Enriched Environment Treatment Research Articles

Experience-dependent grooming microstructure alterations and gastrointestinal dysfunction in the SAPAP3 knockout mouse model of compulsive behaviour

BackgroundCompulsive- and anxiety-like behaviour can be efficiently modelled in SAPAP3 knockout (KO) mice, a preclinical model of relevance to obsessive-compulsive disorder (OCD). Although there is emerging evidence in the clinical literature of gastrointestinal dysfunction in OCD, no previous studies have investigated gut function in preclinical models of relevance to OCD. Similarly, the effects of voluntary exercise (EX) or environmental enrichment (EE) have not yet been explored in this context. MethodWe comprehensively phenotyped the SAPAP3 KO mouse model, including the assessment of grooming microstructure, anxiety- and depressive-like behaviour, and gastrointestinal function. Mice were exposed to either standard housing (SH), exercise (EX, provided by giving mice access to running wheels), or environmental enrichment (EE) for 4 weeks to investigate the effects of enriched housing conditions in this animal model relevant to OCD. FindingsOur study is the first to assess grooming microstructure, perseverative locomotor activity, and gastrointestinal function in SAPAP3 KO mice. We are also the first to report a sexually dimorphic effect of grooming in young-adult SAPAP3 KO mice; along with changes to grooming patterning and indicators of gut dysfunction, which occurred in the absence of gut dysbiosis in this model. Overall, we found no beneficial effects of voluntary exercise or environmental enrichment interventions in this mouse model; and unexpectedly, we revealed a deleterious effect of wheel-running exercise on grooming behaviour. We suspect that the detrimental effects of experimental housing in our study may be indicative of off-target effects of stress—a conclusion that warrants further investigation into the effects of chronic stress in this preclinical model of compulsive behaviour.

Environmental Enrichment Prevents Gut Dysbiosis Progression and Enhances Glucose Metabolism in High-Fat Diet-Induced Obese Mice.

Obesity is a global health concern implicated in numerous chronic degenerative diseases, including type 2 diabetes, dyslipidemia, and neurodegenerative disorders. It is characterized by chronic low-grade inflammation, gut microbiota dysbiosis, insulin resistance, glucose intolerance, and lipid metabolism disturbances. Here, we investigated the therapeutic potential of environmental enrichment (EE) to prevent the progression of gut dysbiosis in mice with high-fat diet (HFD)-induced metabolic syndrome. C57BL/6 male mice with obesity and metabolic syndrome, continuously fed with an HFD, were exposed to EE. We analyzed the gut microbiota of the mice by sequencing the 16s rRNA gene at different intervals, including on day 0 and 12 and 24 weeks after EE exposure. Fasting glucose levels, glucose tolerance, insulin resistance, food intake, weight gain, lipid profile, hepatic steatosis, and inflammatory mediators were evaluated in serum, adipose tissue, and the colon. We demonstrate that EE intervention prevents the progression of HFD-induced dysbiosis, reducing taxa associated with metabolic syndrome (Tepidimicrobium, Acidaminobacteraceae, and Fusibacter) while promoting those linked to healthy physiology (Syntrophococcus sucrumutans, Dehalobacterium, Prevotella, and Butyricimonas). Furthermore, EE enhances intestinal barrier integrity, increases mucin-producing goblet cell population, and upregulates Muc2 expression in the colon. These alterations correlate with reduced systemic lipopolysaccharide levels and attenuated colon inflammation, resulting in normalized glucose metabolism, diminished adipose tissue inflammation, reduced liver steatosis, improved lipid profiles, and a significant reduction in body weight gain despite mice's continued HFD consumption. Our findings highlight EE as a promising anti-inflammatory strategy for managing obesity-related metabolic dysregulation and suggest its potential in developing probiotics targeting EE-modulated microbial taxa.

