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Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hypersomnolence is a common and disruptive side effect of cranial radiotherapy and is associated with fatigue and disturbances in mood and cognition in primary brain tumor (PBT) patients. The biological underpinnings of this effect are not understood. Our laboratory has previously found that the presence of a single nucleotide polymorphism (rs934945, G-E mutation) in the PERIOD2 (PER2) clock gene was associated with a decreased likelihood of fatigue in PBT patients. Here, we aim to understand the effects of PER2 polymorphism on radiation susceptibility within a murine model of cranial-irradiation-induced hypersomnolence (C-RIH)., Methods: Male and female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse PER2:CRY1 binding domain with its human isoform with (h E 1244 KI) or without the SNP rs934945 (h G 1244 KI). Activity and sleep were monitored continuously 10 days before and after cranial irradiation (whole brain, 15Gy, single fraction). Behavioral assessments measuring anxiety, depression, and working memory were used to assess mood and cognitive changes 2 months postradiation., Results: During their active phase, h E 1244 knock-ins (KIs) had less radiation-induced suppression of activity relative to h G 1244 KIs and female h E 1244 KIs saw a reduction of hypersomnolence over 10 days. h E 1244 KIs displayed less anxiety behavior and were more ambulatory within all behavioral tests., Conclusions: The PER2 rs934945 polymorphism had long-lasting behavioral effects associated with radiation toxicity, particularly in sleep in females and the activity of all animals. Our findings shed light on biological mechanisms underlying C-RIH., Competing Interests: None declared., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Cocaine, one of the most abused drugs worldwide, is capable of activating microglia in vitro and in vivo. Several neuroimmune pathways have been suggested to play roles in cocaine-mediated microglial activation. Previous work showed that cocaine activates microglia in a region-specific manner in the brains of self-administered mice. To further characterize the effects of cocaine on microglia and neuroimmune signaling in vivo, we utilized the brains from both sexes of outbred rats with cocaine self-administration to explore the activation status of microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, corticotropin-releasing factor (CRF) signaling, and NF-κB levels in the striatum and hippocampus (HP). Age-matched rats of the same sex (drug naïve) served as controls. Our results showed that cocaine increased neuroinflammation in the striatum and HP of both sexes with a relatively higher increases in male brains. In the striatum, cocaine upregulated NLRP3 inflammasome activity and CRF levels in males but not in females. In contrast, cocaine increased NLRP3 inflammasome activity in the HP of females but not in males, and no effects on CRF signaling were observed in this region of either sex. Interestingly, cocaine increased NF-κB levels in the striatum and HP with no sex difference. Taken together, our results provide evidence that cocaine can exert region- and sex-specific differences in neuroimmune signaling in the brain. Targeting neuroimmune signaling has been suggested as possible treatment for cocaine use disorders (CUDs). Our current results indicate that sex should be taken into consideration when determining the efficacy of these new therapeutic approaches., Competing Interests: The authors declared no conflicts of interests.

Environmental cues (e.g., light-dark cycle) have an immediate and direct effect on behavior, but these cues are also capable of "masking" the expression of the circadian pacemaker, depending on the type of cue presented, the time-of-day when they are presented, and the temporal niche of the organism. Masking is capable of complementing entrainment, the process by which an organism is synchronized to environmental cues, if the cues are presented at an expected or predictable time-of-day, but masking can also disrupt entrainment if the cues are presented at an inappropriate time-of-day. Therefore, masking is independent of but complementary to the biological circadian pacemaker that resides within the brain (i.e., suprachiasmatic nucleus) when exogenous stimuli are presented at predictable times of day. Importantly, environmental cues are capable of either inducing sleep or wakefulness depending on the organism's temporal niche; therefore, the same presentation of a stimulus can affect behavior quite differently in diurnal vs. nocturnal organisms. There is a growing literature examining the neural mechanisms underlying masking behavior based on the temporal niche of the organism. However, the importance of these mechanisms in governing the daily behaviors of mammals and the possible implications on human health have been gravely overlooked even as modern society enables the manipulation of these environmental cues. Recent publications have demonstrated that the effects of masking weakens significantly with old age resulting in deleterious effects on many behaviors, including sleep and wakefulness. This review will clearly outline the history, definition, and importance of masking, the environmental cues that induce the behavior, the neural mechanisms that drive them, and the possible implications for human health and medicine. New insights about how masking is affected by intrinsically photosensitive retinal ganglion cells, temporal niche, and age will be discussed as each relates to human health. The overarching goals of this review include highlighting the importance of masking in the expression of daily rhythms, elucidating the impact of aging, discussing the relationship between dysfunctional masking behavior and the development of sleep-related disorders, and considering the use of masking as a non-invasive treatment to help treat humans suffering from sleep-related disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gall and Shuboni-Mulligan.)

Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving the onset of sleep disturbances after cranial radiation remains unclear but may result from treatment-induced injury to neural circuits controlling sleep behavior, both circadian and homeostatic. Here, we develop a mouse model of cranial radiation-induced hypersomnolence which recapitulates the human experience. Additionally, we used the model to explore the impact of radiation on the brain. We demonstrated that the DNA damage response following radiation varies across the brain, with homeostatic sleep and cognitive regions expressing higher levels of γH2AX, a marker of DNA damage, than the circadian suprachiasmatic nucleus (SCN). These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes. Moreover, in our mouse model, MRI identified structural effects in cognitive and homeostatic sleep regions two-months post-treatment. While the findings are preliminary, they suggest that homeostatic sleep and cognitive circuits are vulnerable to radiation and these findings may be relevant to optimizing treatment plans for patients., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Sleep disturbance (SD) is common in patients with cancer and has been associated with worse clinical outcomes. This cross-sectional study explored the prevalence of SD in a primary brain tumor (PBT) population, identified associated demographic and clinical characteristics, and investigated co-occurrence of SD with other symptoms and mood disturbance., Methods: Demographic, clinical characteristics, MD Anderson Symptom Inventory-Brain Tumor, and Patient Reported Outcome Measurement Information System Depression and Anxiety Short-Forms were collected from PBT patients at study entry. Descriptive statistics, Chi-square tests, and independent t -tests were used to report results., Results: The sample included 424 patients (58% male, 81% Caucasian) with a mean age of 49 years (range 18-81) and 58% with high-grade gliomas. Moderate-severe SD was reported in 19% of patients and was associated with younger age, poor Karnofsky Performance Status, tumor progression on MRI, and active corticosteroid use. Those with moderate-severe SD had higher overall symptom burden and reported more moderate-severe symptoms. These individuals also reported higher severity in affective and mood disturbance domains, with 3 to 4 times higher prevalence of depressive and anxiety symptoms, respectively. The most frequently co-occurring symptoms with SD were, drowsiness, and distress, though other symptoms typically associated with tumor progression also frequently co-occurred., Conclusions: PBT patients with moderate-severe SD are more symptomatic, have worse mood disturbance, and have several co-occurring symptoms. Targeting interventions for sleep could potentially alleviate other co-occurring symptoms, which may improve life quality for PBT patients. Future longitudinal work examining objective and detailed subjective sleep reports, as well as underlying genetic risk factors, will be important., (Published by Oxford University Press 2022.)

Circadian clock genes have been linked to clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established markers that predict the prognosis, including mutations in Isocitrate Dehydrogenase ( IDH ), which characterize the majority of lower-grade gliomas and secondary high-grade gliomas. To demonstrate the connection between circadian clock genes and glioma outcomes while accounting for the IDH mutational status, we analyzed multiple publicly available gene expression datasets. The unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas showed distinct molecular subtypes representing different disease states and showed the differential prognosis of these groups by a Kaplan-Meier analysis. Further analyses of these groups showed that a low period ( PER ) gene expression was associated with the negative prognosis and enrichment of the immune signaling pathways. These findings prompted the exploration of the relationship between the microenvironment and clock genes in additional datasets. Circadian clock gene expression was found to be differentially expressed across the anatomical tumor location and cell type. Thus, the circadian clock expression is a potential predictive biomarker in glioma, and further mechanistic studies to elucidate the connections between the circadian clock and microenvironment are warranted.

