Environmental Enrichment Protects Against Sepsis-Associated Encephalopathy-Induced Learning and Memory Deficits by Enhancing the Synthesis and Release of Vasopressin in the Supraoptic Nucleus

Abstract

Background As a severe complication of sepsis, sepsis-associated encephalopathy (SAE) usually manifests as impaired learning and memory ability in survivors. Previous studies have reported that environmental enrichment (EE) can increase the learning and memory ability in different brain injury models. However, there has been no research on the possible positive effect of EE on SAE. Aim The present study aimed to test the effect of EE on SAE-induced impairment of learning and memory and its related mechanisms. Methods A Morris water maze test (MWM) was used to evaluate the learning and memory ability of SAE rats that received EE housing or not. The expression of vasopressin (VP) was assessed using immunofluorescence microscopy and enzyme-linked immunosorbent assays (ELISAs). The synthesis of VP in the supraoptic nucleus (SON) was determined using quantitative real-time reverse transcription-PCR analysis. Moreover, inflammatory markers and brain-derived neurotrophic factor (BDNF) were detected using ELISA. Results The results showed that SAE induced a decreased learning and memory ability, while EE reversed this impairment. EE also enhanced the synthesis and secretion of VP in the SON. Blocking the action of VP in the hippocampus interrupted the EE-induced amelioration of learning and memory impairment. Moreover, EE induced changes to the levels of BDNF and cytokines in the hippocampus and these effects were mediated by VP binding to the VP receptor 1a. Conclusion Our findings demonstrated that the enhanced synthesis and secretion of VP in the SON are a key determinant responsible for EE-induced alleviation of learning and memory deficits caused by SAE.

Environmental Enrichment Protects Against Cognition Deficits Caused by Sepsis-Associated Encephalopathy

“…In the present study, SAE induced significant increases in the levels of TNF-α, IL-6, and IL-1β in the brain, which further confirmed the role of neuroinflammation in SAE-induced cognitive dysfunction. Interestingly, our recent study showed that the hippocampal TNF-α content between Sham-SE, SAE-SE, and SAE-EE rats did not change [9]. We propose that neither an environmental factor nor a SAE factor influenced the hippocampal TNF-α level, suggesting that TNF-α is not involved in SAE-induced deficits in spatial learning and memory.…”

“…Housing conditions comprising social interactions, novelty, and various forms of exercise are referred to as environmental enrichment (EE). Numerous studies have reported the positive effect of EE on cognitive function under various brain injuries [9]. For example, EE can improve the sensory and memory ability for traumatic brain injury (TBI) rats by changing the levels of proinflammatory cytokines and anti-inflammatory cytokines [10][11][12].…”

Pre-Exposure to Environmental Enrichment Protects against Learning and Memory Deficits Caused by Infrasound Exposure

“…In addition, the present study found that EE pre-exposure counteracted the IE-induced change in inflammatory mediators in the hippocampus, suggesting a positive effect of EE on the learning and memory ability under IE conditions. In fact, it has been reported that EE affects cytokines, various immune components, and glial cells under various pathological conditions [ 24 , 56 – 58 ]. The antineuroinflammatory effect of EE might be achieved through several immune pathways [ 59 , 60 ]: (i) increased migration of macrophages into the CNS and enhancement of their regulatory effects on microglia; (ii) upregulation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), which exhibits negatively regulatory roles in proinflammatory macrophage MAPK activation; and (iii) modulation of hippocampal T cells, which are responsible for the modulation of microglia.…”

“…EE: Rats were housed in a large cage (40 cm ×54 cm ×30 cm) with six rats per cage. As previously described, the cages contained multiple objects including wooden blocks, plastic bone-shaped toys, a running wheel, and a plastic tunnel [ 24 ]. Suspended ropes allowed for climbing from one level to another.…”

“…In this process, EE alleviated oxidative stress, suppressed neuroinflammation, reduced cytokines, and alleviated astroglial activation [ 21 – 23 ]. Our recent research also showed that EE can protect against sepsis-associated encephalopathy- (SAE-) induced learning and memory deficits by decreasing the cytokines in the hippocampus and this effect was mediated by vasopressin (VP) binding to the VP receptor 1a [ 24 ]. Although EE therapy is effective in reducing negative outcomes, its efficacy is limited by the fact that the damage has already occurred, and its usage is palliative rather than preventative.…”