Environmental enrichment and the combined interventions of EE and metformin enhance hippocampal neuron survival and hippocampal-dependent memory in type 2 diabetic rats under stress through the BDNF-TrkB signaling pathways

BackgroundType 2 diabetes (T2D) with depression causes severe cognitive impairments. The devastating conditions will further compromise the overall quality of life. The overconsumption of high-fat and high-sucrose (HFS) diet is one of the modifiable risk factors for T2D, depression, and cognitive impairments. Thus, it is essential to identify effective therapeutic strategies to overcome the cognitive impairments in T2D with depression. We proposed environmental enrichment (EE) which encompasses social, cognitive, and physical components as the alternative treatment for such impairments. We also investigated the potential neuroprotective properties of the antidiabetic drug metformin. This study aimed to investigate the effects of EE and metformin interventions on hippocampal neuronal death, and hippocampal-dependent memory impairment in T2D rats under stress. MethodsThirty-two male rats (200–250 g) were divided into four groups: C group (standard diet + conventional cage), DS group [HFS-induced T2D + restraint stress (RS)], DSE group [HFS-induced T2D + RS + EE] and DSEM group [HFS + RS + EE + metformin]. Serum corticosterone (CORT) was measured to evaluate stress levels. The serum Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defence Test (FORD) were measured to evaluate the systemic oxidative status (OS). Serum brain-derived neurotrophic factor (BDNF) and T-maze tasks were performed to evaluate cognitive functions. Rats were humanely sacrificed to collect brains for histological, morphometric, and hippocampal gene expression studies. ResultsThe CORT and the serum FORT levels in the DSE and DSEM groups were lower than in the DS group. Meanwhile, the serum BDNF, T-maze scores, histological, and morphometric analysis were improved in the DSE and DSEM groups than in the DS group. These findings supported that EE and the combined interventions of EE and metformin had neuroprotective properties. The hippocampal gene expression analysis revealed that the DSE and DSEM groups showed improved regulation of BDNF-TrkB signalling pathways, including the BDNF/TrkB binding, PI3K – Akt pathway, Ras–MAPK pathway, PLCγ–Ca2+ pathway, and CREB transcription. ConclusionEE and the combined interventions of EE and metformin improved hippocampal neuron survival and hippocampal-dependent memory in T2D rats under stress by enhancing gene expression regulation of neurogenesis and synaptic plasticity.

Dorsal dentate gyrus mediated enriched environment-induced anxiolytic and antidepressant effects in cortical infarcted mice

Anxiety and depression are the most common mental health disorders worldwide, each affecting around 30% stroke survivors. These complications not only affect the functional recovery and quality of life in stroke patients, but also are distressing for caregivers. However, effective treatments are still lacking. Enriched environment (EE), characterized with novel and multi-dimensional stimulation, has been reported to exert therapeutic effects on physical and cognitive function. In addition, EE also had potential positive effects on emotional disorders after ischemic stroke; however, the underling mechanisms have not been well elucidated. This study aimed to explore the effectiveness of EE on emotional disorders after cerebral ischemia and its underling mechanism. Sensorimotor cortical infarction was induced by photothrombosis with stable infarct location and volume, resulting in motor dysfunction, anxiety and depression-like behaviors in mice, with decreased ALFF and ReHo values and decreased c-fos expression in the infarction area and adjacent regions. Seven days' EE treatment significantly improved motor function of contralateral forelimb and exhibited anxiolytic and antidepressant effects in infarcted mice. Compared to the mice housing in a standard environment, those subjected to acute EE stimulation had significantly increased ALFF and ReHo values in the bilateral somatosensory cortex (S1, S2), dorsal dentate gyrus (dDG), dorsal CA1 of hippocampus (dCA1), lateral habenular nucleus (LHb), periaqueductal gray (PAG), ipsilateral primary motor cortex (M1), retrosplenial cortex (RSC), parietal association cortex (PtA), dorsal CA3 of hippocampus (dCA3), claustrum (Cl), ventral pallidum (VP), amygdala (Amy), and contralateral auditory cortex (Au). Some of, but not all, the ipsilateral brain regions mentioned above showed accompanying increases in c-fos expression with the most significant changes in the dDG. The number of FosB positive cells in the dDG, decreased in infarcted mice, was significantly increased after chronic EE treatment. Chemogenetic activation of dDG neurons reduced anxiety and depressive-like behaviors in infarcted mice, while neuronal inhibition resulted in void of the anxiolytic and antidepressant effects of EE. Altogether, these findings indicated that dDG neurons may mediate EE-triggered anxiolytic and antidepressant effects in cortical infarcted mice.

