Enriched Housing Research Articles

Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.

The authors demonstrated the efficacy of enriched housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by environmental enrichment in adulthood following brain insult.

Acute treatment with the 5-HT 1A receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Acute treatment with the 5-HT 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15 min later by a single intraperitoneal injection of 8-OH-DPAT (0.5 mg/kg) or saline vehicle (1.0 mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1–5 and 14–18, respectively. Hippocampal CA 1/CA 3 neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA 3 cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI + 8-OH-DPAT + STD and TBI + VEHICLE + STD groups ( P = 0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups versus the TBI + VEHICLE + STD group ( P = 0.0007 and 0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups locating the escape platform quicker than the TBI + VEHICLE + STD group ( P's < 0.0001). MWM differences were also observed between the TBI + 8-OH-DPAT + EE and TBI + 8-OH-DPAT + STD groups ( P = 0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

Enriched environment treatment counteracts enhanced addictive and depressive-like behavior induced by prenatal chronic stress

Prenatal stress can cause many long-term behavior changes in offspring, but whether prenatal stress can alter addictive behavior in offspring and postnatal enriched environment treatment (EE) can restore these changes are unknown. We reported here that prenatal chronic stress (10 unpredictable, 1 s, 0.8 mA foot-shocks per day during gestational days 13–19) enhanced morphine-induced (10 mg/kg, s.c., per day, 6 consecutive days) place preference. Moreover, prenatal chronic stress caused higher depressive-like behavior in forced swimming test in adult offspring. However, enriched environment housing treatment on postnatal days 22–52 counteracted both the abnormal behaviors alterations. This work observed a phenomenon that might contribute to the understanding of clinically important interactions among addiction, prenatal stress and enriched environment treatment. Postnatal enriched environment treatment might be an important therapeutic intervention in preventing the prenatal stress-induced addictive disorders.

Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions

Environmental enrichment promotes structural and behavioral plasticity in the adult brain. We have evaluated the efficacy of enriched environment on the dendritic morphology and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of ventral subicular–lesioned rats.Bilateral ventral subicular lesion has significantly reduced the dendritic architecture and spine density of hippocampal pyramidal neurons. The lesioned rats exposed to enriched housing for 10 days showed a significant degree of morphological plasticity in terms of enhanced dendritic branching and spine density. However, the BDNF expression in the hippocampus remained unchanged following subicular lesion and following environmental enrichment. We suggest the participation of other neurotrophic factors in mediating the synaptic plasticity events following exposure to environmental enrichment in ventral subicular–lesioned rats.

PR_006: The Combination of a 5-HT 1A Receptor Agonist and Environmental Enrichment After Traumatic Brain Injury Confers Greater Functional Benefits Than Either Treatment Alone

Objective: To determine whether combining 2 interventions that have been shown to benefit motor and cognitive outcome, when provided individually after experimental traumatic brain injury (TBI), would confer additional benefits. Design: Randomized controlled trial. Setting: Experimental research laboratory. Animals: 58 adult male Sprague-Dawley rats. Interventions: Anesthetized rats received a cortical impact or sham injury followed 15 minutes later by a single administration of 8-OH-DPAT (0.5mg/kg, intraperitoneal) or saline vehicle (VEH; 1mL/kg) and were then randomly assigned to either environmental enrichment (EE) or standard (STD) housing.

Brain‐derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment

Neurogenesis continues to occur in the adult mammalian hippocampus and is regulated by both genetic and environmental factors. It is known that exposure to an enriched environment enhances the number of newly generated neurons in the dentate gyrus. However, the mechanisms by which enriched housing produces these effects are poorly understood. To test a role for neurotrophins, we used heterozygous knockout mice for brain-derived neurotrophic factor (BDNF+/-) and mice lacking neurotrophin-4 (NT-4-/-) together with their wild-type littermates. Mice were either reared in standard laboratory conditions or placed in an enriched environment for 8 weeks. Animals received injections of the mitotic marker bromodeoxyuridine (BrdU) to label newborn cells. Enriched wild-type and enriched NT-4-/- mice showed a two-fold increase in hippocampal neurogenesis as assessed by stereological counting of BrdU-positive cells in the dentate gyrus and double labelling for BrdU and the neuronal marker NeuN. Remarkably, this enhancement of hippocampal neurogenesis was not seen in enriched BDNF+/- mice. Failure to up-regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice. We conclude that BDNF but not NT-4 is required for the environmental induction of neurogenesis.

