pigs might reflect differences in explorative patterns rather than in cognitive processes.