[Research progress on the role of microglia in sepsis-associated encephalopathy].

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by sepsis, which is characterized by decreased attention, directional impairment, being prone to irritation, and in severe cases the patient will experience drowsiness and coma. The pathogenesis of SAE mainly includes neuroinflammation, damage of blood-brain barrier, cerebral vascular dysfunction, and neurometabolic changes, among which neuroinflammation is the core pathological process. Microglia are considered to be important immune cells of the central nervous system and play an important role in neuroinflammation. This article systematically describes the role of microglia in the development of SAE, and discusses the phenotype and related signaling pathways of microglia, in order to clarify the role of microglia in SAE and provide a theoretical basis for clinical treatment of SAE.

Betaine prevents cognitive dysfunction by suppressing hippocampal microglial activation in chronic social isolated male mice.

Chronic social isolation (SI) stress, which became more prevalent during the COVID-19 pandemic, contributes to abnormal behavior, including mood changes and cognitive impairment. Known as a functional nutrient, betaine has potent antioxidant and anti-inflammatory properties in vivo. However, whether betaine can alleviate the abnormal behavior induced by chronic SI in mice remains unknown. In this study, we investigated the efficacy of betaine in the treatment of behavioral changes and its underlying mechanism. Three-week-old male mice were randomly housed for 8 weeks in either group housing (GH) or SI. The animals were divided into normal saline-treated GH, normal saline-treated SI, and betaine-treated SI groups in the sixth week. The cognitive and depression-like behavior was determined in the eighth week. We found that long-term betaine administration improved cognitive behavior in SI mice but failed to prevent depression-like behavior. Moreover, long-term betaine administration inhibited hippocampal microglia over-activation and polarized microglia toward the M2 phenotype, which effectively inhibited the expression of inflammatory factors in SI mice. Finally, the protective effect of betaine treatment in SI mice might not be due to altered activity of the hypothalamic-pituitary-adrenal axis. Collectively, our findings reveal that betaine can improve SI-induced cognitive impairment, thus providing an alternative natural source for the prevention of memory loss caused by SI or loneliness.

IGF2/IGF2R/Sting signaling as a therapeutic target in DSS-induced ulcerative colitis.

Ulcerative colitis is an inflammatory bowel disease with increasing prevalence and incidence. Current treatments for ulcerative colitis are not generally applicative and are often accompanied by side effects. IGF2 is an endogenous protein that plays roles in anti-inflammation and stemness maintenance, but little is known about its mechanism and function in the progression of ulcerative colitis. In this study, mouse recombinant IGF2 was used in a mouse model of ulcerative colitis established by DSS. IGF2 expression was reduced in colon tissues but not plasma of DSS-induced colitis mice. IGF2R expression was also decreased in colitis colons, which was then elevated by recombinant IGF2. Recombinant IGF2 alleviated colon injury in colitis, which was evaluated by colon shortening, body weight loss and DAI score. IGF2 treatment also relieved the inflammatory response in colitis, which was assessed by the spleen weight index, MPO activity and proinflammatory cytokine expression and was also detected in LPS-stimulated RAW264.7 cells in vitro. Moreover, IGF2R was predicted and further verified to interact with the Sting protein, and the cGAS-Sting pathway as a key pathway for stemness regulation, was upregulated in colonic colons, which was blocked by IGF2 treatment. Additionally, IGF2 treatment can maintain colonic stemness and further repair colonic tight junction function in DSS-induced colitis. In conclusion, IGF2/IGF2R downregulated the cGAS-Sting pathway to sustain colonic stemness and barrier integrity to protect against ulcerative colitis induced by DSS.

Targeting PERK mediated endoplasmic reticulum stress attenuates neuroinflammation and alleviates lipopolysaccharide-induced depressive-like behavior in male mice.

