Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1 (IL1) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.
Obesity increases risk of age-related cognitive decline and is accompanied by peripheral inflammation. Studies in rodent models of obesity have demonstrated that impaired hippocampal function correlates with microglial activation, but the possibility that neuron/microglia interactions might be perturbed in obesity has never been directly examined. The goal of this study was to determine whether high fat diet-induced obesity promotes synaptic stripping by microglia, and whether any potential changes might be reversible by a return to low-fat diet (LFD). Time course experiments revealed that hippocampal inflammatory cytokine induction and loss of synaptic protein expression were detectable after three months of HFD, therefore subsequent groups of mice were maintained on HFD for three months before being switched to LFD for an additional two months on LFD (HFD/LFD). Additional HFD mice continued to receive HFD during this period (HFD/HFD), while another group of mice were maintained on LFD throughout the experiment (LFD/LFD). Dietary obesity impaired hippocampus-dependent memory, reduced long-term potentiation (LTP), and induced expression of the activation marker major histocompatibility complex II (MHCII) in hippocampal microglia. Diet reversal only partially attenuated increases in adiposity in HFD/LFD mice, but plasticity deficits and MHCII induction were normalized to within the range of LFD/LFD mice. Microglial activation and deficits in hippocampal function were accompanied by perturbation of spatial relationships between microglial processes and synaptic puncta. Analysis of primary microglia isolated from HFD/HFD mice revealed selective increases in internalization of synaptosomes labeled with a pH-sensitive fluorophore. Taken together, these findings indicate that dietary obesity reversibly impairs hippocampal function, and that deficits may be attributable to synaptic stripping by microglia.
Accumulating evidence indicates that obesity accelerates the onset of cognitive decline. While mechanisms are still being identified, obesity promotes peripheral inflammation and increases blood-brain barrier (BBB) permeability. However, no studies have manipulated vascular permeability in obesity to determine whether BBB breakdown underlies memory deficits. Protein kinase Cb (PKCb) activation destabilizes the BBB, and we used a PKCb inhibitor (Enzastaurin) to block BBB leakiness in leptin receptor-deficient (db/db) mice. Enzastaurin reversed BBB breakdown in db/db mice and normalized hippocampal function without affecting obesity or metabolism. Flow cytometric analysis of forebrain mononuclear cells (FMCs) from db/db mice revealed macrophage infiltration and induction of the activation marker MHCII in microglia and macrophages. Enzastaurin eliminated macrophage infiltration and MHCII induction, and protein array profiling revealed parallel reductions in IL1b, IL6, MCP1, and TNFa. To investigate whether these signals attract peripheral monocytes, FMCs from Wt and db/db mice were plated below migration inserts containing peritoneal macrophages. Peritoneal macrophages from db/db mice exhibit increases in transmigration that were blocked by recombinant IL1RA. These studies indicate that BBB breakdown impairs cognition in obesity and diabetes by allowing macrophage infiltration, with a potential role for IL1b in trafficking of peripheral monocytes into the brain.
Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical in shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibit increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT–vSTR versus PFC–vSTR neuronal activity differentially regulates dendritic spine plasticity and social avoidance.
db/db mice are a model of obesity and diabetes due to their lack of functional leptin receptors, which leads to insulin resistance, elevated corticosterone levels, and persistent inflammation. Because stress-induced elevations in glucocorticoids sensitize microglia to immune challenges, we hypothesized that corticosteroids might act similarly in the diabetic brain. To test this hypothesis, db/db and wildtype mice were treated with the glucocorticoid synthesis inhibitor metyrapone every day for two weeks. This treatment revealed corticosterone-dependent increases in microglial number and accumulation of the pro-inflammatory cytokines interleukin 1beta and tumor necrosis factor alpha in the hippocampus of db/db mice. Analysis of microglial responses to lipopolysaccharide stimulation revealed that glucocorticoids lower the threshold for release of pro-inflammatory cytokines, underscoring the role of corticosteroids as a precipitating factor for neuroinflammation in obesity and diabetes.
Type 2 diabetes is increasingly recognized as a risk factor for Alzheimer’s disease (AD), but the underlying mechanisms remain poorly understood. Hyperphosphorylation of the microtubule-associated protein tau has been reported in rodent models of diabetes, including db/db mice, which exhibit insulin resistance and chronically elevated glucocorticoids due to leptin receptor insufficiency. In this report, we investigated endocrine mechanisms for hippocampal tau phosphorylation in db/db and wildtype (Wt) mice. By separately manipulating peripheral and intrahippocampal corticosterone levels, we determined that hippocampal corticosteroid exposure promotes tau phosphorylation and activates glycogen synthase kinase 3β (GSK3β). Subsequent experiments in hippocampal slice preparations revealed evidence for a nongenomic interaction between glucocorticoids and GSK3β. To examine whether GSK3β activation mediates tau phosphorylation and impairs memory in diabetes, db/db and Wt mice received intrahippocampal infusions of TDZD-8, a non-ATP competitive thiadiazolidinone inhibitor of GSK3β. Intrahippocampal TDZD-8 blocked tau hyperphosphorylation and normalized hippocampus-dependent memory in db/db mice, suggesting that pathological synergy between diabetes and AD may involve glucocorticoid-mediated activation of GSK3β.
Background: Enteral nutrition is commonly initiated 24 hours after percutaneous endoscopic gastrostomy (PEG) in children. Adult studies report safe refeeding within 1 to 6 hours of PEG, and these findings have been cautiously applied to children. Comparative studies assessing early versus next-day refeeding in children are currently lacking. This study evaluates feeding tolerance and complications following early versus next-day refeeding in children. Methods: This is a single-center, pre-post study. In June 2015 our clinical practice changed to begin refeeding within 6 hours of PEG. Children receiving early refeeding from December 2015 to August 2017 were included. A retrospective cohort from February 2013 to April 2015 was used for comparison. Results: Forty-six children received early refeeding after PEG and 37 received next-day refeeding. Gender distribution was similar in the 2 groups. Early refeeding patients were slightly older (3.5 vs 2.2 years) and heavier (15.5 vs 11.5 kg) at PEG placement compared to next-day refeeding patients. Early refeeding patients experienced greater postprocedural nausea and/or vomiting (19% vs 8%, P < 0.001) and leakage, irritation, and infection around the stoma (19% vs 0.0%, P < 0.001). Compared to early refeeders, next-day refeeding patients experienced higher occurrence of fever (35% vs 13%, P = 0.021), longer nutritional disruption (24.6 vs 3.7 hours, P < 0.001), and longer length of stay (51 vs 27 hours; P < 0.001). One next-day refeeding patient experienced peritonitis. One early refeeding patient experienced cellulitis requiring hospitalization and a second experienced gastrostomy tube migration into the peritoneal cavity requiring removal. Conclusion: Early refeeders experienced higher rates of postprocedural nausea or vomiting and irritation, leakage, or infection around the stoma; but experienced lower rates of postoperative fever. Early refeeding resulted in reduced nutritional interruption and hospital length of stay.
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