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

The etiology of autism spectrum disorder (ASD) has been linked to both genetic and epigenetic factors. Among the epigenetic factors, exposure to valproic acid (VPA), an antiepileptic and mood-modulating drug, has been shown to induce characteristic traits of ASD when exposed to during embryogenesis. Conversely, in animal models, enriched environment (EE) has demonstrated positive behavioral and neural effects, suggesting its potential as a complementary treatment to pharmacological approaches in central nervous system disorders. In this study, we utilized zebrafish to model ASD characteristics induced by VPA and hypothesized that sensory stimulation through EE could ameliorate the behavioral and neuroanatomical features associated with ASD. To test this hypothesis, we assessed social behavior, cerebellar volume, and Purkinje cell populations via histology and immunohistochemistry after exposing the fish to EE. The results revealed that zebrafish exposed to VPA exhibited social deficits, reduced cerebellar cortex volume, and a decrease in c-Fos-positive cells in the Purkinje layer. In contrast, VPA-exposed fish treated with EE showed increased socialization, augmented cerebellar cortex volume, and an elevation in c-Fos-positive Purkinje cells. These findings suggest that alterations induced by VPA may be ameliorated through EE treatment, highlighting the potential therapeutic impact of sensory stimulation in conditions related to ASD.

The role of the sensory input intervention in recovery of the motor function in hypoxic ischemic encephalopathy rat model.

Motor disturbances predominantly characterize hypoxic-ischemic encephalopathy (HIE). Among its intervention methods, environmental enrichment (EE) is strictly considered a form of sensory intervention. However, limited research uses EE as a single sensory input intervention to validate outcomes postintervention. A Sprague-Dawley rat model subjected to left common carotid artery ligation and exposure to oxygen-hypoxic conditions is used in this study. EE was achieved by enhancing the recreational and stress-relief items within the cage, increasing the duration of sunlight, colorful items exposure, and introducing background music. JZL184 (JZL) was administered as neuroprotective drugs. EE was performed 21 days postoperatively and the rats were randomly assigned to the standard environment and EE groups, the two groups were redivided into control, JZL, and vehicle injection subgroups. The Western blotting and behavior test indicated that EE and JZL injections were efficacious in promoting cognitive function in rats following HIE. In addition, the motor function performance in the EE-alone intervention group and the JZL-alone group after HIE was significantly improved compared with the control group. The combined EE and JZL intervention group exhibited even more pronounced improvements in these performances. EE may enhance motor function through sensory input different from the direct neuroprotective effect of pharmacological treatment.NEW & NOTEWORTHY Rarely does literature assess motor function, even though it is common after hypoxia ischemic encephalopathy (HIE). Previously used environmental enrichment (EE) components have not been solely used as sensory inputs. Physical factors were minimized in our study to observe the effects of purely sensory inputs.

Environmental Enrichment Has Minimal Impact on Fresh and Processed Meat Quality of Turkeys

The objective of this study was to determine impacts of environmental enrichment (EE) on turkey meat quality. A randomized complete block design was used with commercial turkeys (n = 420) randomly assigned to 6 EE treatments (control [C], pecking block [PB], platform [P], wooden platform þ straw bale [PSB], straw bale [SB], and tunnel [T]) across 24 pens (16 to 18 turkeys/pen). At 19 wk, turkeys were weighed (live weight [LW]), and 6 birds per pen were harvested, a subset (n = 96 carcasses) fabricated into wings, drumsticks, and boneless breasts and thighs. From the breast and thigh, samples were taken for pH and drip loss. From the breast, samples were taken for instrumental color and shear force, with remaining breast portions further processed into boneless turkey breast logs. From each log, slices were taken for packaged purge loss (PPL), expressed moisture loss (EML), instrumental color, and texture. All EE treatments were analyzed using PROC GLM. For LW, SB turkeys were lightest, PB turkeys were heaviest, and T, PSB, C, and P were intermediate (P = 0.01). For fresh turkey, EE treatment did not impact the fabrication values, fresh breast color, breast or thigh drip loss, or breast or thigh pH (P > 0.05) and had minimal impact to thigh color with significant differences only in the b* values (P = 0.04). For processed turkey, EE did not impact processing yield, PPL, a*, b*, or texture (P > 0.05). For L*, SB, T, P, and PSB were lighter, C were darker, and PB had intermediate values (P = 0.02). PB, PSB, C, and T had greater EML loss, P had the least, and SB had intermediate EML (P = 0.04). The results indicate some variations of turkey quality due to EE, but the impacts of specific enrichments were not consistent across quality parameters.

