Acute and long-term cognitive impairment following sepsis: mechanism and prevention.

INTRODUCTION: Sepsis is a severe host response to infection, which induces both acute and long-term cognitive impairment. Despite its high incidence following sepsis, the underlying mechanisms remain elusive and effective treatments are not available clinically. AREA COVERED: This review focuses on elucidating the pathological mechanisms underlying cognitive impairment following sepsis. Specifically, the authors discuss the role of systemic inflammation response, blood-brain barrier disruption, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and Aß accumulation and tau phosphorylation in cognitive impairment after sepsis. Additionally, they review current strategies to ameliorate cognitive impairment. EXPERT OPINION: Potential interventions to reduce cognitive impairment after sepsis include earlier diagnosis and effective infection control, hemodynamic homeostasis, and adequate brain perfusion. Furthermore, interventions to reduce inflammatory response, reactive oxygen species, blood-brain barrier disruption, mitochondrial dysfunction, neuronal injury or death could be beneficial. Implementing strategies to minimize delirium, sleep disturbance, stress factors, and immobility are also recommended. Furthermore, avoiding neurotoxins and implementing early rehabilitation may also be important for preventing cognitive impairment after sepsis.

Dysfunction of NRG1/ErbB4 Signaling in the Hippocampus Might Mediate Long-term Memory Decline After Systemic Inflammation.

Accumulating evidence has suggested that a great proportion of sepsis survivors suffer from long-term cognitive impairments after hospital discharge, leading to decreased life quality and substantial caregiving burdens for family members. However, the underlying mechanism remains unclear. In the present study, we established a mouse model of systemic inflammation by repeated lipopolysaccharide (LPS) injections. A combination of behavioral tests, biochemical, and in vivo electrophysiology techniques were conducted to test whether abnormal NRG1/ErbB4 signaling, parvalbumin (PV) interneurons, and hippocampal neural oscillations were involved in memory decline after repeated LPS injections. Here, we showed that LPS induced long-term memory decline, which was accompanied by dysfunction of NRG1/ErbB4 signaling and PV interneurons, and decreased theta and gamma oscillations. Notably, NRG1 treatment reversed LPS-induced decreases in p-ErbB4 and PV expressions, abnormalities in theta and gamma oscillations, and long-term memory decline. Together, our study demonstrated that dysfunction of NRG1/ErbB4 signaling in the hippocampus might mediate long-term memory decline in a mouse model of systemic inflammation induced by repeated LPS injections. Thus, targeting NRG1/ErbB4 signaling in the hippocampus may be promising for the prevention and treatment of this long-term memory decline.

Integrated Proteomic and Phosphoproteomic Analysis of the Hippocampus in a Mouse Model of Early Life Inflammation.

INTRODUCTION: Inflammation in early life is a risk factor for the development of neuropsychiatric diseases later in adolescence and adulthood, yet the underlying mechanism remains elusive. In the present study, we performed an integrated proteomic and phosphoproteomic analysis of the hippocampus to identify potential molecular mechanisms of early life inflammation-induced cognitive impairment. METHODS: Both female and male mice received a single intraperitoneal injection of 100 µg/kg lipopolysaccharide (LPS) on postnatal day 10 (P10). Behavioral tests, including open field, elevated plus-maze, and Y-maze tests, were performed on P39, P40, and P41, respectively. After behavioral tests, male mice were sacrificed. The whole brain tissues and the hippocampi were harvested on P42 for proteomic, phosphoproteomic, Western blot, and Golgi staining. RESULTS: Early life LPS exposure induced cognitive impairment in male mice but not in female mice, as assessed by the Y-maze test. Therefore, following biochemical tests were conducted on male mice. By proteomic analysis, 13 proteins in LPS group exhibited differential expression. Among these, 9 proteins were upregulated and 4 proteins were downregulated. For phosphoproteomic analysis, a total of 518 phosphopeptides were identified, of which 316 phosphopeptides were upregulated and 202 phosphopeptides were downregulated in the LPS group compared with the control group. Furthermore, KEGG analysis indicated that early life LPS exposure affected the glutamatergic synapse and neuroactive ligand-receptor interaction, which were associated with synaptic function and energy metabolism. Increased level of brain protein i3 (Bri3), decreased levels of PSD-95 and mGLUR5, and dendritic spine loss after early life LPS exposure further confirmed the findings of proteomic and phosphoproteomic analysis. CONCLUSIONS: Our findings demonstrated that neuroinflammation and impaired synapse may be involved in early life inflammation-induced cognitive impairment. Future studies are required to confirm our preliminary results.

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhibitory and excitatory input onto PV interneurons enwrapped by PNN, and decreased gamma oscillations in hippocampal CA1. Notably, MMP-9 inhibitor SB-3CT treatment rescued most of these abnormalities. Taken together, our study demonstrates that active MMP-9 mediated PNN remodeling, leading to reduced inhibitory and excitatory input onto PV interneurons and abnormal gamma oscillations in hippocampal CA1, which consequently contributed to cognitive impairments after LPS injection.

Deficit of perineuronal net induced by maternal immune activation mediates the cognitive impairment in offspring during adolescence.