Neuroinflammation plays a key role in the development of depression-like behaviors.Endoplasmic reticulum (ER) stress,defined as accumulation of unfolded proteins in the ER,is suggested tocollaboratewithinflammation process to drive sustained neuroinflammation. Protein kinase R-like endoplasmic reticulum kinase (PERK) is ofparticularly attractive target because it plays key rolein the regulation of ER stress-induced neuroinflammation, however, little isknown whether PERKmediatedER stress is implicated in LPS-induced depression-like behaviors.Thus, we aimed to evaluate the induction of PERK pathwayin mice with depression-like behaviors induced by LPS, as well as the alterations in depression-like behaviorsfollowing the blocking of PERK pathway.We found that LPS challenges resulted in enhanced PERK in the hippocampus, with no alteration in the prefrontal cortex. Importantly, we found that PERKinhibitorISRIB reducedthe proinflammatory responsesof microglia in the context of acute LPS-induced brain inflammation, and subsequent the preserved hippocampal neurogenesis, and improvement in depression-like behavioroutcomes following LPS challenges.It was also worth mentioning thatISRIB treatmentreduced the peripheral pro-inflammatory cytokines includingIL-1ß, IL-6 and IL-18. Thus, targetingPERK mediated Endoplasmic reticulum stress may be a promising antidepressant and anti-inflammatory candidate drug for the alleviation of neuroinflammationmediated depression, and PERKinhibitorISRIBmay havebenefits for combating major depressive disorder.

The critical role of the hippocampal NLRP3 inflammasome in social isolation-induced cognitive impairment in male mice.

Early life stress exerts detrimental effects on cognitive function, but the mechanism by which this occurs is unknown. The NLRP3 inflammasome-mediated inflammatory response has emerged as a prominent contributor to cognitive impairment induced by chronic stress. In the present study, we showed that 8-week chronic social isolation (SI) led to cognitive impairment in mice, remarkably increasing expression of the hippocampal NLRP3 inflammasome. Furthermore, the 8-week SI procedure significantly increased the levels of hippocampal IL-1ß and IL-18 without significant alteration of the level of serum IL-1ß, suggesting a central mechanism for IL-1ß-related CNS inflammation. Moreover, inflammatory microglial and expression of AMPAR were reduced in the hippocampus of SI mice. Minocycline is an antibiotic that limits microglia responses, and previous study also showed that minocycline could prevent stress-induced pro-inflammatory cytokine expression in the brain. Our experiment found that minocycline improved cognitive behavior in SI mice. Minocycline also prevented expression of the hippocampal NLRP3 inflammasome, indicating that microglia might be the primary contributor to SI-induced hippocampal NLRP3 inflammasome activation. Furthermore, alterations in SI mice were also restored by chronic treatment with the NLRP3 inhibitor MCC950. These results indicate that the microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to social isolation and that specific NLRP3 inflammasome inhibition using MCC950 may represent a promising therapeutic approach for early stress induced cognitive impairment.

Acute restraint stress alters food-foraging behavior in rats: Taking the easier Way while suffered.

Stress can influence decision-making in humans from many cognitive perspectives, while the underlying neurobiological mechanism remains incompletely understood. Food-foraging is a rodent behavior involving strategic possessing of nutritional supply in social context; experimental model of this behavior could help explore the effect of stress on decision-making and the brain mechanism thereof. In the present study, the influence of stress on food-foraging behavior was assessed in rats using an open field choosing paradigm wherein food collection (standard food or sweet food) were associated with social competition (with or without a rat in the cage). Acute restraint stress (ARS) was induced by placing the rat in a plastic restrainer for 2 h before food-foraging behavioral tests, with the effect of stress also determined biochemically and immunohistochemically. Restraint stressed rats showed anxiety-like behavior and elevation of serum corticosterone (CORT) and epinephrine (EPI) relative to controls. Both restraint and control animals preferred sugared food. However, the former group tended to forage food from a cage not occupied by a conspecific rat, whereas the control rats preferred to obtain food from the cage with a social competitor. Thus, the total amount of food foraged and eaten are reduced in the restrained rats than in controls. While the restraint animals had normal social interaction with other rats, they displayed enhanced social agonistic behavior. In brain examination, ARS attenuated the increase in immunolabeling and protein levels of c-fos, p-CREB, p-ERK1/2 in the anterior cingulate cortex (ACC) observed in control animals in association with food-foraging. These results indicate that restraint stressed rats tend to forage food by taking the advantage of a less competitive opportunity. Mechanistically, this decision-making alternative appears to be mediated through a neuronal deactivation in the ACC. The current findings provide novel insights into neuronal processing of decision-making behavior under the influence of stress.