Enriched environments, experience-dependent plasticity and disorders of the nervous system

Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity. The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns. A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions. Here, we review these findings on the environmental modulators of pathogenesis and gene-environment interactions in CNS disorders, and discuss their therapeutic implications.

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice: Involvement of Multiple Pathways

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice: Involvement of Multiple Pathways

Enriched environment during adolescence changes brain-derived neurotrophic factor and TrkB levels in the rat visual system but does not offer neuroprotection to retinal ganglion cells following axotomy

The purpose of the present experiment was to characterize changes in TrkB signaling in the rat visual system resulting from exposure to enriched environment. Female Sprague–Dawley rats were placed in enriched or impoverished conditions for 1, 7 or 28 days. Levels of BDNF protein and its predominant receptor TrkB were examined in the retina, superior colliculus and visual cortex. In the retina, 1 day of enrichment increased full-length TrkB and after 28 days increased BDNF. In the superior colliculus, enrichment for 7 days reduced full-length TrkB and after 28 days increased BDNF and full-length TrkB. One day of enrichment significantly increased BDNF, reduced full-length TrkB and increased truncated TrkB in the visual cortex. Consequently, we further investigated whether exposure to enriched environment and the subsequent changes in BDNF and TrkB translates into a neuroprotective effect on retinal ganglion cells (RGCs) following transection of the optic nerve. Although exogenous intraocular application of BDNF provides neuroprotection to RGCs after axotomy, the endogenous increase in BDNF in the retina after 28 days of enrichment had no effect on RGC survival. While enriched housing conditions offer a model of non-invasive rehabilitation treatment for injury and modulates changes in BDNF and TrkB levels, these molecular changes did not translate into a neuroprotective effect on RGCs following transection of the optic nerve.

Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms

Lifelong cognitive stimulation is associated with a lower risk of Alzheimer's disease (AD), but causality is difficult to prove. We therefore sought to investigate the preventative potential of environmental enrichment (EE) using mice expressing both human mutant presenilin-1 and the amyloid precursor protein (PS1/PDAPP). At weaning, mice were placed into either an enriched or standard housing environment. Behavioral testing at 4.5–6 months showed that environmentally enriched PS1/PDAPP mice outperformed mice in standard housing, and were behaviorally indistinguishable from non-transgenic mice across multiple cognitive domains. PS1/PDAPP mice exposed to both environmental enrichment and behavioral testing, but not to EE alone, showed 50% less brain β-amyloid without improved dendritic morphology. Microarray analysis revealed large enrichment-induced changes in hippocampal expression of genes/proteins related to Aβ sequestration and synaptic plasticity. These results indicate that EE protects against cognitive impairment in AD transgenic mice through a dual mechanism, including both amyloid dependent and independent mechanisms.

Effect of enriched housing on fibulin‐4 knockout mice

Fibulin-4 is one of a family of newly recognized extracellular matrix proteins that are expressed by smooth muscle cells and are found in large and small blood vessels. Experiments were performed to test the following hypothesis: arterial pathologies in fibulin-4 knock-out mice are altered by housing conditions. Knock-out mice and wild-type mice were housed four per cage in standard cages, as is the usual practice. After 3 weeks the mice were sacrificed, and the aortas perfusion-fixed and excised for light and electron microscopy. Localized regions of disorganized extracellular matrix and collagen fibers consistently appeared between some of the medial smooth muscle cells in the knockout mice. In the wild-type mice the smooth muscle cells were closely connected to each other and the media was inherently more compact. The number of disorganized regions per 1,000 square microns was significantly greater for knock-out mice (0.172 ± 0.043 (SEM)) than for wild-type mice (0.015 ± 0.008) (p<0.05, n = 8). This study was repeated with the mice housed two per cage in larger cages, each cage containing a tunnel and a wheel. In this case the knock-out mice showed significantly fewer disorganized regions than those in standard cages (0.035 ± 0.012) (p<0.01, n = 8). The wild type mice also showed fewer disorganized regions (0.003 ± 0.002) but this difference was not significant. These results indicate that arterial pathologies manifested in fibulin-4 knock-out mice can be reduced by improving housing conditions, and imply that appropriate environments can counteract the effects of some genetic deficiencies. Supported by NCCAM P20AT00774

