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1.
Brain Behav Immun ; 41: 218-31, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24907587

ABSTRACT

Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1ß in the brain by 2-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1ß in the brain.


Subject(s)
Adenosine/toxicity , Anxiety/chemically induced , Brain/metabolism , Caspase 1/physiology , Interleukin-1beta/biosynthesis , Nerve Tissue Proteins/physiology , Receptor, Adenosine A2A/physiology , Adenosine/pharmacology , Amygdala/metabolism , Animals , Anxiety/physiopathology , Carbazoles/pharmacology , Caspase 1/deficiency , Cyclic AMP-Dependent Protein Kinases/physiology , Enzyme Activation/drug effects , Exploratory Behavior/drug effects , Feeding Behavior/drug effects , Glyburide/pharmacology , Interleukin-1beta/genetics , Interleukin-1beta/physiology , Ion Transport/drug effects , KATP Channels/physiology , Locomotion/drug effects , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/deficiency , Potassium/metabolism , Pyrroles/pharmacology , Receptor, Adenosine A2A/deficiency , Receptor, Adenosine A2A/drug effects , Receptors, Interleukin-1 Type I/deficiency , Receptors, Interleukin-1 Type I/physiology
2.
J Neurosci ; 32(40): 13945-55, 2012 Oct 03.
Article in English | MEDLINE | ID: mdl-23035103

ABSTRACT

After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1ß generated through adenosine-dependent activation of caspase 1 after reoxygenation.


Subject(s)
Adenosine/physiology , Amnesia, Anterograde/enzymology , Amygdala/physiology , Caspase 1/physiology , Hypoxia, Brain/complications , Adenosine/pharmacology , Amino Acid Chloromethyl Ketones/pharmacology , Amnesia, Anterograde/etiology , Amnesia, Anterograde/physiopathology , Amygdala/drug effects , Amygdala/enzymology , Animals , Caffeine/pharmacology , Caspase 1/drug effects , Caspase Inhibitors/pharmacology , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Cues , Enzyme Activation , Fear/drug effects , Fear/physiology , Hypoxia, Brain/physiopathology , Interleukin 1 Receptor Antagonist Protein/pharmacology , MAP Kinase Signaling System , Male , Maze Learning/drug effects , Maze Learning/physiology , Mental Recall , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxygen/metabolism , Oxygen/pharmacology , Receptors, Interleukin-1 Type I/deficiency , Receptors, Purinergic P1/physiology , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Theobromine/analogs & derivatives , Theobromine/pharmacology , Xanthines/pharmacology
3.
Acta Neuropathol Commun ; 6(1): 139, 2018 12 12.
Article in English | MEDLINE | ID: mdl-30541620

ABSTRACT

Mesenchymal stem cells (MSCs) transfer healthy mitochondria to damaged acceptor cells via actin-based intercellular structures. In this study, we tested the hypothesis that MSCs transfer mitochondria to neural stem cells (NSCs) to protect NSCs against the neurotoxic effects of cisplatin treatment. Our results show that MSCs donate mitochondria to NSCs damaged in vitro by cisplatin. Transfer of healthy MSC-derived mitochondria decreases cisplatin-induced NSC death. Moreover, mitochondrial transfer from MSCs to NSCs reverses the cisplatin-induced decrease in mitochondrial membrane potential. Blocking the formation of actin-based intercellular structures inhibited the transfer of mitochondria to NSCs and abrogated the positive effects of MSCs on NSC survival. Conversely, overexpression of the mitochondrial motor protein Rho-GTPase 1 (Miro1) in MSCs increased mitochondrial transfer and further improved survival of cisplatin-treated NSCs.In vivo, MSC administration prevented the loss of DCX+ neural progenitor cells in the subventricular zone and hippocampal dentate gyrus which occurs as a result of cisplatin treatment. We propose mitochondrial transfer as one of the mechanisms via which MSCs exert their therapeutic regenerative effects after cisplatin treatment.


