Environmental enrichment influences mouse hippocampal neuroinflammatory response

Background: Many studies have shown the positive effects of environmental enrichment on brain plasticity with significant implications for development, behavior, learning, memory, and recovery from brain damage (1). Experimental and clinical studies report that one’s living environment can modulate cellular and molecular responses in the brain, counteracting cognitive decline, alleviating anxiety, and depressive behaviours, as well as moderating the outcome of pharmacological treatments (2). Neuroinflammation has been well established as an important factor in the aetiopathogenesis and progression of brain disorders. It can affect neural development and alters hippocampal plasticity thus resulting in cognitive impairments. Neuroinflammation is characterized by a dysregulation of the NLRP3 inflammasome activation, an increase in the expression of inflammatory cytokines, and a decrease of neurotrophic factors (3). Behavioral and neurochemical changes, caused by neuroinflammation, have been most frequently investigated through peripheral administration of lipopolysaccharide (LPS), which can, directly and indirectly, affect the central nervous system (4). Based on these premises, the aim of this study was to explore the molecular effects of the quality of the living environment in modulating the LPS-induced neuroinflammatory response in the hippocampus of wild-type mice. Methods: Male C57BL6J mice (13 weeks-old) were randomly housed in Impoverished (IE) or Enriched Environment (EE) condition for 28 days, then exposed to LPS (0.830 mg/Kg, i.p.) or saline (SAL). Twenty-four hours after injection hippocampi were removed for gene expression analysis performed by means of qRT-PCR. Data from groups were analyzed by Two-way ANOVA followed by Tukey’s post hoc test. Results: The analysis of the environmental effects on the LPS signaling system highlighted the downregulation of the membrane-bound protein LBP, the receptor TLR4 and the co-receptor cluster CD14 expression levels in EE-housed animals compared to their counterparts. The exposure to an EE condition was able to attenuate the LPS-induced increase of TLR4 and NLRP3 inflammasome mRNA levels. Gene expression analysis revealed a significant downregulation of the pro-inflammatory cytokines IL-1β and TNFα levels in EE-housed mice while LPS exposure strongly increased IL-1β and TNFα mRNA levels irrespective of the housing conditions. Moreover, EE-exposed mice showed a significant upregulation of BDNF hippocampal mRNA levels, although no effects were observed after LPS treatment in both conditions. Conclusions: Our results displayed the beneficial effect of EE in regulating the expression of inflammatory mediators involved in the LPS-induced response in the hippocampus, a key area for learning, memory, and emotion. These data suggest that living environment may exert a positive and protective role on the brain by reducing susceptibility toward neurodegenerative or neuropsychiatric disorders.