Long-Term Environmental Enrichment Relieves Dysfunctional Cognition and Synaptic Protein Levels Induced by Prenatal Inflammation in Older CD-1 Mice

Abstract

A mounting body of evidence suggests that prenatal inflammation may enhance the rate of age-associated cognitive decline and may involve aberrant amounts of synaptic proteins in the hippocampus, including synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc). However, little is known about the specific impact of adolescent environmental enrichment (EE) on age-associated cognitive decline and the changes in synaptic proteins caused by prenatal inflammation. In this study, CD-1 mice in late pregnancy were given intraperitoneal doses of lipopolysaccharide (LPS, 50 μg/kg) or normal saline. Offspring arising from LPS dams were divided into a LPS group and a LPS plus EE (LPS-E) group. The LPS-E mice were exposed to EE from 2 months of age until the end of the experiment (3 or 15 months old). The Morris water maze (MWM) was used to assess the spatial learning and memory capacities of experimental mice, while western blotting and RNA-scope were used to determine the expression levels of Arc and Syt1 in the hippocampus at the protein and mRNA levels, respectively. Analysis revealed that at 15 months of age, the control mice experienced a reduction in cognitive ability and elevated expression levels of Arc and Syt1 genes when compared to control mice at 3 months of age. The LPS-E group exhibited better cognition and lower protein and mRNA levels of Arc and Syt1 than mice in the LPS group of the same age. However, the enriched environment mitigated but did not counteract, the effects of prenatal inflammation on cognitive and synaptic proteins when tested at either 3 or 15 months of age. Our findings revealed that long-term environmental enrichment improved the expression levels of synaptic proteins in CD-1 mice and that this effect was linked to the dysfunctional cognition caused by prenatal inflammation; this process may also be involved in the reduction of hippocampal Arc and Syt1 gene expression.

Environmental Enrichment Reverses Maternal Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Impairment in CD-1 Mice

“…The results are in accordance with a previous report that upregulation of Syt-1 in the hippocampus has been found to cause neuron damage associated with prenatal stress-and hypothyroidism-induced cognitive impairment (Vara et al, 2002;Jia et al, 2010). Moreover, EE could improve MSD associated-cognitive deficits by reducing Syt-1 expression, which was consistent with our previous study that exposure to an EE from adolescence improved age-associated cognitive decline by downregulating the expression of Syt-1 (Zhang et al, 2022). The contradictory results regarding the relationship between Syt-1 expression level and cognitive function could be a result of differences in the specific mechanisms leading to cognitive impairment in different pathological models.…”

Altered cognition and anxiety in adolescent offspring whose mothers underwent different-pattern maternal sleep deprivation, and cognition link to hippocampal expressions of Bdnf and Syt-1

“…The offspring were reared up to adolescence (2-month-old) after birth (Spear, 2000 ; Kota et al, 2011 ; Zhang Z. Z. et al, 2022 ). Finally, a total of 16 mice, including 8 males and 8 females, were included in each group for behavioral analyses, western blotting, and RT-PCR experiments.…”

Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview

“…More recently, studies based on MIA induced by daily i.p. LPS injections during G 15–17 showed that spatial learning and memory of pups were impaired until middle age [ 92 , 93 ], suggesting that embryonic inflammation may accelerate the cognitive impairment associated with brain aging. Mice about 8-weeks-old were exposed to EE from 2 months of age [ 92 ] or from weaning [ 93 ] until the end of the experiments, i.e., about 3 or 15 months of age.…”

“…LPS injections during G 15–17 showed that spatial learning and memory of pups were impaired until middle age [ 92 , 93 ], suggesting that embryonic inflammation may accelerate the cognitive impairment associated with brain aging. Mice about 8-weeks-old were exposed to EE from 2 months of age [ 92 ] or from weaning [ 93 ] until the end of the experiments, i.e., about 3 or 15 months of age. EE alleviated deficits of hippocampal synaptic plasticity (hippocampal expression of the RNA-binding protein Staufen), memory performance, and anxiety symptoms caused by embryonic inflammation [ 92 ].…”

“…High levels of activity-regulated cytoskeleton-associated protein (Arc) and synaptotagmin-1 (Syt1) genes were observed in middle-aged mice of LPS-injected dams. Once more, a beneficial effect of EE was revealed [ 93 ]. Moreover, the exposure to EE from adolescence facilitated spatial learning and memory by downregulating the expression of Arc and Syt1 in the hippocampus [ 93 ].…”