Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview
Abstract
:1. Introduction
1.1. Lipopolysaccharide (LPS)
1.2. Environmental Enrichment (EE)
2. Methodology of the Literature Search
- As the population of interest, we selected rodents, both healthy and pathological models, with no sex or age restrictions.
- As the intervention of interest, we selected multidimensional EE exposure of animals submitted to LPS treatment carried out in any period of life, before or after the exposure to EE. For models based on transgenerational and MIA models, studies on enriched mothers and LPS-injected pups, and vice versa, were also considered.
- As the control group of interest, we selected animals submitted to LPS treatment and reared under standard laboratory conditions.
- As outcomes of interest, we selected cognitive, emotional, motor, and social effects and related structural, physiological, or biochemical processes.
3. Beneficial Effects of Exposure to EE on Neuroinflammation Induced by LPS Injections
- The first section reports the findings related to the beneficial effects of EE in case of prenatal neuroinflammation induced by LPS injections. The beneficial effects provided by exposure to EE for mother and offspring, respectively, are described.
- The second section is devoted to the beneficial effects of EE in case of neuroinflammation induced by LPS injections in early age.
- Finally, the third section includes the beneficial effects of EE in case of neuroinflammation induced by LPS injections in adult age.
3.1. Beneficial Effects of Exposure to EE on Mothers and Offspring in Case of Gestational Neuroinflammation Induced by LPS Injection
3.1.1. Beneficial Effects of the Mother’s Exposure to EE in Case of Gestational Inflammation Induced by LPS Injection
3.1.2. Beneficial Effects of the Offspring’s Exposure of EE in Case of Gestational Inflammation Induced by LPS Injection
3.2. Beneficial Effects of Exposure to EE in Case of Early Postnatal Neuroinflammation Induced by LPS Injection
3.3. Beneficial Effects of Exposure to EE in case of Neuroinflammation Induced in Adulthood by LPS Injection
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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References | Species | Environmental Enrichment | LPS Injection(s) | ||
---|---|---|---|---|---|
(Age and Timing of Evaluations) | Type of Enrichment | Subjects and Duration | (Time and Dose) | ||
EE on dams | Schander et al., 2020 [84] | BALB/c mice Dams: 6 weeks (Effects on: mothers (pregnancy)) | Large cage (640 × 420 × 200 mm) with running wheels and objects (toys, tunnels, shelters, and stairs) of different shapes, textures, and colors changed once a week. Every 3–4 days, one object removed, moved, or added. Ten animals per cage. | On dams: EE for 6 weeks; mating (regular cages); EE until G15. | On dams: G15, two i.p. injections of LPS (1°—0.13 mg/kg; 2°—0.39 mg/kg). (LPS after EE protocol) |
Schander et al., 2021 [85] | BALB/c mice Dams: 6 weeks (Effects on: mothers (pregnancy); offspring (P 1–P 22) | Large cage (640 × 420 × 200 mm) with running wheels and objects (toys, tunnels, shelters and stairs) of different shapes, textures, and colors changed once a week. Every 3–4 days, one object removed, moved or added. Ten animals per cage. | On dams: EE for 6 weeks; mating (regular cages); EE until G15. | On dams: G15, two i.p. injections of LPS (1°—0.13 mg/kg; 2°—0.39 mg/kg). (LPS after EE protocol) | |
Zhuang et al., 2021 [86] | CD-1 mice Dams: 7/8 weeks (Effects on: mothers (after pregnancy)) | Large cage (52 × 40 × 20 cm3) with toys (running wheels, tunnels, poplar wood block toys, and rings). Ten to fifteen animals per cage. | On dams: EE from weaning of pups until about 6 or 18 months of age of the mothers. | On dams: G15–17, daily i.p. injection of LPS (50 μg/kg). (LPS before EE protocol) | |
EE on offspring | Connors et al., 2014 [87] | Sprague–Dawley rats Dams: age not specified (Effects on: offspring (P 36–P 40)) | Multi-level cage with toys changed two times weekly, tubes, chew bone, Nestlets©, and ramps. Pair-housed animals. | On dams: EE for about 2 months. On pups: EE from P 1 to P 40. | On dams: G11, i.p. injection of LPS (100 μg/kg). (LPS during EE protocol) |
