Environmental Enrichment Conditions Research Articles

The impact of 3,4-methylendioxymetamphetamine (MDMA) abstinence on seeking behavior and the expression of the D2-like and mGlu5 receptors in the rat brain using saturation binding analyses.

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2-like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2-like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2-like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2-like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.

HDAC2 (Histone deacetylase 2): A critical factor in environmental enrichment-mediated stroke recovery.

Environmental enrichment (EE) is a generally accepted strategy to promote stroke recovery and its beneficial effect is positively correlated with neuroplasticity. However, the mechanisms underlying it remain elusive. Histone deacetylase 2 (HDAC2), a negative regulator of neuroplasticity, is up-regulated after stroke. Thus, we hypothesized that HDAC2 may participate in EE-mediated stroke recovery. In this study, focal stroke was induced by photothrombosis in male mice exposing to EE or standard housing (SH) conditions. Recombinant virus vectors, including Ad-HDAC2-Flag, AAV-CAG-EGFP-Cre, LV-shHDAC2, or their controls were microinjected into the motor cortex at 3days before stroke. Grid-walking and cylinder tasks were conducted to assess motor function. Western blot and immunostaining were used to uncover the mechanisms underlying EE-mediated stroke recovery. We found that EE exposure reversed stroke-induced HDAC2 up-regulation, implicating HDAC2 in EE-mediated functional recovery. Importantly, EE-dependent stroke recovery was counteracted by over-expressing HDAC2, and HDAC2 knockdown promoted functional recovery from stroke to the similar extent as EE exposure. Moreover, the knockdown of HDAC2 epigenetically enhanced expressions of neurotrophins and neuroplasticity-related proteins, with similar effects as EE, and consequently, whole brain and corticospinal tract (CST) rewiring. Together, our findings indicate that HDAC2 is critical for EE-dependent functional restoration. Precisely targeting HDAC2 may mimic EE and serve as a novel therapeutic strategy for stroke recovery.

The effects of environmental enrichment on skin barrier recovery in humans: a randomised trial

This study investigated whether environmental enrichment (EE) could reduce stress and improve wound healing in humans. 120 participants underwent a standardised tape-stripping procedure and were then randomised to interact for 30 minutes with one of three EE interventions (comfort blankets as tactile enrichment, music as auditory enrichment or a Paro robot as multi-sensory enrichment) or to a control group. Skin barrier recovery (SBR) was measured using transepidermal water loss at baseline, after tape-stripping and after the intervention. Psychological variables, cortisol and alpha-amylase were measured at the three time-points. SBR did not significantly differ between the EE conditions and the control condition. The music condition had higher stimulation levels than the control condition, and the comfort condition had significantly lower relaxation levels than the control condition after the intervention. The EE interventions tested were not beneficial for wound healing compared to a control group. Limitations were that the sample were not stressed and an active control condition was used.

Environmental enrichment reduces behavioural sensitization in mice previously exposed to toluene: The role of D1 receptors

It has been reported that environmental stimuli can positively influence addictive responses and the pharmacological effects of drugs of abuse. In this work, we evaluated the ability of environmental enrichment (EE) to attenuate addictive behaviours in mice after repeated exposure to toluene. We also analysed the role of D1 receptors (D1R) in animals chronically exposed to toluene and in those housed under EE. Mice (Swiss Webster) were exposed to toluene (0, 2000 or 4000 ppm, 30 min a day), and addictive responses were examined in the behavioural sensitization model. The induction of sensitization was evaluated over 4 weeks, and its expression was assessed in animals repeatedly exposed to toluene (0 or 4000 ppm, 30 min a day/4 weeks) and then housed under EE conditions during 4 more weeks. D1R levels were measured under these two experimental conditions in the prefrontal cortex, nucleus accumbens, hippocampus and caudate. The results showed that D1R levels decreased during toluene-induced behavioural sensitization. An increase in D1R levels was found in animals housed in EE conditions, in addition to the attenuated expression of behavioural sensitization. These results indicate that environmental stimulation attenuates addictive behaviour induced by toluene and that dynamic changes in D1R are linked in this response.

Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model.

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer’s disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions.

An enriched environment increases the expression of fibronectin type III domain-containing protein 5 and brain-derived neurotrophic factor in the cerebral cortex of the ischemic mouse brain.