The Role of miR-150 in Stress-Induced Anxiety-Like Behavior in Mice.

Stress plays a crucial role in several psychiatric disorders, including anxiety. However, the underlying mechanisms remain poorly understood. Here, we used acute stress (AS) and chronic restraint stress (CRS) models to develop anxiety-like behavior and investigate the role of miR-150 in the hippocampi of mice. Corticosterone levels as well as glutamate receptors in the hippocampus were evaluated. We found that anxiety-like behavior was induced after either AS or CRS, as determined by the open-field test (OFT) and elevated plus-maze test (EPM). Increased corticosterone levels were observed in the blood of AS and CRS groups, while the expression of miR-150 mRNA in the hippocampus was significantly decreased. The expressions of GluN2A, GluR1, GluR2, and V-Glut2 in the hippocampus were decreased after either AS or CRS. Hippocampal GAD67 expression was increased by AS but not CRS, and GluN2B expression was decreased by CRS but not AS. Adult miR-150 knockout mice showed anxiety-like behavior, as assessed by the OFT and EPM. The expressions of GluN2A, GluN2B, GluR1, and GluR2 were also downregulated, but the expression of V-Glut2 was upregulated in the hippocampi of miR-150 knockout mice compared with wild-type mice. Interestingly, we found that the miR-150 knockout mice showed decreased dendrite lengths, dendrite branchings, and numbers of dendrite spines in the hippocampus compared with wild-type mice. These results suggest that miR-150 may influence the synaptic plasticity of the hippocampus and play a significant role in stress-induced anxiety-like behavior in adult mice.

Role of early environmental enrichment on the social dominance tube test at adulthood in the rat.

RATIONALE: Environmental enrichment (EE) could influence brain plasticity and behavior in rodents. Whether the early EE may predispose individuals to a particular social hierarchy in the social dominance tube test (SDTT) at adulthood is still unknown. OBJECTIVE: The present study directly investigated the influence of EE on competitive success in the SDTT among adult rats. METHODS: Male rats were maintained in EE from postnatal days 21 to 35. Social dominance behavior was determined by SDTT, competitive food foraging test, and mate preference test at adulthood. IBA-1 expression in the hypothalamus was examined using immunohistochemistry and western blot. RESULTS: EE rats were prone to become submissive during a social encounter with standard environment (SE) rats in the SDTT. No difference was found in food foraging in the competitive food foraging test between SE and EE rats. Male EE rats were more attractive than the SE to the female rats in the mate preference test. IBA-1 expression was found to be decreased in the hypothalamus of EE rats compared to SE group. Infusion of a microglia inhibitor reduced percentage of forward in SE rats in the SDTT. Infusion of DNA methyltransferase inhibitor prevented the development of subordinate status in EE rats and restored the expression of IBA-1 in the hypothalamus. CONCLUSIONS: The results suggest that early EE did not lead to reduced social hierarchy in the male rat. However, EE caused a reduction in the percentage of forward in the SDTT, which might be associated with reduced number of microglia in the hypothalamus.

Roles of NMDA and dopamine in food-foraging decision-making strategies of rats in the social setting.