Rajesh et al., 2016 [88] | Wistar rats Dams: 3 months (Effects on: male offspring (P 61–P 66)) | EE: Large cage (120 × 100 × 100 cm) with plastic tunnels, raised platform with ladder, various size metal balls, toys, and steel swing. Objects were changed on alternate days. Treadmill running exercise: 1.5 m/min–10.9 m/min; 15 min/day. Number of animals per cage not specified. | On pups: EE (4 h/day) or/and treadmill from P 15 to P 60. | On dams: From G14 till parturition on alternate days i.p. injection of LPS (0.5 mg/Kg). | |
Rajesh et al., 2018 [89] | Wistar rats Dams: 3 months (Effects on: male offspring (P 67)) | EE: Large cage (120 × 100 × 100 cm) with plastic tunnels, raised platform with ladder, various size metal balls, toys, and steel swing. Objects were changed on alternate days. Treadmill running exercise: 1.5 m/min -10.9 m/min; 15 min/day. Number of animals per cage not specified. | On pups: EE (4 h/day) or/and treadmill from P 15 to P 60. | On dams: From G14 till parturition on alternate days i.p. injection of LPS (0.5 mg/Kg). | |
Bakos et al., 2004 [90] | Wistar rats Dams: 8th day-pregnant—age not specified (Effects on: male offspring (~P 83)) | Large cage (1 m × 0.5 m × 0.5 m) with bedding changed once a week, running wheels, wooden swings, plastic tubes, and beams changed three times a week. Occasionally added pieces of food (nuts, apples). Six animals per cage. | On pups: EE after weaning, for 2 months. | On dams: G15–19, daily subcutaneous injection of LPS in increasing doses of 20, 20, 40, 40, 80 μg/kg/mL. | |
Kentner et al., 2016 [91] | Sprague-Dawley rats Dams: 12th day- pregnant—age not specified (Effects on: male offspring (~P 92)). | Communal nesting: larger-style one-level cage with tube, chew bone, and Nestlets©. Four animals per cage. EE: multi-level cage with chew bone, Nestlets©, ramps, novel toys, and tubes. Toys and tubes changed twice a week. Four animals per cage. | On pups: EE from P 50, for 6 weeks. | On dams: G15 i.p. injection of LPS (100 μg/kg). | |
Wu et al., 2020 [92] | CD-1 mice Dams: 8 weeks (Effects on: male offspring (3 months old; 15 months old)) | Large cage with pipes, plastic running wheels, balls, and toys changed every week. Number of animals per cage not specified. | On pups: EE from 2 months of age until 3 or 15 months of age. | On dams: G15–17, daily i.p. injection of LPS (50 μg/kg). | |
Zhang et al., 2022 [93] | CD-1 mice Dams: 6/8 weeks (Effects on: male offspring (3 months old; 15 months old)) | Large cage (36 × 23 × 18 cm) with climbing ladders, running wheel, ball, plastic and wooden objects suspended from the cage top, paper, cardboard boxes, nesting material, and toys (changed every 1–2 days). Eight animals per cage. | On pups: EE after weaning until 3 or 15 months of age. | On dams: G15–17, daily i.p. injection of LPS (50 μg/kg). | |
Zhao et al., 2020 [94] | Sprague-Dawley rats Dams: 12th day- pregnant—age not specified (Effects on: female offspring (~P 92)) | Communal nesting: larger-style one-level cage with tube, chew bone, and Nestlets©. Four animals per cage. EE: multi-level cage with chew bone, Nestlets©, ramps, novel toys, and tubes. Toys and tubes changed twice a week. Four animals per cage. | On pups: EE from P 50, for 6 weeks. | On dams: G15 i.p. injection of LPS (100 μg/kg). | |
Zeraati et al., 2021 [95] | NMRI mice Dams: 70–80 days (Effects on: offspring—(P 121–P 142)) | Cage (58 × 38 × 20 cm) with one running wheel, two plastic shelters, four tunnels, and two cotton nestlets replaced once a week. Four animals per cage. | On pups: EE from P 21 to P 120. | On dams: G17, i.p. injection of LPS (300 μg/kg/100 μL). |
References | Main Effects of Environmental Enrichment | ||
---|---|---|---|
On Mothers | On Offspring | ||