Subject(s)
Cisplatin/pharmacology , Mesenchymal Stem Cells/physiology , Mitochondria/metabolism , Neural Stem Cells/drug effects , Neurotoxins/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Cells, Cultured , Cerebral Cortex/cytology , Cholera Toxin/metabolism , Doublecortin Domain Proteins , Doublecortin Protein , Energy Metabolism/drug effects , Enzyme Inhibitors/pharmacology , Male , Membrane Potential, Mitochondrial/drug effects , Mesenchymal Stem Cells/drug effects , Mice , Mice, Inbred C57BL , Microtubule-Associated Proteins/metabolism , Mitochondria/drug effects , Neuropeptides/metabolism , Oligomycins/pharmacology , Thiazolidines/pharmacology , Wheat Germ Agglutinins/metabolism
4.
Front Behav Neurosci ; 12: 78, 2018.
Article in English | MEDLINE | ID: mdl-29755330

ABSTRACT

Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.

5.
Oncotarget ; 9(85): 35581-35597, 2018 Oct 30.
Article in English | MEDLINE | ID: mdl-30473752

ABSTRACT

Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called 'chemobrain'. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.

6.
Nutr Metab (Lond) ; 15: 55, 2018.
Article in English | MEDLINE | ID: mdl-30093912

ABSTRACT

BACKGROUND: Reducing caloric intake is a proven intervention for mitigating and modulating morbidities associated with overnutrition. Caloric restriction is difficult to affect clinically, therefore, dietary interventions that ameliorate the adverse consequences of overnutrition in the presence of a high-calorie diet would be of value. METHODS: Mice were fed an obesogenic diet containing 60% fat + 10% cellulose (HFC), or a control diet containing 10% fat + 10% cellulose (LFC) for 12 wks. Subgroups of mice were then switched from HFC to each of the following diets for an additional 5 wks: 1) 60% fat + 10% pectin (HFP), 2) LFC or 3) 10% fat + 10% pectin (LFP). To test for statistical differences, one-way or two-way ANOVAs were used with or without repeated measurements as needed. RESULTS: In comparison to HFC, HFP prevented additional weight gain while LFC and LFP triggered weight loss of 22.2 and 25.4%, respectively. Mice continued on HFC experienced a weight increase of 26% during the same 5 wk. interval. After 12 wks, HFC decreased mouse locomotion by 18% when compared to control diet, but a diet switch to LFC or LFP restored mouse movement. Importantly, HFP, LFC, and LFP reduced fasting blood glucose when compared to HFC. Likewise, HFP, LFC and LFP improved glucose tolerance and decreased fatty liver by 37.9, 49.8, 53.6 and 20.2%, 37.2, 43.7%, respectively. CONCLUSIONS: Taken together, the results indicate that the dietary fiber pectin can mitigate some adverse consequences of overnutrition even in the presence of high-fat.

7.
Cancer Res ; 77(3): 742-752, 2017 02 01.
Article in English | MEDLINE | ID: mdl-27879267

ABSTRACT

Cognitive impairment, termed chemobrain, is a common neurotoxicity associated with chemotherapy treatment, affecting an estimated 78% of patients. Prompted by the hypothesis that neuronal mitochondrial dysfunction underlies chemotherapy-induced cognitive impairment (CICI), we explored the efficacy of administering the small-molecule pifithrin (PFT)-µ, an inhibitor of mitochondrial p53 accumulation, in preventing CICI. Male C57BL/6J mice injected with cisplatin ± PFT-µ for two 5-day cycles were assessed for cognitive function using novel object/place recognition and alternation in a Y-maze. Cisplatin impaired performance in the novel object/place recognition and Y-maze tests. PFT-µ treatment prevented CICI and associated cisplatin-induced changes in coherency of myelin basic protein fibers in the cingular cortex and loss of doublecortin+ cells in the subventricular zone and hippocampal dentate gyrus. Mechanistically, cisplatin decreased spare respirator capacity of brain synaptosomes and caused abnormal mitochondrial morphology, which was counteracted by PFT-µ administration. Notably, increased mitochondrial p53 did not lead to cerebral caspase-3 activation or cytochrome-c release. Furthermore, PFT-µ administration did not impair the anticancer efficacy of cisplatin and radiotherapy in tumor-bearing mice. Our results supported the hypothesis that neuronal mitochondrial dysfunction induced by mitochondrial p53 accumulation is an underlying cause of CICI and that PFT-µ may offer a tractable therapeutic strategy to limit this common side-effect of many types of chemotherapy. Cancer Res; 77(3); 742-52. ©2016 AACR.