Enriched environment treatment promotes neural functional recovery together with microglia polarization and remyelination after cerebral ischemia in rats

BackgroundMicroglia activation and oligodendrocyte maturation are critical for remyelination after cerebral ischemia. Studies have shown that enriched environment (EE) can effectively alleviate stroke-induced neurological deficits. However, little is known about the mechanism associated with glial cells underlying the neuroprotection of EE. Therefore, this study focuses on investigating the effect of EE on activated microglia polarization as well as oligodendrogenesis in the progress of remyelination following cerebral ischemia. MethodsThe ischemia/reperfusion (I/R) injury model was established by middle cerebral artery occlusion (MCAO) in rats. Animals executed 4 weeks of environmental intervention after performing MCAO or sham surgery and were divided into sham, MCAO, and MCAO+EE groups. Cognitive function, myelin damage, microglia activation and polarization, inflammation, oligodendrogenesis, remyelination, and protein expression of the PI3K/AKT/GSK3β signaling pathway were determined. ResultsThe staining of NeuN indicated that the infarct size of MCAO rats was decreased under EE. EE intervention improved animal performance in the Morris water maze test and novel object recognition test, promoting the recovery of cognitive function after I/R injury. EE treatment alleviated myelin damage in MCAO rats, as evidenced by the lower fluorescence intensity ratio of SMI-32/MBP in MCAO+EE group. EE increased the fluorescence intensity ratio of NG2+/Ki67+/Olig2+, MBP, and MOG, enhancing the proliferation and differentiation of OPCs and oligodendrogenesis after MCAO. In terms of remyelination, more myelinated axons and lower G/ratio were detected in MCAO+EE rats compared with MCAO group. Moreover, EE treatment decreased the number of Iba1+/CD86+ M1 microglia, increased the number of Iba1+/CD206+ M2 microglia, and suppressed the inflammation response after I/R injury, which could be attributed to the augmented expression of PI3K/AKT/GSK3β axis. ConclusionEE improved long‑term recovery of cognitive function after cerebral I/R injury, at least in part by promoting M2 microglia transformation through activation of the PI3K/AKT/GSK3β signaling pathway, inhibiting inflammation to provide a favorable microenvironment for oligodendrocyte maturation and remyelination. The effect of the EE on myelin and inflammation could account for the neuroprotection provided by EE.

Three-phase Enriched Environment Improves Post-stroke Gait Dysfunction via Facilitating Neuronal Plasticity in the Bilateral Sensorimotor Cortex: A Multimodal MRI/PET Analysis in Rats.

The three-phase Enriched Environment (EE) paradigm has been shown to promote post-stroke functional improvement, but the neuronal mechanisms are still unclear. In this study, we applied a multimodal neuroimaging protocol combining magnetic resonance imaging (MRI) and positron emission tomography (PET) to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor cortex. Rats were subjected to permanent middle cerebral artery occlusion. The motor function of the rats was examined using the DigiGait test. MRI was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex. [18F]-fluorodeoxyglucose PET was used to detect glucose metabolism. Blood oxygen level-dependent (BOLD)-functional MRI (fMRI) was used to identify the regional brain activity and functional connectivity (FC). In addition, the expression of neuroplasticity-related signaling pathways including neurotrophic factors (BDNF/CREB), axonal guidance proteins (Robo1/Slit2), and axonal growth-inhibitory proteins (NogoA/NgR) as well as downstream proteins (RhoA/ROCK) in the bilateral sensorimotor cortex were measured by Western blots. Our results showed the three-phase EE improved the walking ability. Structural T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor cortex. PET-MRI fused images showed improved glucose metabolism in the corresponding regions after EE intervention. Specifically, the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory cortex. In addition, FC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE intervention. In addition, a strong correlation was found between increased functional connectivity and improved motor performance of limbs. Specifically, EE regulated the expression of neuroplasticity-related signaling, involving BDNF/CREB, Slit2/Robo1, as well as the axonal growth-inhibitory pathways Nogo-A/Nogo receptor and RhoA/ROCK in the bilateral sensorimotor cortex. Our results indicated that the three-phase enriched environment paradigm enhances neuronal plasticity of the bilateral sensorimotor cortex and consequently ameliorates post-stroke gait deficits. These findings might provide some new clues for the development of EE and thus facilitate the clinical translation of EE.

