Background At subanesthetic doses, ketamine, an N-Methyl-D-aspartate (NMDA) glutamate receptor antagonist, increases glutamate release. Here, we imaged the acute effect of ketamine on brain metabotropic glutamatergic receptors subtype 5 (mGluR5) with a high affinity PET ligand [11C]ABP688 ((E)-3-((6-methylpyridin-2-yl)ethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a negative allosteric modulator of mGluR5. Methods Ten healthy nonsmoking human volunteers (34±13 years old) received two [11C]ABP688 PET scans on the same day – before (scan 1) and during i.v. ketamine administration (0.23mg/kg over 1min, then 0.58mg/kg over 1h; scan 2). PET data were acquired for 90 min immediately following [11C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. Results A significant reduction in [11C]ABP688 volume of distribution (VT) was observed in scan 2 relative to scan 1 of 21.3 ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p<0.05) that resolved after completion of the scan. Discussion This study provides first evidence that ketamine administration decreases [11C]ABP688 binding in vivo in human subjects. Results suggest that [11C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.
Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in postmortem nucleus accumbens from donors (N = 26) with known loneliness measures. Loneliness was associated with 1 710 differentially expressed transcripts from 1 599 genes (DEGs; FDR p < 0.05, fold-change ≥ |2|, controlling for confounds) previously associated with behavioral processes, neurological disease, psychological disorders, cancer, organismal injury, and skeletal and muscular disorders, as well as networks of upstream RNA regulators. Furthermore, a number of DEGs were associated with Alzheimer's disease genes (which was correlated with loneliness in this sample, although gene expression analyses controlled for AD diagnosis). These results identify novel targets for future mechanistic studies of gene networks in nucleus accumbens and gene regulatory mechanisms across a variety of diseases exacerbated by loneliness.Loneliness has been defined as a negative emotional state of unfulfilled intimate and social needs (1). It can also be considered as a behavioral trait, because it is stable over time (2, 3), difficult to alter with interventions (4), and heritable (5). Loneliness is a subjective perception of social isolation and therefore independent of objective measures such as social network size (1), making it a challenge to study in non-human animals.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Supplementary information is available at Molecular Psychiatry's website. Conflict of InterestThe authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptLoneliness has a profoundly negative impact on psychological/behavioral processes including mental health, particularly in aging populations. For example, loneliness is associated with depression and anxiety (6-8). Longitudinal studies of cognition reported that loneliness at baseline predicted cognitive decline in recall memory over a 4-year period (9), was associated with lower levels of perceptual processing and memory at baseline (10), overall cognitive decline (11) and incident dementia (12), as well as a decline in motor function (13). The underlying molecular-genetic mechanisms of these associations are currently unknown, in part because gene expression as a function of loneliness has not yet been examined in the human brain.Loneliness is also associated with increased risk for neurological and neurodegenerative diseases such as Alzheimer's disease (AD) (10), as well as cancer (17,18), and organismal and muscular diseases and...
Background Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis, recent research also suggests that exosomes are a reliable source of biomarkers in disease progression. In this study, we analyzed total urine proteome, and exosomes isolated form urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). Methods For feasibility studies, mice were irradiated at 10.4 Gy WBI, urine and serum samples were collected 24 and 72 hr post-irradiation. Exosomes were isolated and analyzed by LC-MS/MS- based workflow for radiation exposure signatures. A DDA and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For validation studies, mice were exposed to 3, 6, 8 or 10 Gy WBI and samples were analyzed for comparison. Results Comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes post-WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury of the liver, gastrointestinal, and genitourinary track, whereas serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Conclusion Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. 47 differentially secreted proteins were identified in urinary and serum exosomes, together these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high dose ionizing radiation. This is a first report employing exosome proteomics approach to identify radiation signatures.
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