Subject(s)
Antineoplastic Agents/toxicity , Brain/drug effects , Cisplatin/toxicity , Neurons/drug effects , Neuroprotective Agents/pharmacology , Sulfonamides/pharmacology , Animals , Blotting, Western , Cognition Disorders/chemically induced , Disease Models, Animal , Head and Neck Neoplasms/pathology , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Mitochondria/drug effects , Real-Time Polymerase Chain Reaction , Tumor Suppressor Protein p53/drug effects
8.
Front Neurosci ; 9: 131, 2015.
Article in English | MEDLINE | ID: mdl-25954147

ABSTRACT

While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

9.
Metabolism ; 63(12): 1491-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25308443

ABSTRACT

Adenosine is a pleiotropic bioactive with potent neuromodulatory properties. Due to its ability to easily cross the blood-brain barrier, it can act as a signaling molecule between the periphery and the brain. It functions through four (A1, A2A, A2B, and A3) cell surface G protein-coupled adenosine receptors (ARs) that are expressed in some combination on nearly all cells types within the CNS. By regulating the activity of adenylyl cyclase and changing the intracellular concentration of cAMP, adenosine can alter neuronal function and neurotransmission. A variety of illnesses related to metabolic dysregulation, such as type 1 diabetes and Alzheimer's disease, are associated with an elevated serum concentration of adenosine and a pathogenesis rooted in inflammation. This review describes the accepted physiologic function of adenosine in neurological disease and explores its new potential as a peripheral to central danger signal that can activate the neuroimmune system and contribute to symptoms of sickness and psychopathologies.


Subject(s)
Adenosine/metabolism , Mental Disorders/immunology , Mental Disorders/metabolism , Nervous System/immunology , Receptors, Purinergic P1/metabolism , Animals , Humans , Mice , Nervous System Diseases/immunology , Nervous System Diseases/metabolism
10.
Metabolism ; 63(9): 1131-40, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25016520

ABSTRACT

OBJECTIVES: Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that last beyond an acute elevation in plasma FFAs. METHODS: Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 h after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions. RESULTS: In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFα but was dependent on fatty acid chain length. Twenty-four hours after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24h after palmitic acid treatment. CONCLUSIONS: Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated.


Subject(s)
Amygdala/metabolism , Anxiety/etiology , Fatty Acids, Nonesterified/adverse effects , Neurons/metabolism , Palmitic Acid/adverse effects , Activating Transcription Factor 4/antagonists & inhibitors , Activating Transcription Factor 4/genetics , Activating Transcription Factor 4/metabolism , Animals , Anxiety/blood , Behavior, Animal , Cerebral Cortex/metabolism , Diet, High-Fat/adverse effects , Fatty Acids, Nonesterified/administration & dosage , Fatty Acids, Nonesterified/blood , Gene Expression Regulation , Hippocampus/metabolism , Hydroxyindoleacetic Acid/metabolism , Hyperphagia/metabolism , Hyperphagia/physiopathology , Injections, Intraperitoneal , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Palmitic Acid/administration & dosage , Palmitic Acid/blood
11.
Psychoneuroendocrinology ; 38(9): 1553-64, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23411461

ABSTRACT

The prevalence of childhood obesity has risen dramatically and coincident with this upsurge is a growth in adverse childhood psychological conditions including impulsivity, depression, anxiety and attention deficit/hyperactive disorder (ADHD). Due to confounds that exist when determining causality of childhood behavioral perturbations, controversy remains as to whether overnutrition and/or childhood obesity is important. Therefore, we examined juvenile mice to determine if biobehaviors were impacted by a short-term feeding (1-3wks) of a high-fat diet (HFD). After 1wk of a HFD feeding, mouse burrowing and spontaneous wheel running were increased while mouse exploration of the open quadrants of a zero maze, perfect alternations in a Y-maze and recognition of a novel object were impaired. Examination of mouse cortex, hippocampus and hypothalamus for dopamine and its metabolites demonstrated increased homovanillic acid (HVA) concentrations in the hippocampus and cortex that were associated with decreased cortical BDNF gene expression. In contrast, pro-inflammatory cytokine gene transcripts and serum IL-1α, IL-1ß, TNF-α and IL-6 were unaffected by the short-term HFD feeding. Administration to mice of the psychostimulant methylphenidate prevented HFD-dependent impairment of learning/memory. HFD learning/memory impairment was not inhibited by the anti-depressants desipramine or reboxetine nor was it blocked in IDO or IL-1R1 knockout mice. In sum, a HFD rapidly impacts dopamine metabolism in the brain appearing to trigger anxiety-like behaviors and learning/memory impairments prior to the onset of weight gain and/or pre-diabetes. Thus, overnutrition due to fats may be central to childhood psychological perturbations such as anxiety and ADHD.