Circulating insulin‐like growth factor I and functional recovery from spinal cord injury under enriched housing conditions

Voluntary locomotor training as induced by enriched housing of rats stimulates recovery of locomotion after spinal cord injury (SCI). Generally it is thought that spinal neural networks of motor- and interneurons located in the ventral and intermediate laminae within the lumbar intumescence of the spinal cord, also referred to as central pattern generators (CPGs), are the 'producers of locomotion' and play a pivotal role in the amelioration of locomotor deficits after SCI. It has been suggested that locomotor training provides locomotor-specific sensory feedback into the CPGs, which stimulates remodeling of central nervous system pathways, including motor systems. Several molecules have been proposed to potentiate this process but the underlying mechanisms are not yet known. To understand these mechanisms, we studied the role of insulin-like growth factor (IGF) I in functional recovery from SCI under normal and enriched environment (EE) housing conditions. In a first experiment, we discovered that subcutaneous administration of IGF-I resulted in better locomotor recovery following SCI. In a second experiment, detailed analysis of the observed functional recovery induced by EE revealed full recovery of hindlimb coordination and stability of gait. This EE-dependent functional recovery was attenuated by alterations in the pre-synaptic bouton density within the ventral gray matter of the lumbar intumescence or CPG area. Neutralization of circulating IGF-I significantly blocked the effectiveness of EE housing on functional recovery and diminished the EE-induced alterations in pre-synaptic bouton density within the CPG area. These results support the use of IGF-I as a possible therapeutic aid in early rehabilitation after SCI.

The effect of routine experimental procedures on physiological parameters in mice kept under different husbandry conditions

AbstractLaboratory animals are frequently subjected to routine procedures, such as injections or the withdrawal of blood samples. Acute stress caused by such procedures is associated with physiological changes that can have a strong impact on experimental results. This study investigated the integrated effects of cage enrichment, social housing and handling on the acute stress response of animals subjected to routine experimental procedures. Female mice of two inbred strains (BALB/c and C57BL/6) were housed under either minimal husbandry conditions (MH: no cage enrichment, infrequent handling and a period of individual housing) or enriched husbandry conditions (EH: with cage enrichment, frequent handling and social housing at all times). One mouse in each cage was implanted with a radio-telemetry transmitter for measuring heart rate (HR) and body temperature (BT). The animals were subjected to intraperitoneal injections or short periods of restraint. In addition to telemetry measurements, thymus weight and tyrosine hydroxylase (TH) activity were assessed. It was found that individual housing under MH conditions, as compared with social housing under EH conditions, elevated both basal HR and BT, and significantly elevated the relative recovery time following routine experimental procedures. Thymus weight and TH activity suggested a long-term stress response under MH conditions following individual housing, although the influence of transmitter implantation and (repeated) acute stress remains to be investigated. The results emphasise that husbandry conditions should be taken into account when evaluating physiological measures after routine procedures.

Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats

The aim of the present study was to investigate the effects of environmental enrichment on the neurogenesis and the extracellular concentrations of glutamate and GABA in the hippocampus of freely moving young and aged rats. Male Wistar rats of 2 (young) and 25 (old) months of age were housed during 8 weeks in an enriched environment; control rats were kept in individual plastic cages during that same period of time. Rats were injected intraperitoneally with bromodeoxyuridine (BrdU; 40 mg/kg; 7 days) during the fourth week of the housing period to detect neurogenesis in the dentate gyrus (DG) of the hippocampus. Rats were sacrified 6 weeks after the last injection of BrdU. During the last week of housing, rats were tested in the water maze for the evaluation of spatial learning. After the housing period, rats were stereotaxically implanted with guide-cannulas to accommodate microdialysis probes in the CA3 area of the hippocampus and the extracellular concentrations of glutamate and GABA were determined. Aged rats showed a decrease in the number of BrdU positive cells in the dentate gyrus compared to young rats. However, neurogenesis in the dentate gyrus of both young and old rats was increased in animals housed in an enriched environment. Microdialysis experiments in the CA3 area of the hippocampus showed that enriched housing conditions increased basal extracellular concentrations of glutamate in aged rats. Perfusion of KCl 100 mM produced a higher increase of extracellular glutamate and GABA in aged rats but not in young rats housed in an enriched environment compared to control rats. These results suggest that enriched housing conditions change both neurogenesis in the dentate gyrus and glutamate and GABA levels in the CA3 area of the hippocampus of aged rats.

Short‐term survival of newborn neurons in the adult olfactory bulb after exposure to a complex odor environment

In the olfactory bulb of adult mice, new neurons are continually integrated into existing neuronal networks. Previous studies have demonstrated that exposure to a complex odor environment increases the incorporation of newborn bulbar neurons without modifying the proliferation rate. Whether this incorporation is transient or leads to the long-lasting presence of new neurons has not yet been answered. Because a transient increase of new neurons impacts olfactory information processing differently than a long-lasting increase, we conducted experiments to investigate the time course of survival and cell death of newly generated bulbar neurons following exposure to an enriched olfactory environment. Dividing cells were labeled with bromodeoxyuridine (BrdU) and were counted at several survival time points thereafter. Interestingly, whereas the number of surviving BrdU-labeled cells was elevated at the time when animals were withdrawn from their enriched housing, this number returned to control level 1 month later. Similarly, when olfactory memory was investigated, we found that the improvement of short-term memory, induced by enriched odor exposure, lasted less than 1 month. These findings indicate not only that the recruitment of newborn neurons closely followed the degree of environment complexity, but also that olfactory memory is tightly associated with the level of ongoing neurogenesis in the adult olfactory bulb.

Post insult enriched housing improves the 8-arm radial maze performance but not the Morris water maze task in ventral subicular lesioned rats

The present study attempted to evaluate the efficacy of enriched housing conditions in promoting behavioral recovery following subicular lesion. Rats with bilateral ibotenic acid lesions of ventral subiculum were exposed to either enriched housing conditions or standard housing for 6 h daily for 10 days. The performance of the lesioned rats reared in standard housing conditions was severely impaired in both 8-arm radial maze and water maze tasks. Lesioned rats exposed to enriched housing showed behavioral recovery in the 8-arm radial maze but not in the water maze. Our study suggests the possibility that recovery may be based on the functional demand of spatial tasks and may require more appropriate environmental stimulation.

Spontaneous stereotypy and environmental enrichment in deer mice ( Peromyscus maniculatus): Reversibility of experience

Spontaneous and persistent stereotypies exhibited by deer mice appear to be prevented by post-weaning rearing in a larger, more complex environment. We sought to determine: (1) if exposure to an enriched environment later in development would still be efficacious in reducing stereotypy, and (2) if exposure to an enriched environment would prevent the development of stereotypy after animals were returned to standard laboratory cages. Enriched housing (24–84 days of age) was associated with substantially lower levels of stereotypy. Moreover, environmental enrichment experienced later in development (84–124 days of age) was as effective as early enrichment. This was not the case, however, for older animals (11–14 months of age) that experienced the same duration of enriched housing. The beneficial effects of early enrichment were found to persist as mice placed in standard cages following enrichment exhibited lower levels of stereotypy than controls. These findings support a sensitive period for the amelioration of abnormal repetitive behavior and suggest a neuroprotective effect of this form of early experience.