Many studies have shown that fibronectin type III domain-containing protein 5 (FDNC5) and brain-derived neurotrophic factor (BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia; however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion (pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16-20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions (based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities (based on the spatial learning scores from the Morris water maze test 16-19 days after operation), and memory abilities (based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF (r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval Nos. 20160858A232, 20160860A234) on February 24, 2016.

Enriched Environmental Conditions Modify the Gut Microbiome Composition and Fecal Markers of Inflammation in Parkinson’s Disease

Recent findings suggest an implication of the gut microbiome in Parkinson’s disease (PD) patients. PD onset and progression has also been linked with various environmental factors such as physical activity, exposure to pesticides, head injury, nicotine, and dietary factors. In this study, we used a mouse model, overexpressing the complete human SNCA gene (SNCA-TG mice) modeling familial and sporadic forms of PD to study whether environmental conditions such as standard vs. enriched environment changes the gut microbiome and influences disease progression. We performed 16S rRNA DNA sequencing on fecal samples for microbiome analysis and studied fecal inflammatory calprotectin from the colon of control and SNCA-TG mice kept under standard environment (SE) and enriched environment (EE) conditions. The overall composition of the gut microbiota was not changed in SNCA-TG mice compared with WT in EE with respect to SE. However, individual gut bacteria at genus level such as Lactobacillus sp. was a significant changed in the SNCA-TG mice. EE significantly reduced colon fecal inflammatory calprotectin protein in WT and SNCA-TG EE compared to SE. Moreover, EE reduces the pro-inflammatory cytokines in the feces and inflammation inducing genes in the colon. Our data suggest that an enriched social environment has a positive effect on the induction of SNCA mediated inflammation in the intestine and by modulating anti-inflammatory gut bacteria.

Environmental enrichment reduces the propensity to relapse following punishment-imposed abstinence of alcohol seeking

Environmental enrichment during periods of abstinence can reduce the risk of relapse to drug-seeking behavior. We trained rats to self-administer alcohol in one environment (Context A), then punished their alcohol-reinforced lever responses in a different environment using contingent foot shock (Context B). Rats were then kept in forced abstinence in either standard housing or environmental enrichment conditions for 31 days. The following day, we examined alcohol seeking behavior. We found a significant reduction in alcohol seeking behavior in Context A after environmental enrichment. Our results suggest that environmental enrichment can reduce alcohol seeking behavior following a period of abstinence.

The Social Component of Environmental Enrichment Is a Pro-neurogenic Stimulus in Adult c57BL6 Female Mice.

In rodents, the hippocampal dentate gyrus gives rise to newly generated dentate granule cells (DGCs) throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature DGCs into the trisynaptic hippocampal circuit. Environmental enrichment (EE) is one of the most potent positive regulators of AHN. This paradigm includes the combination of three major stimulatory components, namely increased physical activity, constant cognitive stimulation, and higher social interaction. In this regard, the pro-neurogenic effects of physical activity and cognitive stimulation have been widely addressed in adult rodents. However, the pro-neurogenic potential of the social aspect of EE has been less explored to date. Here we tackled this question by specifically focusing on the effects of a prolonged period of social enrichment (SE) in adult female C57BL6 mice. To this end, 7-week-old mice were housed in groups of 12 per cage for 8 weeks. These mice were compared with others housed under control housing (2–3 mice per cage) or EE (12 mice per cage plus running wheels and toys) conditions during the same period. We analyzed the number and morphology of Doublecortin-expressing (DCX+) cells. Moreover, using RGB retroviruses that allowed the labeling of three populations of newborn DGCs of different ages in the same mouse, we performed morphometric, immunohistochemical, and behavioral determinations. Both SE and EE increased the number and maturation of DCX+ cells, and caused an increase in dendritic maturation in certain populations of newborn DGCs. Moreover, both manipulations increased exploratory behavior in the Social Interaction test. Unexpectedly, our data revealed the potent neurogenesis-stimulating potential of SE in the absence of any further cognitive stimulation or increase in physical activity. Given that an increase in physical activity is strongly discouraged under certain circumstances, our findings may be relevant in the context of enhancing AHN via physical activity-independent mechanisms.

Osteopontin Promotes Colorectal Cancer Cell Invasion and the Stem Cell-Like Properties through the PI3K-AKT-GSK/3β-β/Catenin Pathway.