Subject(s)
Central Nervous System Stimulants/therapeutic use , Dietary Fats/adverse effects , Learning Disabilities/prevention & control , Memory Disorders/prevention & control , Methylphenidate/therapeutic use , Overnutrition/psychology , 3,4-Dihydroxyphenylacetic Acid/analysis , Animals , Antidepressive Agents/pharmacology , Anxiety/etiology , Anxiety/prevention & control , Blood Glucose/analysis , Body Weight/drug effects , Brain-Derived Neurotrophic Factor/biosynthesis , Brain-Derived Neurotrophic Factor/genetics , Central Nervous System Stimulants/pharmacology , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Cytokines/biosynthesis , Cytokines/genetics , Desipramine/pharmacology , Dopamine/analysis , Exploratory Behavior/drug effects , Gene Expression Regulation/drug effects , Hippocampus/chemistry , Hippocampus/drug effects , Hippocampus/physiopathology , Homovanillic Acid/analysis , Indoleamine-Pyrrole 2,3,-Dioxygenase/deficiency , Learning Disabilities/chemically induced , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Methylphenidate/pharmacology , Mice , Mice, Knockout , Monoamine Oxidase/analysis , Morpholines/pharmacology , Motor Activity/drug effects , Overnutrition/physiopathology , Physical Endurance/drug effects , Reboxetine , Receptors, Interleukin-1 Type I , Recognition, Psychology/drug effects
12.
Obesity (Silver Spring) ; 19(8): 1586-94, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21527899

ABSTRACT

The neuroimmunological and behavioral consequences of a high-fat diet (HFD) are not well delineated. This is especially true when short term (24 h) fasting is used as a physiologic stressor. In this study, we examined the impact of a HFD on learning and memory and depressive-like behaviors to understand how fasting impacts neuroimmunity and whether obesity modulates the response. Mice were fed diets containing either 10% (low-fat diet (LFD) mice) or 60% (HFD mice) calories from fat for 10-12 weeks. Gene transcripts for 26 pro-/anti-inflammatory cytokines and markers of macrophage activation were examined in adipose tissue and whole brain. Mouse learning and memory (spontaneous alternation, novel object) and depressive-like behaviors (saccharin preference, burrowing, forced swim) were studied in the fed and fasted state as were gene transcripts for F4/80, CD11b, interleukin-1α (IL-1α), IL-1ß, IL-1R1, IL-1R2, IL-1RA, IL-6 and tumor necrosis factor-α in cortex, hippocampus and hypothalamus. In the fed state, HFD mice compared to LFD mice had reduced locomotor activity, and were adverse to saccharin and burrowed less. After fasting, LFD mice vs. HFD mice lost 18 vs. 5% of their body weight, respectively. In addition, HFD mice failed to downregulate gene transcripts for the myeloid-cell associated proteins F4/80, CD11b and IL-1α in the brain, failed to appropriately explore a novel object, failed to reduce locomotor activity and had increased saccharin consumption and burrowing. These data indicate that fasting induces an anti-inflammatory effect on the neuroimmune system which a HFD prevents. This breakdown appears linked to the IL-1 system because of the association of this cytokine with memory and learning.


Subject(s)
Depression/physiopathology , Dietary Fats/adverse effects , Fasting/physiology , Inflammation Mediators/metabolism , Memory/drug effects , Neuroimmunomodulation/drug effects , Obesity/immunology , Animals , Antigens, Differentiation/metabolism , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/metabolism , CD11b Antigen/metabolism , Depression/immunology , Dietary Fats/immunology , Food Preferences , Interleukin-1alpha/genetics , Interleukin-1alpha/metabolism , Locomotion , Male , Memory/physiology , Mice , Mice, Inbred C57BL , Obesity/etiology , Obesity/psychology , Stress, Physiological/immunology , Weight Loss/physiology
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