Schander et al., 2020 [84] | EE reduced - body weight gain in nonpregnant mice; - cholesterol and triglycerides serum levels in pregnant mice;- LPS-induced preterm birth rate and offspring perinatal death (by 40%); - expression of TLR4 and CD14 in the uterus of LPS-challenged mice. EE prevented - LPS-induced increase in corticosterone serum levels; - LPS-induced neutrophil infiltration into the cervix as well as metalloprotease activity in this tissue. EE induced molecular changes in uterus and cervix of LPS-induced preterm birth mice. | ||
Schander et al., 2021 [85] | EE modulated - white blood cell count and its response to systemic LPS administration; - amniotic fluid response to LPS administration, promoting a tolerogenic microenvironment. | EE prevented the negative influence of intrauterine exposure to an inflammatory environment on physical landmarks (pinnae detachment, lower incisors eruption, eye opening) of the offspring’s development during lactation. | |
Zhuang et al., 2021 [86] | Long-term exposure to EE - reduced spatial learning and memory impairment (MWM) in aged dams resulting from LPS-induced gestational inflammation; - improved dynamics in hippocampi of LPS-injected dams; - alleviated the accelerated changes in mitochondrial biogenesis and mitophagy resulting from gestational inflammation in aged mice. | ||
EE on offspring / EE on dams | Connors et al., 2014 [87] | EE prevented - elevations in hippocampal corticosterone level; - decreased glucocorticoid receptor expression in hippocampus; - reductions in social contact (SI) in juvenile male rats treated with LPS in utero. | |
Rajesh et al., 2016 [88] | Rats of LPS + EE + exercise group showed a significant enhancement in learning and memory performance (MWM), compared with other groups. | ||
Rajesh et al., 2018 [89] | Rats of LPS + EE + exercise group showed a significant enhancement in dendritic arborization of CA3 hippocampal neurons, compared with other groups. | ||
Bakos et al., 2004 [90] | EE reversed LPS-induced nucleus accumbens dopamine level decrement. | ||
Kentner et al., 2016 [91] | EE prevented the LPS-induced reduction of the expression of the EAAT-2 gene in the PFC; EE mitigated LPS-induced downregulation of BDNF in the hippocampus and neurotrophic tyrosine kinase receptor type 2 genes in PFC; colony nesting mitigated LPS-induced spatial and object memory impairment (object-in-place test). | ||
Wu et al., 2020 [92] | EE alleviated LPS-induced memory impairments (MWM) in middle-aged mice. | ||
Zhang et al., 2022 [93] | EE improved learning and memory performance (MWM) deteriorated by LPS injection; EE reduced protein and mRNA levels of Arc and Syt1 genes in the hippocampus increased by LPS injection. | ||
Zhao et al., 2020 [94] | EE attenuated - recognition memory (object-in-place test) deficits observed in MIA offspring; - social (SI) deficits observed in MIA offspring; - the elevation of plasma corticosterone in MIA offspring. | ||
Zeraati et al., 2021 [95] | EE improved - anxiety-like behavior in LPS offspring treated with water or PTZ compared to control groups (open field; light–dark box); - spatial working memory in LPS offspring treated with PTZ compared to control groups (Y-maze); - recognition ratio in LPS offspring treated with PTZ compared to control groups (novel object recognition test). EE decreased - Seizure scores; - TNF-α and IL-10 levels in the hippocampus of LPS offspring treated with PTZ compared to normal-PTZ LPS offspring. |
References | Species | Environmental Enrichment | LPS Injection(s) | |
---|---|---|---|---|
(Age and Timing of Evaluations) | Type of Enrichment | Subjects and Duration | (Time and Dose) | |
MacRae et al., 2015 [120] | Sprague–Dawley rats Dams: age not specified Pups: newborn (Evaluation of effects in male and female offspring (P 40–P 90)) | Large multi-level cage with toys and tubes changed twice weekly, chew bone, Nestlets©, and ramps. Four to six animals per cage. | On dams: EE was conducted from breeding to weaning of pups. On pups: EE was conducted from birth to the end of the experiment (P 1–P 90). | On pups: P 3 and P 5, 2 i.p. injections of LPS (50 μg/kg). (LPS administered when EE protocol is already ongoing) |