Age plays a critical role in disease development and tolerance to cancer treatment, often leading to an increased risk of developing negative symptoms including sleep disturbances. Circadian rhythms and sleep become disrupted as organisms age. In this study, we explored the behavioral alterations in sleep, circadian rhythms, and masking using a novel video system and interrogate the long-term impact of age-based changes in the non-image forming visual pathway on brain anatomy. We demonstrated the feasibility and utility of the novel system and establish that older mice have disruptions in sleep, circadian rhythms, and masking behaviors that were associated with major negative volume alterations in the non-imaging forming visual system, critical for the induction and rhythmic expression of sleep. These results provide important insights into a mechanism, showing brain atrophy is linked to age in distinct non-image forming visual regions, which may predispose older individuals to developing circadian and sleep dysfunction when further challenged by disease or treatment.

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO x ) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO x nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO x NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO x @MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO x @PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO x @PLGA NPs and TaO x @MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO x . This work solidifies that TaO x -based NPs are versatile contrast agents for CT.

Purpose: Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers., Methods: A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique., Results: Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer., Conclusions: Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.

Daily rhythms in light exposure influence the expression of behavior by entraining circadian rhythms and through its acute effects on behavior (i.e., masking). Importantly, these effects of light are dependent on the temporal niche of the organism; for diurnal organisms, light increases activity, whereas for nocturnal organisms, the opposite is true. Here we examined the functional and morphological differences between diurnal and nocturnal rodents in retinorecipient brain regions using Nile grass rats ( Arvicanthis niloticus ) and Sprague-Dawley (SD) rats ( Rattus norvegicus ), respectively. We established the presence of circadian rhythmicity in cFOS activation in retinorecipient brain regions in nocturnal and diurnal rodents housed in constant dark conditions to highlight different patterns between the temporal niches. We then assessed masking effects by comparing cFOS activation in constant darkness (DD) to that in a 12:12 light/dark (LD) cycle, confirming light responsiveness of these regions during times when masking occurs in nature. The intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPN) exhibited significant variation among time points in DD of both species, but their expression profiles were not identical, as SD rats had very low expression levels for most timepoints. Light presentation in LD conditions induced clear rhythms in the IGL of SD rats but eliminated them in grass rats. Additionally, grass rats were the only species to demonstrate daily rhythms in LD for the habenula and showed a strong response to light in the superior colliculus. Structurally, we also analyzed the volumes of the visual brain regions using anatomical MRI, and we observed a significant increase in the relative size of several visual regions within diurnal grass rats, including the lateral geniculate nucleus, superior colliculus, and optic tract. Altogether, our results suggest that diurnal grass rats devote greater proportions of brain volume to visual regions than nocturnal rodents, and cFOS activation in these brain regions is dependent on temporal niche and lighting conditions.

The subventricular zone (SVZ) is a neurogenic niche in the mammalian brain, giving rise to migratory neural progenitor cells (NPC). In rodents, it is well-established that neurogenesis decreases with aging. MRI-based cell tracking has been used to measure various aspects of neurogenesis and NPC migration in rodents, yet it has not yet been validated in the context of age-related decrease in neurogenesis. This validation is critical to using these MRI techniques to study changes in neurogenesis that arise in diseases prevalent in aging populations and their combination with advanced cellular therapeutic approaches aiming to combat neurodegeneration. As such, in this work we used MRI-based cell tracking to measure endogenous neurogenesis and cell migration from the SVZ along the rostral migratory stream to the olfactory bulb, for 12 days duration, in rats aged 9 weeks to 2 years old. To enable the specific detection of NPCs by MRI, we injected micron sized particles of iron oxide (MPIOs) into the lateral ventricle to endogenously label cells within the SVZ, which then appeared as hypo-intensive spots within MR images. In vivo MRI data showed that the rate of NPC migration was significantly different between all ages examined, with decreases in the distance traveled and migration rate as age progressed. The total number of MPIO-labeled cells within the olfactory bulb on day 12, was significantly decreased when compared across ages in ex vivo high-resolution scans. We also demonstrate for the first-time, provocative preliminary data suggesting age-dependent MPIO uptake within the dentate gyrus (DG) as well. Histology to identify doublecortin-positive NPCs, verified the decrease in cell labeling as a function of aging, for both regions. The dramatic reduction of NPC labeling within the SVZ observed with MRI, validates the sensitivity of MRI-based cell tracking to neurogenic potential and demonstrates the importance of understanding the impact of age on the relationship of NPC and disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for the light signaling properties of non-image forming vision. Melanopsin-expressing ipRGCs project to retinorecipient brain regions involved in modulating circadian rhythms. Melanopsin has been shown to play an important role in how animals respond to light, including photoentrainment, masking (i.e., acute behavioral responses to light), and the pupillary light reflex (PLR). Importantly, ipRGCs are resistant to various forms of damage, including ocular hypertension, optic nerve crush, and excitotoxicity via N-methyl-D-aspartic acid (NMDA) administration. Although these cells are resistant to various forms of injury, the question still remains whether or not these cells remain functional following injury. Here we tested the hypothesis that ipRGCs would be resistant to excitotoxic damage in a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). In addition, we hypothesized that following insult, grass rats would maintain normal circadian entrainment and masking to light. In order to test these hypotheses, we injected NMDA intraocularly and examined its effect on the survivability of ipRGCs and RGCs, along with testing behavioral and functional consequences. Similar to findings in nocturnal rodents, ipRGCs were spared from significant damage but RGCs were not. Importantly, whereas image-forming vision was significantly impaired, non-image forming vision (i.e, photoentrainment, masking, and PLR) remained functional. The present study aims to characterize the resistance of ipRGCs to excitotoxicity in a diurnal rodent model., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use., Methods: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T 1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured., Results: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts., Conclusion: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models., (© 2019 International Society for Magnetic Resonance in Medicine.)

Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous drugs including gadoxetate disodium (Gd-EOB-DTPA). As master pharmacokinetic regulators, the altered expression of OATPs in diabetes could have a profound and clinically significant influence on drug therapies. Here, we report a method to noninvasively measure OATP activity in T2D mice by quantifying the transport of hepatobiliary-specific gadolinium-based contrast agents (GBCAs) within the liver and kidneys using dynamic contrast-enhanced MRI (DCE-MRI). By comparing GBCA uptake in control and OATP knockout mice, we confirmed liver clearance of the hepatobiliary-specific GBCAs, Gd-EOB-DTPA, and gadobenate dimeglumine, primarily though OATP transporters. Then, we measured a reduction in the hepatic uptake of these hepatobiliary GBCAs in T2D ob / ob mice, which mirrored significant reductions in the mRNA and protein expression of OATP1A1 and OATP1B2. As these GBCAs are U.S. Food and Drug Administration-approved agents and DCE-MRI is a standard clinical protocol, studies to determine OATP1B1/1B3 deficiencies in human individuals with diabetes can be easily envisioned., (© 2018 by the American Diabetes Association.)

The study of neurogenesis and neural progenitor cells (NPCs) is important across the biomedical spectrum, from learning about normal brain development and studying disease to engineering new strategies in regenerative medicine. In adult mammals, NPCs proliferate in two main areas of the brain, the subventricular zone (SVZ) and the subgranular zone, and continue to migrate even after neurogenesis has ceased within the rest of the brain. In healthy animals, NPCs migrate along the rostral migratory stream (RMS) from the SVZ to the olfactory bulb, and in diseased animals, NPCs migrate toward lesions such as stroke and tumors. Here we review how MRI-based cell tracking using iron oxide particles can be used to monitor and quantify NPC migration in the intact rodent brain, in a serial and relatively non-invasive fashion. NPCs can either be labeled directly in situ by injecting particles into the lateral ventricle or RMS, where NPCs can take up particles, or cells can be harvested and labeled in vitro , then injected into the brain. For in situ labeling experiments, the particle type, injection site, and image analysis methods have been optimized and cell migration toward stroke and multiple sclerosis lesions has been investigated. Delivery of labeled exogenous NPCs has allowed imaging of cell migration toward more sites of neuropathology, which may enable new diagnostic and therapeutic opportunities for as-of-yet untreatable neurological diseases.

Rapid dissolution of Bi Nanocrystals (NCs) in lysosomal conditions results in poor biocompatibility. We report that an in situ surface coating of Bi nanocrystals with Ganex® V216, a cosmetic dispersant, limits its dissolution under physiological conditions. These Bi Ganex (BiG) NCs are readily encapsulated in FDA approved polymer poly(dl-lactic-co-glycolic acid) (PLGA) by an oil-in-water emulsion technique and also undergo facile SiO2 coating. BiG NCs in BiG@PLGA and BiG@SiO2 nanoparticles dissolve slowly under physiological conditions and exhibit excellent biocompatibility, as opposed to uncoated Bi NCs. Finally, these Bi nanoconstructs are shown to be strong CT CAs, even at relatively low Bi concentrations.