The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise ...mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes and reduced O2 consumption. Furthermore, the application of the GPR84 agonist 6-n-octylaminouracil (6-OAU) counteracted these effects, effectively reinstating the brown adipocyte activity. These compelling in vivo and in vitro findings converge to highlight mitochondrial dysfunction as the primary cause of BAT anomalies in GPR84-KO mice. The activation of GPR84 induced an increase in intracellular Ca2+ levels, which intricately influenced mitochondrial respiration. By modulating mitochondrial Ca2+ levels and respiration, GPR84 acts as a potent molecule involved in BAT activity. These findings suggest that GPR84 is a potential therapeutic target for invigorating BAT and ameliorating metabolic disorders.
Alcohol abuse affects the brain regions responsible for memory, coordination and emotional processing. Binge alcohol drinking has shown reductions in brain activity, but the molecular targets have ...not been completely elucidated. We hypothesized that brain cells respond to excessive alcohol by releasing a novel inflammatory mediator, called cold inducible RNA-binding protein (CIRP), which is critical for the decreased brain metabolic activity and impaired cognition.
Male wild type (WT) mice and mice deficient in CIRP (CIRP
) were studied before and after exposure to binge alcohol level by assessment of relative brain glucose metabolism with fluorodeoxyglucose (
FDG) and positron emission tomography (PET). Mice were also examined for object-place memory (OPM) and open field (OF) tasks.
Statistical Parametric Analysis (SPM) of
FDG-PET uptake revealed marked decreases in relative glucose metabolism in distinct brain regions of WT mice after binge alcohol. Regional analysis (post hoc) revealed that while activity in the temporal (secondary visual) and limbic (entorhinal/perirhinal) cortices was decreased in WT mice, relative glucose metabolic activity was less suppressed in the CIRP
mice. Group and condition interaction analysis revealed differing responses in relative glucose metabolism (decrease in WT mice but increase in CIRP
mice) after alcohol in brain regions including the hippocampus and the cortical amygdala where the percent changes in metabolic activity correlated with changes in object discrimination performance. Behaviorally, alcohol-treated WT mice were impaired in exploring a repositioned object in the OPM task, and were more anxious in the OF task, whereas CIRP
mice were not impaired in these tasks.
CIRP released from brain cells could be responsible for regional brain metabolic hypoactivity leading to cognitive impairment under binge alcohol conditions.
Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, ...studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human–mutant–tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET 11C raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment—on both tau and behavior—that may have relevance to AD and other tauopathies.
Abstract
Background
Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new ...diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge.
Methods
Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer (
11
CPBR28 – for microglial activation and
18
FFDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis.
Results
There were significant increases in
11
CPBR28 and
18
FFDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels.
Conclusions
Together, these findings demonstrate the applicability of
11
CPBR28 -
18
FFDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions “classically” characterized by peripheral inflammatory and metabolic pathogenesis.
In sepsis and other disorders characterized by peripheral immune and metabolic dysregulation, the brain also is affected and brain dysfunction, including neuroinflammation, metabolic changes and ...cognitive impairment have been reported (Annu Rev Immunol, 2018, 36:783‐812). Non‐invasive evaluation of neuroinflammation is important for strategizing new diagnostic and therapeutic approaches targeting the brain. Here we utilized Micro Positron Emission Tomography (microPET) with 18FFluoro‐2‐deoxy‐2‐D‐glucose (18FDG) and 11C‐Peripheral Benzodiazepine Receptor (11CPBR) to evaluate brain metabolic alterations and microglia activation (indicating neuroinflammation) during murine endotoxemia. Lipopolysaccharide (LPS, endotoxin) (2 mg/kg) or saline was injected (i.p.) in male C57Bl/6 mice 6 hrs prior to microPET imaging. 11C PBR28 (~0.5 mCi) was injected via the tail vein followed by 60 mins dynamic imaging. Subsequently, 18FDG (0.5 mCi) was injected i.p. with a 10 mins static scan acquired following 40 mins uptake. Brain images were analyzed in a standard anatomical space using Statistical Parametric Mapping. Significantly (P<0.01) increased glucose metabolism in endotoxemic mice (vs controls) was observed in the hippocampal CA2/CA3 region and other brain areas. Increased 11CPBR28 binding (P<0.05) was also determined in the hippocampal CA2/CA3 region. These brain alterations were associated with significantly increased serum cytokine levels (TNF, IL‐6, IL‐1β, and IL‐10) at 6 hrs following administration of the same (2mg/kg, i.p.) endotoxin dose. These results indicate brain hypermetabolic activity and neuroinflammation during endotoxemia specifically affecting the hippocampus – an area with a primary role in memory and cognition. These findings support further development of PET‐based evaluation of neuroinflammation in preclinical and clinical settings of inflammatory and metabolic disorders.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Brain dysfunction, including neuroinflammation, metabolic changes, and cognitive impairment has been reported in sepsis and other disorders “traditionally” characterized by peripheral immune ...and metabolic dysregulation (Annu Rev Immunol, 2018, 36:783–812). In this context, non-invasive evaluation of neuroinflammation is important for strategizing new diagnostic and therapeutic approaches targeting the brain. We utilized Micro Positron Emission Tomography (microPET) with 18FFluoro-2-deoxy-2-D-glucose (18FDG) and 11C-Peripheral Benzodiazepine Receptor (11CPBR) to evaluate brain metabolic alterations and microglia activation (indicating neuroinflammation) during murine endotoxemia. Lipopolysaccharide (LPS, endotoxin) (2 mg/kg) or saline was injected (i.p.) in male C57Bl/6 mice 6 hrs prior to microPET imaging. 11C PBR28 (~0.5 mCi) was injected via the tail vein followed by 60 mins dynamic imaging. Subsequently, 18FDG (0.5 mCi) was injected i.p. with a 10 mins static scan acquired following 40 mins uptake. Brain images were analyzed in a standard anatomical space using Statistical Parametric Mapping. Significantly (P<0.01) increased glucose metabolism in endotoxemic mice (vs controls) was observed in the hippocampal CA2/CA3 region and other brain areas. Increased 11CPBR28 binding (P<0.05) was also determined in the hippocampal CA2/CA3 region. These results indicate brain hypermetabolic activity and neuroinflammation during endotoxemia specifically affecting the hippocampus – an area with a primary role in memory and cognition. These findings support further development of PET-based evaluation of neuroinflammation in preclinical and clinical settings of inflammatory and metabolic disorders.
Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, ...females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using
FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.
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Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, ...studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human–mutant–tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET sup.11C raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment—on both tau and behavior—that may have relevance to AD and other tauopathies.
Current pain management outcomes rely on questionnaires to quantify what is an inherently subjective experience. A known gender bias currently exists in many preclinical biomedical research ...disciplines including the neurosciences. It is known that females respond and manifest pain differently than males, but current standards of care do not take gender into account when treating. Opioids are the gold standard of effective pain relief, but abuse has become an increasingly relevant danger when treating chronic pain. In this study, we examined brain glucose metabolism in male and female rats while simultaneously capturing the behavioral expression of inflammatory pain using the formalin assay. We obtained a quantifiable gender-specific metabolic pattern of tonic pain captured using 18FFluoro-2-deoxy-2-D-glucose ( 18F-FDG) and MicroPET. To determine if gender impacts opioid analgesia, we used γ-vinyl GABA (GVG), an FDA-approved compound that elevates GABA levels and blocks the appetitive effects of a number of addictive drugs, in combination with morphine at a dose that is medically appropriate for pain management to see if metabolic patterns of pain could be attenuated. Methods: Male (n=35) and female (n=35) rats were acclimated separately to behavioral surroundings for 5 days, and afterward received baseline 18FDG microPET scans after receiving 50µL saline subcutaneous injections into the left rear paw pad. Two days later, male and female rodents were separated into three groups each: Formalin (no pain treatment), GVG 20mg/kg given 2.5 hours before formalin combined with sub-analgesic morphine (2.5mg/kg) given 10 minutes before formalin, or sub-analgesic morphine alone (2.5mg/kg) given 10 minutes before formalin. On testing days, animals received 50µL of 2.5% formalin solution into the left rear paw pad followed by either volume-matched saline, GVG 20mg/kg+sub-analgesic morphine (2.5mg/kg), or sub-analgesic morphine (2.5mg/kg) followed by 18F-FDG, with all behavior captured simultaneously during radiotracer uptake. Results: Regional changes in metabolic metabolism were compared to baseline and were statistically significant (p<0.001) as follows: Formalin: Female rodents showed bilateral increases in relative glucose metabolism in the post thalamic nuclear group. Decreases were observed in the amygdaloid nucleus, the nucleus accumbens shell, A13 dopamine cells, and dorsolateral entorhinal cortex. An average pain score of 1.43 was detected at the start of the tonic phase. Male rodents showed bilateral increases in relative glucose metabolism in the paracentral thalamic nuclear group, the right primary hindlimb somatosensory area, and the caudate putamen. An averaged pain score was 0.49 at the start of the tonic phase. Sub-analgesic morphine+GVG prior to formalin: Female rodents showed statistically significant increases in the granular insular cortex and the right primary somatosensory cortex. Decreases in the same female group included ventral hippocampal commissure and oriens layer of the hippocampus. The behavioral results revealed an unexpected suppression of acute pain with a score of 0.41 at observation bin 1 (0–3 minutes). Pain expression between 2 and 2.5 was observed across bins 6 through 9. Male rodents exhibited increases in the caudate putamen, secondary somatosensory cortex, agranular insular cortex, and central inferior colliculus. Decreases included the agranular insular cortex, and a small region of the primary somatosensory cortex. Males had a pain expression score of 2.07 at observation bin 1. Pain expression vacillated between 2.04 and 2.17 across bins 6 through 9. Sub analgesic morphine 2.5mg/kg: Female rodents had statistically significant bilateral increases in the post-thalamic nuclear group, and decreases in the lateral orbital cortex, molecular layer subiculum/parasubiculum and entorhinal cortex. Behavior showed no suppression of acute pain at bin 1 and no pain suppression across bins 6 through 9. Male rodents treated with sub analgesic morphine 2.5mg/kg showed significant increases bilaterally in the post and ventral thalamic nuclear group and a significant decrease in the cingulate cortex area 1. For behavior, an acute pain score of 1.8 during bin 1 was observed. Pain expression vacillated between 1.48 and 2.06 across bins 6 through 9. Conclusion: In our study, the formalin pain assay produced increased 18FDG metabolic activations in both male and female groups within the posterior and paracentral thalamic nuclear groups under identical conditions of pain. It appears the thalamus is a consistent region of increased metabolic activity in tonic inflammatory pain. Male formalin rodents exhibited metabolic increases in the ipsilateral (left) caudate putamen, which is an integral part of the nigrostriatal pathway and may play a role in modulating pain in males. Female rodents manifested metabolic decreases observed in the amygdaloid nucleus, A13 dopamine cells, and dorsolateral entorhinal cortex. The amygdaloid nucleus is a limbic area closely associated with the hypothalamus, cingulate, and hippocampus, and plays a role in emotional behavior, motivation, and olfaction. (Abstract shortened by ProQuest.)
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