Environmental bias? Effects of housing conditions, laboratory environment and experimenter on behavioral tests

Behavioral testing does not always yield similar results when replicated in different laboratories, and it usually remains unclear whether the variability in results is caused by different laboratory environments or different experimenters conducting the tests. In our study, we applied a systematic variation of housing conditions, laboratories and experimenters in order to test the influence of these variables on the outcome of behavioral tests. We wanted to know whether known effects of different housing conditions on behavior can be demonstrated regardless of the respective laboratory and experimenters. In this study, we compared the behavior of mice kept under enriched housing conditions with mice kept in unstructured cages regarding their exploratory, locomotor and anxiety-related behavior in the barrier test, in the open-field test and in the elevated plus-maze test. Experiments were conducted by six different persons in two different laboratories. In spite of an extensive protocol standardizing laboratory environment, animal maintenance and testing procedures, significant differences in absolute values between different laboratories as well as between different experimenters were noticed in the barrier test and in the elevated plus-maze test but not in the open-field test. However, with regard to the differences between enriched and unstructured housing conditions, overall consistent results were achieved by different experimenters in both laboratories. We conclude that the reliability of behavioral phenotyping is not challenged seriously by experimenter and laboratory environment as long as appropriate standardizations are met and suitable controls are involved.

Environmental enrichment prevents cognitive decline and induces memory-related gene expression in a mouse model of Alzheimer’s disease

A lifelong pattern of cognitive stimulation or mental activity such as high educational attainment correlates with lower risk of Alzheimer's disease (AD) and thus may be protective. Since prospective long-term human studies needed to establish a causal relationship between environmental enrichment (EE) and AD are impractical, we sought to answer pathological and genetic questions about preventative EE using a doubly transgenic mouse model of AD. From weaning, mice expressing both human mutant presenilin-1 and amyloid precursor protein (PS/APP) were placed into either an enriched or standard housing (SH) environment. Mice were behaviorally tested and their brains analyzed for AD pathology at six months of age using immunohistochemistry, ELISA, and Golgi staining. To determine possible mechanisms of EE-induced memory improvement, we performed microarray analysis using hippocampal tissue. We found that PS/APP mice raised in EE outperformed those in SH, and were indistinguishable from NT mice. These results showing cognitive protection by EE were independent of any changes in AD pathology. Microarray analysis revealed that transthyretin, an Aβ sequestering protein, was up-regulated in mice exposed to EE. Furthermore, several genes related to memory enhancement were also up-regulated, whereas several memory repressors were down-regulated. Lastly, we found several up-regulated genes whose products culminate in the phosphorylation of proteins known to suppress apoptosis and promote cell survival. Pharmacological agents designed to mimic EE-induced changes in gene expression may provide new approaches to Alzheimer's disease therapy/prevention.

Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome

Ts65Dn mouse is the most widely accepted model for Down syndrome. We previously showed that environmental enrichment improved spatial learning in female but deteriorated it in male Ts65Dn mice. This study analyzed the factors contributing to the disturbed cognition of male Ts65Dn mice after enriched housing, by allocating male control and Ts65Dn mice in four conditions after weaning: small ( n = 2–3) and large group ( n = 8–10) housing, and enriched housing in small (2–3) and large groups (8–10). Learning, aggressive behavior, anxiety-like behavior and biochemical correlates of stress were evaluated when Ts65Dn and control mice were 4–5 months old. Environmental enrichment in large mixed colonies of Ts65Dn and diploid littermates disturbed behavioral and learning skills of Ts65Dn mice in the Morris water maze. ACTH and testosterone levels were not modified in any group of mice. Ts65Dn and control mice subjected to enriched housing in large groups and Ts65Dn mice housed in large groups showed higher corticosterone levels. Aggressive behavior was evaluated by measuring the number of attacks performed in the presence of an intruder. Ts65Dn mice performed less attacks than controls in all conditions, especially after enriched housing, indicating subordination. In the plus maze, cognitive aspects (i.e. risk assessment) and motor components (open arm avoidance) of anxiety behavior were evaluated; no difference in any condition was found. It is suggested that an excess of social and/or physical stimulation in Ts65Dn mice may affect cognition by disturbing the emotional and behavioral components of the learning process.