BackgroundOsteopontin (OPN) is a molecule expressed in numerous cancers including colorectal cancer (CRC) that correlates disease progression. The interaction of OPN that promotes CRC cell migration, invasion, and cancer stem-like cells (CSCs) have not been elucidated. Hence, we aimed to investigate the mechanisms that might be involved.Material/MethodsExpression of OPN in tumor tissues derived from patients was monitored with real-time quantitative polymerase chain reaction and western blot. Wound healing and Transwell assay were used to test the differences in migration and invasion in an OPN enriched environment and OPN knockdown condition. Aldehyde dehydrogenase 1 (ALDH1) positive stem cells were isolated using fluorescence-activated cell sorting (FACS) following the protocol of the ALDEFLUOR™ kit. The expression of protein participation in the PI3K-Akt-GSK/3β-β/catenin pathway was detected by western blot.ResultsOPN exhibited increased levels in CRC tumor tissue compared with non-tumor normal tissue and the high level of which correlated with lymphatic metastasis and late TNM stage. Additional rhOPN co-cultured low-expression CRC cells demonstrated more aggressive capability of proliferation, migration, and invasion. For knockdown of OPN in high-expression CRC cells, the bioactivities of proliferation, migration, and invasion were significantly inhibited. Interestingly, the percentage of ALDH1 labeled stem cells was dramatically decreased by OPN inhibition. The phosphorylation of PI3K-Akt-GSK/3β-β/catenin pathway was involved in the OPN signaling. Furthermore, Ly294002, a specific PI3K inhibitor, can reverse the promotion of bioactivities and stem cell proportion among rhOPN treated CRC cells.ConclusionsOPN promoted cell proliferation, migration, and invasion, and was accompanied by upregulation of ALDH1-positive CSC in CRC through activation of PI3K-Akt-GSK/3β-β/catenin pathway.

Protective and therapeutic benefits of environmental enrichment on binge-like sucrose intake in C57BL/6J mice

Binge eating disorder (BED) is characterized, in part, by recurrent episodes of eating large quantities of food in a short period of time. Repetitive binge episodes are a common pattern of consumption during the early stages of substance abuse, and it has been proposed that binge patterns of consumption might favor the transition to BED and “food addiction”. Therefore, it is of paramount importance to provide new behavioral strategies that protect vulnerable binge-prone individuals from transitioning to BED and food addiction. Recently, we showed protective and therapeutic benefits of environmental enrichment (EE) on binge-like intake of ethanol in C57BL/6J mice, in agreement with previous evidence showing EE modulation of drug intake, drug relapse and drug reward. In the present study, adolescent mice reared under EE conditions were evaluated for binge-like consumption of sucrose during adulthood in a long-term drinking in the dark (DID) procedure that effectively models binge consumption in humans. Additionally, we tested binge-like intake in adults reared under standard conditions (SE) with long-term exposure to sucrose DID and the effects on sucrose DID of switching from SE to EE conditions. We report here, for the first time, that early EE exposure protects mice from binge-like excessive sucrose intake during adulthood. Ongoing binge-like high sucrose intake in SE-reared mice was also significantly reduced when switched to EE conditions. The present observations suggest that EE exposure might be a promising tool for preventing repetitive binge-like sucrose consumption from transitioning to BED and food addiction.

Environmental Enrichment During Adulthood Reduces Sucrose Binge-Like Intake in a High Drinking in the Dark Phenotype (HD) in C57BL/6J Mice.