The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus

BackgroundChronic cerebral hypoperfusion (CCH) is a frequently observed underlying pathology of both Alzheimer's disease (AD) and vascular dementia (VD), which is a common consequence of cerebral blood flow (CBF) dysregulation. Synaptic damage has been proven as a crucial causative factor for CCH-related cognitive impairment. This study aimed to investigate the neuroprotective impact of environmental enrichment (EE) intervention on CCH-induced synaptic destruction and the consequent cognitive impairment. Furthermore, the underlying mechanism of this neuroprotective effect was explored to provide new insights into therapeutic interventions for individuals suffering from AD or VD. MethodsIn this experiment, all rats were initially acclimatized to a standard environment (SE) for a period of one week. On the seventh day, rats underwent either bilateral common carotid artery occlusion (2VO) surgery or sham surgery (Sham) before being subjected to a four-week procedure of exposure to an EE, except for the control group. During the EE or SE procedure, intraperitoneal injection of chloroquine (CQ) into rats was performed once daily for four weeks. Following this, cognitive function was assessed using the Morris water maze (MWM) test. The synapse ultrastructure was subsequently observed using transmission electron microscopy. Expression levels of autophagy-related proteins (LC3, LAMP1, and P62) and synapse-related proteins (Synapsin I and PSD-95) were detected through Western blotting. Finally, immunofluorescence was used to examine the expression levels of Synapsin I and PSD-95 and the colocalization of LAMP-1 and LC3 in the hippocampus. ResultsAfter undergoing 2VO, rats exposed to SE exhibited cognitive impairment, autophagic dysfunction, and synapse damage. The synapse damage was evidenced by ultrastructural damage and degradation of synapse-related proteins. However, these effects were significantly mitigated by exposure to an EE intervention. Moreover, the intervention led to an improvement in autophagic dysfunction. ConclusionThe study found that EE had a positive impact on CCH-induced synaptic damage. Specifically, EE was found to increase synaptic plasticity-associated proteins and postsynaptic density thickness, while decreasing synaptic space. This multifaceted effect resulted in an amelioration of CCH-induced cognitive impairment. It was shown that this beneficial outcome was mediated via the activation of the autophagy-lysosomal pathway. Overall, the findings suggest that EE may have a therapeutic potential for cognitive impairments associated with CCH through autophagy-mediated synaptic improvement.

Environmental enrichment in combination with Bifidobacterium breve HNXY26M4 intervention amplifies neuroprotective benefits in a mouse model of Alzheimer’s disease by modulating glutamine metabolism of the gut microbiome

The gut microbiota-brain axis has emerged as a novel target for Alzheimer’s disease (AD), a neurodegenerative disease characterised by behavioural and cognitive impairment. However, most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements. Here, we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment (EE) training. In this study, we found that compared with EE or B. breve treatment alone, B. breve intervention combined with EE amplified its neuroprotective effects on AD mice, as reflected by improved cognition, inhibited neuroinflammation and enhanced synaptic function. Moreover, using microbiome and metabolome profiling, we found that the combination of B. breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes. Finally, by integrating behavioural and neurological data with metabolomic profiles, we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut–brain interactions. Collectively, combined B. breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome. Our findings provide a promising multidomain intervention strategy, with a combination of dietary microbiome-based and lifestyle-targeted interventions, to promote brain function and delay the progression of AD.

Efficacy of an environmental enrichment intervention for endometriosis: a pilot study.