Wu et al., 2022 [121] | C57BL/6 mice. Pups: 10 days (Evaluation of effects in male offspring P 39–P 42) | Cage (60 × 32 × 38 cm) with running wheel, swing, platforms and toys. Objects were changed twice a week. Number of animals per cage not specified. | On pups: EE was conducted four hours per day during P 10–P 38. | On pups: P 10, i.p. injection of LPS (100 μg/kg). (LPS before EE protocol) |
Pavlova et al., 2022 [122] | Wistar rats Pups: newborn (Evaluation of effects in male and female offspring P 90–P 105) | Plastic box (51 × 40.5 × 30 cm) containing stairs, a running wheel, tubes, and materials for burying (sawdust, foam filler, paper, etc.). Four to six animals per cage. | On pups: EE was conducted for 20 min every other day, from the age of 45 days until the end of experiment (~3.5 months). | On pups: P 3 and P 5, 2 i.p. injection of LPS (dose of 50 μg/kg in a volume of 10 μL/g). (LPS before EE protocol) |
References | Main Effects of Environmental Enrichment | |
---|---|---|
On Mothers | On Offspring | |
MacRae et al., 2015 [120] | EE dams started retrieving pups earlier and reunited the entire litter more quickly than standard-housed rats. | EE partially protected against the consequences of inflammation on juvenile social (social interaction test) behavior. EE prevented LPS-induced glutathione level reduction in the juvenile PFC. |
Wu et al., 2022 [121] | EE improved LPS-induced working memory impairment (Y-maze). EE attenuated - LPS-induced microglial activation in the hippocampus and mPFC; - LPS-induced loss of dendritic spines in the hippocampus. EE reversed LPS-induced decrease in parvalbumin expression in the hippocampus and mPFC. | |
Pavlova et al., 2022 [122] | EE increased anxiety (open field) and depression-like behavior (sucrose preference test) in female LPS group. |
References | Species | Environmental Enrichment | LPS Injection(s) |
---|---|---|---|
(Age) | (Type and Duration) | (Time and Dose) | |
Mlynarik et al., 2004 [123] | Male Wistar rats 2 months | Plexiglas box (1 × 0.5 × 0.5 m) with sawdust straw bedding, several platforms, swings, and a variety of miscellaneous objects (plastic boxes, tunnels, cartons, iron ladders, glass bottles, laboratory beakers, natural branches, water pools, spin wheels). The floor configuration was changed every second working day and aforementioned items were randomly put in or taken out at the same time. A small amount of extra food (e.g., pieces of apples or oranges, peanuts, dried bread, and curd) were occasionally served or hidden in the straw bedding. Ten animals per cage. EE was conducted for ~5 weeks. | Daily i.p. injection of LPS in increasing doses of 10, 10, 20, 20, and 40 μg/kg/mL for 5 consecutive days. (LPS after EE protocol) |
Williamson et al., 2012 [124] | Male Sprague-Dawley rats 60 days | Boxes (55.9 × 35.6 × 30.5 cm) contained quarter-inch corn-cob bedding, a running wheel, a PVC tube, and various small objects and toys. Pair-housed animals. EE was conducted for 7 weeks for 12 h per day. | i.p. injection of LPS (100 μg/kg). (LPS after EE protocol) |
Kawano et al., 2014 [125] | Male Wistar rats 24–25 months | Large cage equipped with plastic toys, a tunnel, a ladder, a platform, nesting material, and a running wheel. Items were routinely rearranged during the experimental period. The multi-modal sensory stimulations were conducted by a buzzer sound (167 Hz), a blinking light-emitting diode (LED) light (3 Hz), and vibration (60 dB) for 1 min using a multi-digital tuner three times daily during the active phase. Pair-housed animals. EE was conducted for 7 days. | i.p. injection of LPS (5 mg/kg). (LPS before EE protocol) |
Keymoradzadeh et al., 2020 [126] | Male Wistar rats 7 weeks | Large cage (96 × 49 × 38 cm) containing running wheels, a tunnel, a small compartment, stairs, and many other colorful objects (e.g., colorful plastic plates, wooden disks of varied colors and sizes, plastic cups, and hanging cubes). Objects were changed every day. Number of animals per cage not specified. EE was conducted for 21 days (3 weeks). | i.p. injection of LPS (1 mg/kg) days 1, 3, 5, and 7. (LPS before EE protocol) |