Repetitive binge episodes favor transition to binge-eating disorders. Experimental evidence points to positive influence of environmental enrichment (EE) on drug/food addiction, although far less is known regarding EE effects over binge-like consumption. Here, we evaluate the following: (1) whether switching from nonenriched standard environment (SE) to EE housing conditions during adulthood alters a stable pattern of voluntary sucrose (10% w/v) binge-like intake in high (HD) vs. low (LD) drinking phenotypes under a drinking in the dark (DID) schedule; and (2) sucrose binge-like intake in a DID task in response to a pharmacological challenge with an OXr1 antagonist in HD/LD subpopulations after long-term exposure to SE or EE conditions. Adolescent (postnatal day 21; PND21) mice were housed in SE conditions. At PND65, all animals were long-term exposed to sucrose DID. On the first episode of DID (PND65), animals were divided into HD vs. LD subpopulations according to their sucrose intake. On PND85, an OXr1 antagonist test was conducted on HD and LD mice with SB-334867 (SB) administration. On PND95, HD and LD subpopulations were again randomly allocated into two subgroups, resulting in the following experimental conditions: HD-SE, HD-EE, LD-SE and LD-EE. Sucrose binge-like intake continued until PND116, when a second SB test was conducted. The main findings are: (1) a single 2 h episode of sucrose binge drinking in a DID procedure consistently segregates two behavioral subpopulations, HD and LD; (2) when adult mice in standard conditions and long-term exposed to sucrose DID were switched to EE conditions, an immediate reduction in sucrose binge-like intake was observed in HD mice, pointing to a therapeutic role of EE exposure; and (3) administration of the OXr1 antagonist caused an acute reduction in sucrose binge-like intake in HD and LD mice exposed to SE conditions. Importantly, exposure to EE conditions blunted the inhibitory effect of SB on sucrose binge consumption in both behavioral phenotypes, indirectly suggesting a potential EE/OXr1 signaling interaction. We propose the hypothesis that EE might regulate OX-dependent anxiety/compulsivity brain systems, which might secondarily modulate sucrose binge-like intake.

Alternation in dopamine D2-like and metabotropic glutamate type 5 receptor density caused by differing housing conditions during abstinence from cocaine self-administration in rats.

Environmental conditions have an important function in substance use disorder, increasing or decreasing the risks of relapse. Several studies strongly support the role of the dopamine D2-like and metabotropic glutamate type 5 receptors in maladaptive neurobiological responses to cocaine reward and relapse. The present study employed cocaine self-administration with yoked-triad procedure in rats to explore whether drug abstinence in different housing conditions affects the drug-seeking behaviour and the dopamine D2-like and metabotropic glutamate type 5 receptor density and affinity in several regions of the animal brain. Rats were trained to self-administer cocaine and later they were forced to abstain either in: (a) enriched environment or (b) isolation cage conditions to evaluate the effect of housing conditions on the drug-seeking behaviour and to assess changes concerning receptors in animals brain. Our results show that exposure to enriched environment conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated a significant increase in the dopamine D2-like receptor density in the prefrontal cortex in animals following drug abstinence in isolation cage or enriched environment conditions, and the reduction in their density in the dorsal striatum provoked by isolation cage conditions. The metabotropic glutamate type 5 receptor density decreased only in the prefrontal cortex after isolation cage and enriched environment abstinence. This study shows the different impacts caused by the type of housing conditions during abstinence from cocaine self-administration on drug-seeking behaviour in rats. The observed changes in the dopamine D2-like and metabotropic glutamate type 5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of cocaine.

Intermittent Administration of Haloperidol after Cortical Impact Injury Neither Impedes Spontaneous Recovery Nor Attenuates the Efficacy of Environmental Enrichment

The administration of haloperidol (HAL) once-daily for 19 days after experimental traumatic brain injury (TBI) impedes recovery and attenuates the efficacy of environmental enrichment (EE). However, it is unknown how intermittent administration of HAL affects the recovery process when paired with EE. Addressing the uncertainty is relevant because daily HAL is not always warranted to manage TBI-induced agitation in the clinic, and indeed intermittent therapy may be a more common approach. Hence, the aim of the study was to test the hypothesis that intermittent HAL would neither impair recovery in standard (STD)-housed controls nor attenuate the efficacy of EE. Anesthetized adult male rats received a cortical impact or sham injury and then were housed in STD or EE conditions. Beginning 24 h later, HAL (0.5 mg/kg; intraperitoneally [i.p.]) was administered either once-daily for 19 days or once every other day, whereas vehicle (VEH; 1 mL/kg; i.p.) was administered once daily. Motor performance and cognition were assessed on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. SHAM controls performed better than all TBI groups on motor and spatial learning [p < 0.05], but did not differ from the TBI + EE + daily VEH group on memory retention [p > 0.05]. The TBI + EE + daily VEH and TBI + EE + intermittent HAL groups did not differ from one another on beam-walk or spatial learning [p > 0.05], and both performed better than all other TBI groups [p < 0.05]. In contrast, the TBI + STD + daily HAL group performed worse than all TBI groups on spatial learning [p < 0.05]. No difference in any endpoint was revealed between the TBI + STD + intermittent HAL and TBI + STD + daily VEH groups [p > 0.05]. The results support the hypothesis that HAL is not detrimental when provided intermittently. If translatable to the clinic, intermittent HAL may be used to control TBI-induced agitation without negatively affecting spontaneous recovery or rehabilitative efficacy.