Maternal immune activation (MIA) during pregnancy is considered a risk factor for neurodevelopment in the offspring, resulting in behavioral abnormalities. Furthermore, adolescence is a vulnerable period for developing different psycho-cognitive deficits. Here, we aimed to observe the cognitive consequences of prenatal MIA exposure in adolescents and explored the underlying mechanisms. We divided dams into CON and MIA groups after inducing a mouse model of MIA using lipopolysaccharide (120 µg/kg) on gestational day 15. Open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were performed on postnatal day (PD) 35-37. The expression of hippocampal Wisteria floribunda agglutinin (WFA)+ perineuronal net (PNN), parvalbumin (PV), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule-1(Iba-1) were evaluated using immunofluorescence, and the expression of matrix metalloprotein-9 (MMP-9) in the hippocampus was assessed using the western blot. Following the infusion of chondroitinase ABC (ChABC) into CA1 in the offspring from the CON group on PD 30, they were divided into ChABC and Sham groups. OF, EPM, and NOR were performed on PD 35-37. Compared to the CON group, decreased exploration time of the novel object and preference ratio were observed in the MIA group. Meanwhile, the MIA group presented significantly decreased WFA+ PNN in CA1, increased Iba-1+ microglia, and MMP-9 in the hippocampus. Additionally, the density of PV+ neurons and GFAP+ astrocytes was comparable between both groups. After digesting the PNN, the exploration time of novel object and preference ratio decreased in the ChABC group compared to the Sham group. Conclusively, the PNN deficit in CA1 caused by prenatal MIA might, at least partially, induce cognitive impairment in adolescents. Microglia and MMP-9 may also be potential candidates for PNN deficit after MIA.

Clinical characteristics and prognostic factors for visual outcome in 669 patients with intraocular foreign bodies.

AIM: To describe the clinical characteristics and analyze prognostic factors that influence visual outcome in 669 patients with intraocular foreign bodies (IOFBs). METHODS: Medical records of 669 patients with IOFBs from West China Hospital were reviewed. Best corrected visual acuity (BCVA) values were recorded using standard Snellen acuity chart and were converted to logarithm of the minimum angle of resolution (logMAR) scale for statistical analysis. The visual outcome was defined by the final BCVA (excellent visual outcome: final BCVA of 20/40 or better; poor visual outcome: final BCVA less than 20/200). Statistical analysis of collected data was performed using IBM SPSS Statistics version 23. A 2-tailed P value of less than 0.05 was considered statistically significant throughout the study. RESULTS: The average age ranged from 1 to 79 years old (mean age, 34.8±12.7 SD) and the majority of patients were men (626, 93.6%). The major cause of ocular injury was hammering (383, 57.2%). Almost all the patients (97.8%) underwent surgeries (97.8%) and the average time interval between injury and surgery was 26.4±322.3d (0-7300), while 327 patients received surgeries within 24h (48.9%) and 590 patients received surgeries within seven days (88.2%) after IOFBs injury. The poor BCVA was associated with older age (P=0.013), larger IOFBs size (P<0.001), presence of complications (P<0.001) and worse presenting BCVA (P<0.001). On the contrary, younger age (P=0.005), smaller IOFBs size (P<0.001), absence of complications (P<0.001) and better presenting BCVA (P<0.001) were considered to relate to excellent BCVA. CONCLUSION: Multiple prognostic factors may influence the final visual outcome, including age, size of IOFBs, complications and presenting BCVA. Meanwhile, further education and promotion on eye protection should be taken for the improvement on self-protection and self-health awareness.

Abnormal theta oscillation aggravated by chronic stress in the CA1 may mediate the deterioration of fear memory impairment induced by lipopolysaccharide.

Both environmental stress and immune challenge can induce abnormal neurobehavior. However, the impact of chronic stress on immune challenge-related neurobehavioral abnormalities is still controversial. Hence, we aimed to investigate the effects of chronic stress on immune challenge-related neurobehavioral abnormalities and explore the possible underlying mechanisms. During the first set of experiments, mice were reared under normal condition (NC) or chronic stress (CS) for 4 consecutive weeks. They were allocated to the following four groups: NC + normal saline (NS) group, CS + NS group, NC + lipopolysaccharide (LPS) group, and CS + LPS group. Open field, elevated plus maze, fear conditioning, novel object recognition, and forced swimming tests were performed, and their tissues were harvested. During the second set of experiments, after rearing the mice under the above conditions for 3 weeks, microelectrodes were implanted into the CA1 of the hippocampus. After recovery for 1 week under the respective environmental conditions, the mice were allocated to four groups, as in the first experiments. The basal (home cage) and task (fear conditioning)-related local field potential (LFP) were recorded. In the present study, LPS significantly induced a decrease in the freezing to context and discrimination ratio. However, only the freezing to context was further reduced by prior chronic stress. This suggested that chronic stress worsened fear memory impairment induced by acute LPS challenge. Consistent with the change in fear memory, LPS significantly decreased the expression of PV in the CA1, which was further downregulated by prior chronic stress. On the other hand, LPS inhibited the power of both basal and task-related θ oscillations in the CA1. Only the task-related θ power was further decreased by chronic stress. In conclusion, our study showed that the phenotypic loss of PV interneurons and the decrease in the power of the θ oscillation in the CA1 aggravated by chronic stress may mediate, at least in part, the deterioration of fear memory impairment induced by LPS.