Keymoradzadehet al., 2022 [127] | Male Wistar rats 7 weeks | Large cage (96 × 49 × 38 cm) containing running wheels, a tunnel, a small compartment, stairs, and many other colorful objects (e.g., colorful plastic plates, wooden disks of varied colors and sizes, plastic cups, and hanging cubes). Objects were changed every day. Number of animals per cage not specified. EE was conducted for 21 days (3 weeks). | i.p. injection of LPS (1 mg/kg) days 1, 3, 5, and 7. (LPS before EE protocol) |
Ji et al., 2017 [128] | Male C57BL/6 mice 3-4 months | Large cage (60 cm × 35 cm × 20 cm) containing a small house, a running wheel for voluntary exercise, and four to five toys that were exchanged three times a week for new toys of different shape and colors. Four to six animals per cage. EE was conducted for 4 weeks. | i.p. injection of LPS (5 mg/kg). (LPS before EE protocol) |
Aranda et al., 2019 [129] | Male Wistar rats 2 months | Big cages (46.5 × 78 × 95 cm) containing 4 floors and several food hoppers, water bottles, running wheels, tubes, ramps, and differently shaped objects (balls, ropes, stones) repositioned once a day and fully substituted once a week. Six animals per cage. Animals were continuously exposed to standard enrichment or EE during different intervals (21, 17, 14, or 3 days). | An amount of 1 μL of 4.5 μg/μL LPS in pyrogen-free saline locally injected in the optic nerve. (LPS before EE protocol) |
References | Main Effects of Environmental Enrichment |
---|---|
Mlynarik et al., 2004 [123] | EE prevented - LPS-induced transient decrease in body weight; - LPS-induced increase in plasma and adrenal corticosterone levels. |
Williamson et al., 2012 [124] | EE increased - density of glial markers within the DG altered by LPS injection; - BDNF mRNA in the hippocampus decreased by LPS injection. EE attenuated hippocampal response to LPS for a subset of cytokines and chemokines. |
Kawano et al., 2014 [125] | Multisensory early rehabilitation environment reverted - LPS-induced memory impairment (novel object recognition test); - LPS-induced elevation of TNF-a and IL-1b levels in hippocampus. |
Keymoradzadeh et al., 2020 [126] | EE ameliorated LPS-induced spatial learning and memory impairment (Morris water maze). EE counteracted LPS-induced increase of hippocampal IL-1β levels. EE further augmented LPS-induced increase of the hippocampal IL-10 levels. |
Keymoradzadeh et al., 2022 [127] | EE counteracted LPS-induced memory impairment (passive avoidance test). EE counteracted LPS-induced increase of IL-6 levels and decrease of BDNF levels in hippocampus. |
Ji et al., 2017 [128] | EE reverted - LPS-induced hippocampal and non-hippocampal-dependent cognitive impairment (fear conditioning test); - LPS-induced increased hippocampal IL-6 expression. |
Aranda et al., 2019 [129] | EE rescued - LPS-induced decrement in pupil light reflex, visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament immunoreactivity, myelination, axon and retinal ganglion cell number; - LPS-induced optic nerve oxidative damage and LPS-increased optic nerve inducible nitric oxide synthase, cyclooxygenase-2, and IL-1b and TNF-α mRNA. EE counteracted the microglial/macrophage reactivity and astrocytosis observed in LPS group. |
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Landolfo, E.; Cutuli, D.; Decandia, D.; Balsamo, F.; Petrosini, L.; Gelfo, F. Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview. Int. J. Mol. Sci. 2023, 24, 5404. https://doi.org/10.3390/ijms24065404
Landolfo E, Cutuli D, Decandia D, Balsamo F, Petrosini L, Gelfo F. Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview. International Journal of Molecular Sciences. 2023; 24(6):5404. https://doi.org/10.3390/ijms24065404
Chicago/Turabian StyleLandolfo, Eugenia, Debora Cutuli, Davide Decandia, Francesca Balsamo, Laura Petrosini, and Francesca Gelfo. 2023. "Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview" International Journal of Molecular Sciences 24, no. 6: 5404. https://doi.org/10.3390/ijms24065404