Short-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington's Disease Transgenic Mice.

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.

Changes in the function and phenotype of resident peritoneal macrophages after housing in an enriched environment

Exposure to an enriched environment (EE) affects not only brain functions but also immune responses upon viral or bacterial infections. In this study, we examined changes in the phagocytic response and chemokine production of resident peritoneal macrophages after mice had been housed under EE conditions for 6 or 8 weeks, and then explored the possibility that EE could cause a change in the macrophage phenotype by means of flow cytometry as well as quantitative RT-PCR. The percentages of EE macrophages phagocytosing S. aureus and apoptotic neutrophils were significantly larger than those of standard environment (SE) macrophages. After coculturing with S. aureus, EE macrophages tended to produce greater amounts of chemokines such as MIP-2, KC and MCP-1 than SE ones, although the increases for MIP-2 and KC were not statistically significant. As compared with SE macrophages, EE macrophages included more CD40-positive cells (M1 marker), and expressed more mRNAs of IL-6 (M1 marker) and IRF4 (M2 marker), and less mRNA of CD38 (M1 marker), suggesting either the possibility that EE macrophages are a mixed population of M1 and M2 macrophages or the possibility that they are a unique population with a mixed M1 and M2 macrophage phenotype.

Environmental Enrichment During Adolescence Acts as a Protective and Therapeutic Tool for Ethanol Binge-Drinking, Anxiety-Like, Novelty Seeking and Compulsive-Like Behaviors in C57BL/6J Mice During Adulthood.

Repetitive drug/ethanol (EtOH) binge-like consumption during pre-addictive stages favors a transition to addiction in vulnerable organisms. Experimental evidence points to the therapeutic and preventive effects of environmental enrichment (EE) on drug and EtOH addiction; however, little is known regarding EE modulation of binge-like consumption in non-dependent organisms. Here, we explore the impact of early EE on binge-like EtOH consumption: (1) we test whether early EE exposure prevents binge-like EtOH intake (20% v/v) in adult mice under an intermittent drinking in the dark (iDID) schedule; (2) we evaluate the therapeutic effects of EE housing conditions on binge-like EtOH consumption in adult animals; and (3) we compare novelty-seeking and compulsive-like behaviors, and anxiety-like behavior, as measured by the Hole Board (HB) and Elevated Plus Maze (EPM) tests, respectively, in adult EE/standard environment (SE) animals. Adolescent (postnatal day 28; PND28) mice were randomly allocated to two housing conditions (4 animals/cage): EE or SE. At PND67 all the animals were exposed to a schedule of EtOH binge-like iDID. On PND92 half of the animals in each environmental condition (EE and SE) were randomly allocated to two subgroups in a crossover design, where environmental conditions were kept similar to those previously experienced or switched, finally leading to four experimental conditions: EE-EE, EE-SE, SE-SE, and SE-EE. EtOH binge-like consumption continued until PND140, when EPM and HB tests were finally conducted. The main observations were: (1) EE-reared mice showed lower EtOH binge-like intake than SE-reared mice during adulthood, which supports a protective role for EE. (2) when adult EtOH drinking SE-reared mice were switched to EE conditions, a reduction in EtOH binge-like consumption was observed, suggesting a therapeutic role for EE; however, losing EE during adulthood triggered a progressive increase in EtOH binge-like intake. Moreover, (3) EE-housed adult animals with long-term exposure to EtOH binge-drinking showed lower anxiety-like, compulsive-like, and novelty-seeking behaviors than SE-housed mice, irrespective of the specific housing conditions during adolescence. We discuss the primary impact of EE on anxiety-like neurobehavioral brain systems through which it secondarily modulates EtOH binge-like drinking.