BACKGROUND: In highly complex social settings, an animal's motivational drive to pursue an object depends not only on the intrinsic properties of the object, but also on whether the decision-making animal perceives an object as being the most desirable among others. Mimetic desire refers to a subject's preference for objects already possessed by another subject. To date, there are no appropriate animal models for studying whether mimetic desire is at play in guiding the decision-making process. Furthermore, the neuropharmacological bases of decision-making processes are not well understood. In this study, we used an animal model (rat) to investigate a novel food-foraging paradigm for decision-making, with or without a mimetic desire paradigm. RESULTS: Faced with the choice of foraging in a competitive environment, rats preferred foraging for the desirable object, indicating the rats' ability for decision-making. Notably, treatment with the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, but not with the dopamine D1 or D2 receptor antagonists, SCH23390 and haloperidol, respectively, suppressed the food foraging preference when there was a competing resident rat in the cage. None of these three antagonists affected the food-foraging preference for palatable food. Moreover, MK-801 and SCH23390, but not haloperidol, were able to abolish the desirable environment effect on standard food-foraging activities in complex social settings. CONCLUSIONS: These results highlight the concept that mimetic desire exerts a powerful influence on food-foraging decision-making in rats and, further, illustrate the various roles of the glutamatergic and dopaminergic systems in mediating these processes.

Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress.

Depression is a common psychiatric disorder associated with chronic stress. Insulin-like growth factor 2 (IGF2) is a growth factor that serves important roles in the brain during development and at adulthood. Here, the role of IGF2 expression in the hippocampus was investigated in a rat model of depression. A chronic restraint stress (CRS) model of depression was established in rats, exhibiting depression-like behavior as assessed with the sucrose preference test (SPT) and forced swimming test (FST), and with evaluation of the corticosterone levels. Hippocampal IGF2 levels were significantly lower in rats suffering CRS than in controls, as were levels of pERK1/2 and GluR1. Lentivirus-mediated hippocampal IGF2 overexpression alleviated depressive behavior in restrained rats, elevated the levels of pERK1/2 and GluR1 proteins, but it did not affect the expression of pGSK3ß, GluR2, NMDAR1, and NMDAR2A. These results suggest the chronic restraint stress induces depressive behavior, which may be mediated by ERK-dependent IGF2 signaling, pointing to an antidepressant role for this molecular pathway.

Development of anxiety-like behavior via hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment.

Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.

Activation of ERK1/2 is required for normal response of isosexual social interactions in male rats.

Previous studies have indicated involvement of the mitogen-activated protein kinase (MAPK) pathway in heterosexual interactions among rats. Very few studies, however, have focused its role in isosexual social interactions. We studied the male rat's isosexual social interactional behavior using (i) the three-chambered social interaction box and (ii) phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) to localize the brain regions that are activated during isosexual behavior. When faced with the social target side of the box versus the inanimate side, all rats preferred the social target side. Within 10min, isosexual social interactions induced a rapid increase in pERK1/2 expression in the brain, especially the main olfactory epithelial (MOE)-related brain regions. After ZnSO4-induced olfactory deprivation, rats showed no preference for either the social target or inanimate side, with a concomitant decrease in pERK1/2 expression in MOE-related brain regions. Additionally, to determine the role of pERK1/2 in isosexual social interactional behavior, rats were injected intraperitoneally with SL327 (30mg/kg, a MAPK kinase inhibitor). Although SL327 dramatically down-regulated expression of brain pERK1/2, experimental animals also spent significantly more time in the social target side. These results indicate that (i) A brief interacting with a male partner induced rapidly phosphorylated ERK1/2 in the rat's brain. (ii) Destroy the function of MOE abolished the rats' isosexual social interactional behavior. (iii) Suppressed the phosphorylated ERK1/2 in the rats' brain disrupt their normal social behaviour.

[Prevention and management of pressure ulcers in critical patients].

The Taiwan Join Commission on Hospital Accreditation identified pressure ulcers as an important clinical care indicator in 2011. Pressure ulcers are a particularly critical medical care issue in hospital intensive care units. Pressure ulcers can influence patient physiology in terms of greater perceived pain, elevated infection and sepsis incidence, increased unplanned surgical treatments, and reduced activities of daily living (ADL). Pressure ulcers can also affect psychology through induced depression, stress, and anxiety. They can also increase patient and societal costs and prolong hospital stay length. This article explores the prevention and management of pressure ulcer in serious illness patients and introduces effective assessment and management techniques. We hope this article raises clinical nurse awareness of this critical issue and helps decrease the incidence of pressure ulcer-related complications in order to enhance overall quality of care.