We have previously shown that Environmental Enrichment (EE), a multi-modal psychosocial intervention consisting of increased social interaction, novelty, and open spaces, improved disease presentation, anxiety, and immune-related disturbances in the rat model of endometriosis. However, there is a knowledge gap regarding the effects of EE interventions in patients with this painful, inflammatory chronic disease. To adapt and test the efficacy of an EE intervention on pelvic pain, mental health, perceived stress, quality of life, and systemic inflammation in endometriosis patients through a randomized clinical trial (RCT). A multidisciplinary team with expertise in physiology, neuroscience, psychology, and women's health adapted and implemented a two-arm RCT comparing an EE intervention with a wait-list control group. Six EE modules administered on alternate weeks were provided to patients in the intervention (N = 29); controls received education only. Survey data and biospecimens were collected at baseline, end-of-study, and 3-months post-intervention to assess pain (Brief Pain Inventory, BPI), endometriosis-related quality of life-QoL (Endometriosis Health Profile-30, EHP30), anxiety (Generalized Anxiety Disorder 7, GAD7), depression (Patient Health Questionnaire for Depression 8, PHQ8), pain catastrophizing (Pain Catastrophizing Score, PCS), stress (Perceived Stress Scale-14, PSS14), and saliva cortisol levels (AM, PM). Compared to the wait-list controls, participants in the EE intervention showed significantly decreased GAD-7 scores at the end of the intervention and 3-month follow-up. Depression, perceived stress, and QoL improved at the 3-month follow-up compared to baseline. While pain levels did not improve, they significantly correlated with anxiety, depression, QoL and pain catastrophizing scores. This pilot RCT demonstrated significant improvements in anxiety and depressive symptoms, QoL, and perceived stress, supporting enriched environments as an integrative psychosocial intervention to be used as adjuvant to the standard of care for endometriosis pain.

Enriched environment alleviates neurological deficits via downregulation of Cx43 after experimental stroke

While it has been demonstrated that enriched environment (EE) can protect against cerebral ischemia/reperfusion (I/R) injury, the underlying mechanism remains largely unknown. Connexin 43 (Cx43) is a key component of gap junctions, which may mediate cell-to-cell communication in neural cells. This study aimed to investigate the neuroprotective effects of EE against cerebral I/R injury in rats by modulating Cx43. A rat model of cerebral I/R injury was established by middle cerebral artery occlusion (MCAO)/reperfusion. Rats were randomly divided into the sham, MCAO, MCAO + EE, MCAO + Gap19, and MCAO + EE + Gap19 groups. The modified neurological severity score test and Morris water maze assay were used to assess neurological deficits. The infarct volume was measured using triphenyltetrazolium chloride (TTC) staining. Neuronal survival was detected by immunofluorescence. The indices of oxidative stress were determined using ELISA, and the reactive oxygen species levels were determined using a dihydroethidium probe. Cx43 and inflammation-related protein expression levels were also measured using western blotting and immunohistochemistry. EE and Gap19 treatment significantly improved neurological deficits, reduced infarct volumes, attenuated neuronal injury, and suppressed inflammatory cytokine expression and oxidative stress. Furthermore, EE and Gap19 treatment notably downregulated the expression of Cx43 and the inflammation-related pathway TLR4/MyD88/NF-κB in the ischemic penumbra. Gap19, a Cx43 inhibitor, markedly enhanced the neuroprotective effects of EE in rats with cerebral I/R injury. EE treatment protects against cerebral I/R injury in rats via Cx43 downregulation. Our findings may shed light on the mechanism underlying the protective efficacy of EE.

Effects of enriched environment on the expression of β-amyloid and transport-related proteins LRP1 and RAGE in chronic sleep-deprived mice.

Sleep plays an important role in the learning process and memory consolidation, and sleep deprivation (SD) leads to inadequate memory consolidation and plays an important role in brain development and plasticity. SD increases β-amyloid levels while impairing cognitive function. We explored the effect of enriched environment (EE) on β-amyloid and transporter protein LRP1 and receptor for advanced glycosylation end-products (RAGE) expression in chronic sleep deprived mice. We randomly divided mice into four groups (n = 10), the standard environment group (Ctrl group), the sleep deprivation group (SD group), the enriched environment intervention group (EE group), and the sleep deprivation plus environmental enrichment intervention group (SD + EE group). A modified multi-platform SD model was used to sleep deprive the mice for 19 h per day. Five hours of EE intervention was performed daily in the EE group and the SD + EE group, respectively. The behavioral measurements of mice were performed by Y-maze method and new object recognition; the expression levels of Aβ1-42, LRP1, and RAGE in prefrontal cortex and hippocampus of mice were measured by immunofluorescence; the expression levels of LRP1 and RAGE in prefrontal cortex and hippocampus were detected by Western blot. The results showed that EE could effectively ameliorate the effects of SD on cognitive impairment, reduce SD induced Aβ deposition, and decrease the expression of RAGE, while increase the expression of LRP1.

Enriched environment ameliorates fear memory impairments induced by sleep deprivation via inhibiting PIEZO1/calpain/autophagy signaling pathway in the basal forebrain.