Environmental Enrichment Results in Both Brain Connectivity Efficiency and Selective Improvement in Different Behavioral Tasks

Exposure to environmental enrichment (EE) has been a useful model for studying the effects of experience on brain plasticity, but to date, few is known about the impact of this condition on the brain functional networks that probably underlies the multiple behavioral improvements. Hence, we assessed the effect of an EE protocol in adult Wistar rats on the performance in several behavioral tasks testing different domains (Open field (OP): locomotor activity; Elevated-zero maze (EZM): anxiety-related behaviors; 5-choice serial reaction time task (5-CSRTT): attentional processes; 4-arm radial water maze (4-RAWM): spatial memory) in order to check its effectiveness in a wide range of functions. After this, we analyzed the functional brain connectivity underlying each experimental condition through cytochrome C oxidase (COx) histochemistry. Our EE protocol reduced both locomotor activity in the OP and anxiety-related behaviors in the EZM. On the other hand, enriched rats showed more accuracy in the 4-RAWM, whereas 5-CSRTT performance was not significantly ameliorated by EE condition. In relation to COx functional connectivity, we found that EE reduced the number of strong positive correlations both in basal and training conditions, suggesting a modulating effect on specific brain connections. Our results suggest that EE seems to have a selective effect on specific brain regions, such as prefrontal cortex and hippocampus, leading to a more efficient brain connectivity.

Enriched environment prevents oxidative stress in zebrafish submitted to unpredictable chronic stress.

BackgroundThe enriched environment (EE) is a laboratory housing model that emerged from efforts to minimize the impact of environmental conditions on laboratory animals. Recently, we showed that EE promoted positive effects on behavior and cortisol levels in zebrafish submitted to the unpredictable chronic stress (UCS) protocol. Here, we expanded the characterization of the effects of UCS protocol by assessing parameters of oxidative status in the zebrafish brain and reveal that EE protects against the oxidative stress induced by chronic stress.MethodsZebrafish were exposed to EE (21 or 28 days) or standard housing conditions and subjected to the UCS protocol for seven days. Oxidative stress parameters (lipid peroxidation (TBARS), reactive oxygen species (ROS) levels, non-protein thiol (NPSH) and total thiol (SH) levels, superoxide dismutase (SOD) and catalase (CAT) activities were measured in brain homogenate.ResultsOur results revealed that UCS increased lipid peroxidation and ROS levels, while decreased NPSH levels and SOD activity, suggesting oxidative damage. EE for 28 days prevented all changes induced by the UCS protocol, and EE for 21 days prevented the alterations on NPSH levels, lipid peroxidation and ROS levels. Both EE for 21 or 28 days increased CAT activity.DiscussionOur findings reinforce the idea that EE exerts neuromodulatory effects in the zebrafish brain. EE promoted positive effects as it helped maintain the redox homeostasis, which may reduce the susceptibility to stress and its oxidative impact.

An Enriched Environment Ameliorates Oxidative Stress and Olfactory Dysfunction in Parkinson’s Disease with α-Synucleinopathy

Parkinson’s disease (PD) features nonmotor symptoms such as olfactory dysfunction referred to as hyposmia, an initial sign of disease progression. Metabolic dysfunction can contribute to neurodegenerative diseases, and various xenobiotics and endogenous compounds are also involved in the pathogenesis of PD. Although aerobic exercise was found to induce preservation or improvement in olfactory function in PD patients in a recent study, the exact underlying mechanism for this effect is not clear. We aimed to investigate the influence of an enriched environment (EE) on olfactory dysfunction especially via metabolic pathways related to detoxification enzymes. Eight-month-old transgenic (Tg) PD mice that overexpress human A53T α-synuclein (α-syn) were randomly allocated to an EE or standard conditions for 2 mo. The buried food test showed that EE group had significantly improved olfactory function compared to the control group. Reverse transcription polymerase chain reaction (PCR) and real-time quantitative PCR showed that expression of the detoxification enzymes––cytochrome P450 family 1 subfamily A member 2, paraoxonase 1, alcohol dehydrogenase 1, UDP glucuronosyltransferase family 2 member A1 complex locus, aldehyde oxidase homolog 2, and aldehyde glutathione peroxidase 6––was significantly increased in the olfactory bulb (OB) of the PD control group, but these enzymes were normalized in the EE group. Immunohistochemical staining of the OB showed that oxidative stress and nitrated α-syn were significantly increased in the control group but decreased in the EE group. In conclusion, we suggest that exposure to an EE decreases both oxidative stress and nitrated α-syn, resulting in normalized detoxification enzymes and amelioration of olfactory dysfunction.