To verify the hypothesis that an enriched environment (EE) alleviates sleep deprivation-induced fear memory impairment by modulating the basal forebrain (BF) PIEZO1/calpain/autophagy pathway. Eight-week-old male mice were housed in a closed, isolated environment (CE) or an EE, before 6-h total sleep deprivation. Changes in fear memory after sleep deprivation were observed using an inhibitory avoidance test. Alterations in BF PIEZO1/calpain/autophagy signaling were detected. The PIEZO1 agonist Yoda1 or inhibitor GsMTx4, the calpain inhibitor PD151746, and the autophagy inducer rapamycin or inhibitor 3-MA were injected into the bilateral BF to investigate the pathways involved in the memory-maintaining role of EE in sleep-deprived mice. Mice housed in EE performed better than CE mice in short- and long-term fear memory tests after sleep deprivation. Sleep deprivation resulted in increased PIEZO1 expression, full-length tropomyosin receptor kinase B (TrkB-FL) degradation, and autophagy, as reflected by increased LC3 II/I ratio, enhanced p62 degradation, increased TFEB expression and nuclear translocation, and decreased TFEB phosphorylation. These molecular changes were partially reversed by EE treatment. Microinjection of Yoda1 or rapamycin into the bilateral basal forebrain induced excessive autophagy and eliminated the cognition-protective effects of EE. Bilateral basal forebrain microinjection of GsMTx4, PD151746, or 3-MA mimicked the cognitive protective and autophagy inhibitory effects of EE in sleep-deprived mice. EE combats sleep deprivation-induced fear memory impairments by inhibiting the BF PIEZO1/calpain/autophagy pathway.

Toluene-Induced Behavioral Sensitization is Attenuated by Voluntary Physical Exercise and Social Interaction

Toluene-based inhalants found in some common products, such as paint thinner or glues, may be used to induce intoxication. Though addiction may be one of its most detrimental consequences, treatment options are insufficient or limited. Environmental enrichment (EE) refers to housing conditions that enhance sensory, cognitive, and motor stimulation. This paradigm induces beneficial effects in a variety of animal models of brain disorders, and also in animal models of drug addiction. Previous studies have shown that toluene induces behavioral sensitization and that EE treatment can reduce this response. Since EE comprises a variety of elements, the aim of the present study was to group mice into five different types of EE-shaping housing conditions (4 weeks) and to identify which of them are key elements in attenuating toluene-induced behavioral sensitization. The experimental groups were: Standard housing with conspecifics; EE with conspecifics; Toys stimulation with conspecifics; Exercise wheels with conspecifics; and Wheel and toy isolated. Mice in Standard housing and previously exposed to toluene exhibited high locomotor activity, suggesting behavioral sensitization. When animals were exposed to toluene and then housed in EE with conspecifics or Exercise wheels with conspecifics conditions an attenuation of behavioral sensitization was observed ( p < 0.001; 100% and 75% effectiveness, respectively). Toy with conspecifics housing also reduced behavioral sensitization, but in a less proportion than the two previous mentioned treatments ( p < 0.002; 33.5% effectiveness). Mice in the Wheel and toy isolated housing did not show significant changes in the assessed behavior ( p = 0.061; 12.4% effectiveness). We suggest that exercise and social interaction are the key enriched main elements to attenuate toluene-induced behavioral sensitization. Our results advise preclinical strategies for inhalant abuse interventions based on social interactions and physical exercise. Also, they provide guidelines to develop experimental models with diverse environments and groups that lead us to understand the complexity of environmental enrichment.

Effect of environmental enrichment on relapse rates in patients with severe alcohol use disorder: protocol for a randomised controlled trial

IntroductionAlcohol use disorder (AUD) ranks among the most prevalent psychiatric disorders worldwide. Despite current treatments, more than half of patients relapse within weeks after treatment. In animal models, exposure to...

An enriched environment improves maternal sleep deprivation-induced cognitive deficits and synaptic plasticity via hippocampal histone acetylation.

Growing evidence clearly demonstrates that maternal rodents exposure to sleep deprivation (SD) during late pregnancy impairs learning and memory in their offspring. Epigenetic mechanisms, particularly histone acetylation, are known to be involved in synaptic plasticity, learning, and memory. We hypothesize that the cognitive decline induced by SD during late pregnancy is associated with histone acetylation dysfunction, and this effect could be reversed by an enriched environment (EE). In the present study, pregnant CD-1 mice were exposed to SD during the third trimester of pregnancy. After weaning, all offspring were randomly assigned to two subgroups in either a standard environment or an EE. When offspring were 3 months old, the Morris water maze was used to evaluate hippocampal-dependent learning and memory ability. Molecular biological techniques, including western blot and real-time fluorescence quantitative polymerase chain reaction, were used to examine the histone acetylation pathway and synaptic plasticity markers in the hippocampus of offspring. The results showed that the following were all reversed by EE treatment: maternal SD (MSD)-induced cognitive deficits including spatial learning and memory; histone acetylation dysfunction including increased histone deacetylase 2 (HDAC2) and decreased histone acetyltransferase (CBP), and the acetylation levels of H3K9 and H4K12; synaptic plasticity dysfunction including decreased brain-derived neurotrophic factor; and postsynaptic density protein-95. Our findings suggested that MSD could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by EE treatment.

Enriched environment remodels the central immune environment and improves the prognosis of acute ischemic stroke in elderly mice with chronic ischemia.

With the aging of many populations, cognitive and motor dysfunction caused by ischemic stroke (IS) secondary to long-term chronic cerebral ischemia presents a global problem. Enriched environment (EE), a classic paradigm of environment response and genetic interaction, has shown tremendous influence on the brain. This research aimed to investigate the potential effect of EE on cognitive and motor function in mice with chronic cerebral ischemia and secondary IS. In the chronic cerebral hypoperfusion (CCH) phase, EE treatment improved behavior performance by alleviating neuronal loss and white matter myelin damage, promoting the expression of brain-derived neurotrophic factor (BDNF) and phosphor-cAMP response element binding protein (p-CREB). Furthermore, infiltration of microglia/macrophages and astrocytes was inhibited, and the levels of IL-1β and TNFα were decreased. In the IS phase, EE altered the neuronal outcome on day 21 but not on day one after IS. In addition, EE inhibited IS-induced infiltration of microglia/macrophages and astrocytes, mediated the polarization of microglia/macrophages, and reduced pro-inflammatory factors. Importantly, EE improved IS-induced cognitive and motor deficits on day 21. Collectively, our work demonstrates that EE protects mice from cognitive and motor dysfunction and inhibits neuroinflammation caused by CCH and IS.

Enriched environment promotes post-stroke angiogenesis through astrocytic interleukin-17A.

Our previous studies have revealed that the protective effect of an enriched environment (EE) may be linked with astrocyte proliferation and angiogenesis. However, the relationship between astrocytes and angiogenesis under EE conditions still requires further study. The current research examined the neuroprotective effects of EE on angiogenesis in an astrocytic interleukin-17A (IL-17A)-dependent manner following cerebral ischemia/reperfusion (I/R) injury. A rat model of ischemic stroke based on middle cerebral artery occlusion (MCAO) for 120 min followed by reperfusion was established, after which rats were housed in either EE or standard conditions. A set of behavior tests were conducted, including the modified neurological severity scores (mNSS) and the rotarod test. The infarct volume was evaluated by means of 2,3,5-Triphenyl tetrazolium chloride (TTC) staining. To evaluate the levels of angiogenesis, the protein levels of CD34 were examined by means of immunofluorescence and western blotting, while the protein and mRNA levels of IL-17A, vascular endothelial growth factor (VEGF), and the angiogenesis-associated factors interleukin-6 (IL-6), JAK2, and STAT3 were detected by western blotting and real-time quantitative PCR (RT-qPCR). We found that EE promoted functional recovery, reduced infarct volume, and enhanced angiogenesis compared to rats in standard conditions. IL-17A expression in astrocytes was also increased in EE rats. EE treatment increased the levels of microvascular density (MVD) and promoted the expression of CD34, VEGF, IL-6, JAK2, and STAT3 in the penumbra, while the intracerebroventricular injection of the IL-17A-neutralizing antibody in EE rats attenuated EE-mediated functional recovery and angiogenesis. Our findings revealed a possible neuroprotective mechanism of astrocytic IL-17A in EE-mediated angiogenesis and functional recovery after I/R injury, which might provide the theoretical basis for EE in clinical practise for stroke patients and open up new ideas for the research on the neural repair mechanism mediated by IL-17A in the recovery phase of stroke.